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Entry
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- *179617 - RAD51 RECOMBINASE; RAD51
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*179617</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/179617">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000051180;t=ENST00000267868" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=5888" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=179617" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000051180;t=ENST00000267868" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001164269,NM_001164270,NM_002875,NM_133487,XM_011521857,XM_011521858,XM_011521859,XM_011521860,XM_011521861,XM_047432925" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_002875" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=179617" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01557&isoform_id=01557_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/RAD51" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/285977,397827,548663,5733658,7407071,7767554,12655203,19924133,27368250,38017105,47077076,47680391,49168602,54696278,119612837,119612838,119612839,119612840,119612841,158257370,164506989,189069251,194381662,256017141,256017143,256017145,767984890,767984892,767984894,2217302253,2217302258,2217302260,2462545395,2462545397,2462545399,2462545401,2462545403,2462545405" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/Q06609" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=5888" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000051180;t=ENST00000267868" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=RAD51" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=RAD51" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+5888" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/RAD51" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:5888" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/5888" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr15&hgg_gene=ENST00000267868.8&hgg_start=40694733&hgg_end=40732340&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/rad51" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=179617[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=179617[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/RAD51/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000051180" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=RAD51" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=RAD51" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=RAD51" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=RAD51&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA34176" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:9817" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0003479.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:97890" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/RAD51#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:97890" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/5888/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=5888" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00004297;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-2286" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
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</a>
|
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</span>
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</span>
|
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5888" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=RAD51&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 254843006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
179617
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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RAD51 RECOMBINASE; RAD51
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</span>
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
|
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
RAD51, S. CEREVISIAE, HOMOLOG OF<br />
|
|
RAD51, S. CEREVISIAE, HOMOLOG OF, A; RAD51A<br />
|
|
RECOMBINATION PROTEIN A; RECA<br />
|
|
RECA, E. COLI, HOMOLOG OF
|
|
</span>
|
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</h4>
|
|
</div>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=RAD51" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RAD51</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/15/103?start=-3&limit=10&highlight=103">15q15.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:40694733-40732340&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">15:40,694,733-40,732,340</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
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</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=114480,617244,614508" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/103?start=-3&limit=10&highlight=103">
|
|
15q15.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Breast cancer, susceptibility to}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/114480"> 114480 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Fanconi anemia, complementation group R
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617244"> 617244 </a>
|
|
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>RAD51 has a critical role in the maintenance of genomic integrity by functioning in the repair of DNA double-strand breaks (DSBs). RAD51 mediates homologous pairing and strand exchange in recombinatory structures known as RAD51 foci in the nucleus (summary by <a href="#22" class="mim-tip-reference" title="Park, J.-Y., Yoo, H.-W., Kim, B.-R., Park, R., Choi, S.-Y., Kim, Y. <strong>Identification of a novel human Rad51 variant that promotes DNA strand exchange.</strong> Nucleic Acids Res. 36: 3226-3234, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18417535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18417535</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18417535[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/nar/gkn171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18417535">Park et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18417535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In Escherichia coli, the RecA protein searches for homologous regions between 2 double-stranded DNA molecules and promotes strand exchange. It is also involved in recombinational repair of DSBs. In Saccharomyces cerevisiae, the protein encoded by rad51 is required for repair of DSBs that occur in mitosis or meiosis. By searching for orthologs of E. coli RecA, <a href="#25" class="mim-tip-reference" title="Shinohara, A., Ogawa, H., Matsuda, Y., Ushio, N., Ikeo, K., Ogawa, T. <strong>Cloning of human, mouse and fission yeast recombination genes homologous to RAD51 and RecA.</strong> Nature Genet. 4: 239-243, 1993. Note: Erratum: Nature Genet. 5: 312 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8358431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8358431</a>] [<a href="https://doi.org/10.1038/ng0793-239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8358431">Shinohara et al. (1993)</a> cloned genes from human, mouse, and Schizosaccharomyces pombe (fission yeast) that are homologous to rad51. Human and mouse RAD51 are identical 339-amino acid proteins and are highly homologous (83%) with the yeast rad51 proteins. The mouse gene was transcribed at a high level in thymus, spleen, testis, and ovary and at a lower level in brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8358431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By screening a testis cDNA library with a RAD51 probe, <a href="#22" class="mim-tip-reference" title="Park, J.-Y., Yoo, H.-W., Kim, B.-R., Park, R., Choi, S.-Y., Kim, Y. <strong>Identification of a novel human Rad51 variant that promotes DNA strand exchange.</strong> Nucleic Acids Res. 36: 3226-3234, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18417535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18417535</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18417535[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/nar/gkn171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18417535">Park et al. (2008)</a> cloned a RAD51 splice variant lacking exon 9, which they called RAD51-delta-ex9. The deduced 280-amino acid protein is identical to full-length RAD51 for the first 259 amino acids, which includes an N-terminal basic motif followed by the Walker A and B ATP-binding motifs. The 2 proteins diverge at their C termini, but both C termini contain basic motifs predicted to function as nuclear localization signals. PCR analysis detected high expression of full-length RAD51 in testis, with moderate expression detected in placenta, thymus, pancreas, and colon, and weaker expression detected in lung, liver, skeletal muscle, kidney, and ovary. RAD51-delta-ex9 was highly expressed in testis, with much weaker expression only in skeletal muscle, pancreas, thymus, and ovary. Western blot analysis of human testis detected RAD51 and RAD51-delta-ex9 at apparent molecular masses of 37 and 31 kD, respectively. RAD51, but not RAD51-delta-ex9, was also detected at a lower level in placenta, lung, and small intestine. Fluorescence-tagged RAD51 and RAD51-delta-ex9 proteins both localized to the nucleus of transfected COS-7 cells, with exclusion from nucleoli. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18417535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Western blot analysis, <a href="#24" class="mim-tip-reference" title="Sage, J. M., Gildemeister, O. S., Knight, K. L. <strong>Discovery of a novel function for human Rad51: maintenance of the mitochondrial genome.</strong> J. Biol. Chem. 285: 18984-18990, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20413593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20413593</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20413593[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M109.099846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20413593">Sage et al. (2010)</a> showed that a part of the cytoplasmic pool of RAD51 in human cell lines fractionated with mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20413593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#22" class="mim-tip-reference" title="Park, J.-Y., Yoo, H.-W., Kim, B.-R., Park, R., Choi, S.-Y., Kim, Y. <strong>Identification of a novel human Rad51 variant that promotes DNA strand exchange.</strong> Nucleic Acids Res. 36: 3226-3234, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18417535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18417535</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18417535[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/nar/gkn171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18417535">Park et al. (2008)</a> determined that the RAD51 gene contains 10 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18417535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#26" class="mim-tip-reference" title="Slupianek, A., Schmutte, C., Tombline, G., Nieborowska-Skorska, M., Hoser, G., Nowicki, M. O., Pierce, A. J., Fishel, R., Skorski, T. <strong>BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance.</strong> Molec. Cell 8: 795-806, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11684015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11684015</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00357-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11684015">Slupianek et al. (2001)</a> demonstrated that RAD51 is important for resistance to cisplatin and mitomycin C in cells expressing the BCR (<a href="/entry/151410">151410</a>)/ABL (<a href="/entry/189980">189980</a>) oncogenic tyrosine kinase. BCR/ABL significantly enhanced the expression of RAD51 and several RAD51 paralogs. RAD51 overexpression was mediated by STAT5 (<a href="/entry/601511">601511</a>)-dependent transcription as well as by inhibition of caspase-3 (<a href="/entry/600636">600636</a>)-dependent cleavage. Phosphorylation of the RAD51 tyr315 residue by BCR/ABL appeared essential for enhanced DSB repair and drug resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11684015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Crystal Structure</em></strong></p><p>
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<a href="#23" class="mim-tip-reference" title="Pellegrini, L., Yu, D. S., Lo, T., Anand, S., Lee, M., Blundell, T. L., Venkitaraman, A. R. <strong>Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.</strong> Nature 420: 287-293, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12442171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12442171</a>] [<a href="https://doi.org/10.1038/nature01230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12442171">Pellegrini et al. (2002)</a> reported the 1.7-angstrom crystal structure of a complex between the BRC repeat, which is an evolutionarily conserved sequence in BRCA2, and the RecA-homology domain of RAD51. The BRC repeat mimics a motif in RAD51 that serves as an interface for oligomerization between individual RAD51 monomers, thus enabling BRCA2 to control the assembly of the RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. The RAD51 oligomerization motif is highly conserved among RecA-like recombinases, highlighting a common evolutionarily origin for the mechanism of nucleoprotein filament formation, mirrored in the BRC repeat. <a href="#23" class="mim-tip-reference" title="Pellegrini, L., Yu, D. S., Lo, T., Anand, S., Lee, M., Blundell, T. L., Venkitaraman, A. R. <strong>Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.</strong> Nature 420: 287-293, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12442171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12442171</a>] [<a href="https://doi.org/10.1038/nature01230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12442171">Pellegrini et al. (2002)</a> showed that cancer-associated mutations that affect the BRC repeat disrupt its predicted interaction with RAD51, yielding structural insight into mechanisms for cancer susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12442171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Chen, Z., Yang, H., Pavletich, N. P. <strong>Mechanism of homologous recombination from the RecA-ssDNA/dsDNA structures.</strong> Nature 453: 489-494, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18497818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18497818</a>] [<a href="https://doi.org/10.1038/nature06971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18497818">Chen et al. (2008)</a> solved the crystal structures of the E. coli RecA-ssDNA and RecA heteroduplex filaments. They showed that ssDNA and ATP bind to RecA-RecA interfaces cooperatively, explaining the ATP dependency of DNA binding. The ATP gamma-phosphate is sensed across the RecA-RecA interface by 2 lysine residues that also stimulate ATP hydrolysis, providing a mechanism for DNA release. The DNA is underwound and stretched globally, but locally it adopts a B-DNA-like conformation that restricts the homology search to Watson-Crick-type basepairing. The complementary strand interacts primarily through basepairing, making heteroduplex formation strictly dependent on complementarity. The underwound, stretched filament conformation probably evolved to destabilize the donor duplex, freeing the complementary strand for homology sampling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18497818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#25" class="mim-tip-reference" title="Shinohara, A., Ogawa, H., Matsuda, Y., Ushio, N., Ikeo, K., Ogawa, T. <strong>Cloning of human, mouse and fission yeast recombination genes homologous to RAD51 and RecA.</strong> Nature Genet. 4: 239-243, 1993. Note: Erratum: Nature Genet. 5: 312 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8358431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8358431</a>] [<a href="https://doi.org/10.1038/ng0793-239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8358431">Shinohara et al. (1993)</a> mapped the RAD51 gene to chromosome 15 by analysis of a somatic cell hybrid panel and localized the mouse gene to chromosome 2F1 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8358431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By FISH analysis, <a href="#28" class="mim-tip-reference" title="Takahashi, E., Matsuda, Y., Hori, T., Yasuda, N., Tsuji, S., Mori, M., Yoshimura, Y., Yamamoto, A., Morita, T., Matsushiro, A. <strong>Chromosome mapping of the human (RECA) and mouse (Reca) homologs of the yeast RAD51 and Escherichia coli RecA genes to human (15q15.1) and mouse (2F1) chromosomes by direct R-banding fluorescence in situ hybridization.</strong> Genomics 19: 376-378, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8188269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8188269</a>] [<a href="https://doi.org/10.1006/geno.1994.1074" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8188269">Takahashi et al. (1994)</a> assigned the RAD51 gene to chromosome 15q15.1 and the mouse gene to chromosome 2F1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8188269" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#27" class="mim-tip-reference" title="Solinger, J. A., Kiianitsa, K., Heyer, W.-D. <strong>Rad54, a Swi2/Snf2-like recombinational repair protein, disassembles Rad51:dsDNA filaments.</strong> Molec. Cell 10: 1175-1188, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12453424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12453424</a>] [<a href="https://doi.org/10.1016/s1097-2765(02)00743-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12453424">Solinger et al. (2002)</a> showed that RAD54 (<a href="/entry/603615">603615</a>) protein dissociates RAD51 from nucleoprotein filaments formed on double-stranded DNA (dsDNA). Addition of RAD54 protein overcame inhibition of DNA strand exchange by RAD51 protein bound to substrate dsDNA. Species preference in the RAD51 dissociation and DNA strand exchange assays underlined the importance of specific RAD54-RAD51 protein interactions. RAD51 protein was unable to release dsDNA upon ATP hydrolysis, leaving it stuck on the heteroduplex DNA product after DNA strand exchange. The authors suggested that RAD54 protein is involved in the turnover of RAD51-dsDNA filaments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12453424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In S. cerevisiae, the Srs2 helicase negatively modulates recombination, and later experiments have suggested that it reverses intermediate recombination structures. <a href="#33" class="mim-tip-reference" title="Veaute, X., Jeusset, J., Soustelle, C., Kowalczykowski, S. C., Le Cam, E., Fabre, F. <strong>The Srs2 helicase prevents recombination by disrupting Rad51 nucleoprotein filaments.</strong> Nature 423: 309-312, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12748645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12748645</a>] [<a href="https://doi.org/10.1038/nature01585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12748645">Veaute et al. (2003)</a> demonstrated that DNA strand exchange mediated in vitro by RAD51 is inhibited by Srs2, and that Srs2 disrupts RAD51 filaments formed on single-stranded DNA. <a href="#33" class="mim-tip-reference" title="Veaute, X., Jeusset, J., Soustelle, C., Kowalczykowski, S. C., Le Cam, E., Fabre, F. <strong>The Srs2 helicase prevents recombination by disrupting Rad51 nucleoprotein filaments.</strong> Nature 423: 309-312, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12748645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12748645</a>] [<a href="https://doi.org/10.1038/nature01585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12748645">Veaute et al. (2003)</a> concluded that their data provided an explanation for the antirecombinogenic role of Srs2 in vivo and highlighted a theretofore unknown mechanism for recombination control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12748645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Krejci, L., Van Komen, S., Li, Y., Villemain, J., Reddy, M. S., Klein, H., Ellenberger, T., Sung, P. <strong>DNA helicase Srs2 disrupts the Rad51 presynaptic filament.</strong> Nature 423: 305-309, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12748644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12748644</a>] [<a href="https://doi.org/10.1038/nature01577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12748644">Krejci et al. (2003)</a> clarified the role of Srs2 in recombination modulation by purifying its encoded product and examining its interactions with the RAD51 recombinase. Srs2 has a robust ATPase activity that is dependent on single-stranded DNA and binds RAD51, but the addition of a catalytic quantity of Srs2 to RAD51-mediated recombination reactions causes severe inhibition of these reactions. <a href="#17" class="mim-tip-reference" title="Krejci, L., Van Komen, S., Li, Y., Villemain, J., Reddy, M. S., Klein, H., Ellenberger, T., Sung, P. <strong>DNA helicase Srs2 disrupts the Rad51 presynaptic filament.</strong> Nature 423: 305-309, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12748644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12748644</a>] [<a href="https://doi.org/10.1038/nature01577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12748644">Krejci et al. (2003)</a> showed that Srs2 acts by dislodging RAD51 from single-stranded DNA. Thus, the attenuation of recombination efficiency by Srs2 stems primarily from its ability to dismantle the RAD51 presynaptic filament efficiently. <a href="#17" class="mim-tip-reference" title="Krejci, L., Van Komen, S., Li, Y., Villemain, J., Reddy, M. S., Klein, H., Ellenberger, T., Sung, P. <strong>DNA helicase Srs2 disrupts the Rad51 presynaptic filament.</strong> Nature 423: 305-309, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12748644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12748644</a>] [<a href="https://doi.org/10.1038/nature01577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12748644">Krejci et al. (2003)</a> suggested that their findings have implications for the basis of Bloom (<a href="/entry/210900">210900</a>) and Werner (<a href="/entry/277700">277700</a>) syndromes, which are caused by mutations in DNA helicases and are characterized by increased frequencies of recombination and a predisposition to cancers and accelerated aging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12748644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Hussain, S., Witt, E., Huber, P. A. J., Medhurst, A. L., Ashworth, A., Mathew, C. G. <strong>Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1.</strong> Hum. Molec. Genet. 12: 2503-2510, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915460</a>] [<a href="https://doi.org/10.1093/hmg/ddg266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915460">Hussain et al. (2003)</a> found that the FANCG protein (<a href="/entry/602956">602956</a>) colocalized in nuclear foci with both BRCA2 (<a href="/entry/600185">600185</a>) and RAD51 following DNA damage with mitomycin C. The authors concluded that BRCA2 is directly connected to a pathway deficient in interstrand crosslink repair, and that at least 1 other Fanconi anemia protein is closely associated with the homologous recombination DNA repair machinery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Dong, Y., Hakimi, M.-A., Chen, X., Kumaraswamy, E., Cooch, N. S., Godwin, A. K., Shiekhattar, R. <strong>Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair.</strong> Molec. Cell 12: 1087-1099, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14636569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14636569</a>] [<a href="https://doi.org/10.1016/s1097-2765(03)00424-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14636569">Dong et al. (2003)</a> isolated a holoenzyme complex containing BRCA1 (<a href="/entry/113705">113705</a>), BRCA2, BARD1 (<a href="/entry/610593">610593</a>), and RAD51, which they called the BRCA1- and BRCA2-containing complex (BRCC). The complex showed UBC5 (see UBE2D1; <a href="/entry/602961">602961</a>)-dependent ubiquitin E3 ligase activity. Inclusion of BRE (<a href="/entry/610497">610497</a>) and BRCC3 (<a href="/entry/300617">300617</a>) enhanced ubiquitination by the complex, and cancer-associated truncations in BRCA1 reduced the association of BRE and BRCC3 with the complex. RNA interference of BRE and BRCC3 in HeLa cells increased cell sensitivity to ionizing radiation and resulted in a defect in G2/M checkpoint arrest. <a href="#9" class="mim-tip-reference" title="Dong, Y., Hakimi, M.-A., Chen, X., Kumaraswamy, E., Cooch, N. S., Godwin, A. K., Shiekhattar, R. <strong>Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair.</strong> Molec. Cell 12: 1087-1099, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14636569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14636569</a>] [<a href="https://doi.org/10.1016/s1097-2765(03)00424-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14636569">Dong et al. (2003)</a> concluded that the BRCC is a ubiquitin E3 ligase that enhances cellular survival following DNA damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14636569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Yang, H., Li, Q., Fan, J., Holloman, W. K., Pavletich, N. P. <strong>The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction.</strong> Nature 433: 653-657, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703751</a>] [<a href="https://doi.org/10.1038/nature03234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703751">Yang et al. (2005)</a> showed that a full-length Brca2 homolog (Brh2, from the fungus Ustilago maydis) stimulates Rad51-mediated recombination at substoichiometric concentrations relative to Rad51. Brh2 recruits Rad51 to DNA and facilitates the nucleation of the filament, which is then elongated by the pool of free Rad51. Brh2 acts preferentially at a junction between double-stranded DNA and single-stranded DNA, with strict specificity for the 3-prime overhang polarity of a resected double-stranded break. <a href="#36" class="mim-tip-reference" title="Yang, H., Li, Q., Fan, J., Holloman, W. K., Pavletich, N. P. <strong>The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction.</strong> Nature 433: 653-657, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703751</a>] [<a href="https://doi.org/10.1038/nature03234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703751">Yang et al. (2005)</a> concluded that their results established a BRCA2 function in RAD51-mediated double-stranded break repair and explained the loss of this repair capacity in BRCA2-associated cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Enomoto, R., Kinebuchi, T., Sato, M., Yagi, H., Kurumizaka, H., Yokoyama, S. <strong>Stimulation of DNA strand exchange by the human TBPIP/Hop2-Mnd1 complex.</strong> J. Biol. Chem. 281: 5575-5581, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407260</a>] [<a href="https://doi.org/10.1074/jbc.M506506200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407260">Enomoto et al. (2006)</a> demonstrated that coexpression of human MND1 (<a href="/entry/611422">611422</a>) and HOP2 (<a href="/entry/608665">608665</a>) in E. coli resulted in the formation of stable heterodimers that stimulated DMC1- and RAD51-mediated DNA strand exchange. <a href="#5" class="mim-tip-reference" title="Chi, P., San Filippo, J., Sehorn, M. G., Petukhova, G. V., Sung, P. <strong>Bipartite stimulatory action of the Hop2-Mnd1 complex on the Rad51 recombinase.</strong> Genes Dev. 21: 1747-1757, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17639080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17639080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17639080[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.1563007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17639080">Chi et al. (2007)</a> found that the Hop2 component of the mouse recombinant Hop2-Mnd1 complex was the major DNA-binding subunit, and that Mnd1 was the Rad51-interacting entity. Hop2-Mnd1 stabilized the Rad51-single-stranded DNA (ssDNA) nucleoprotein filament, and enhanced the ability of the Rad51-ssDNA nucleoprotein filament to capture duplex DNA, which is an obligatory step in the formation of the synaptic complex critical for DNA joint formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17639080+16407260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By combining optical tweezers with single-molecule fluorescence microscopy and microfluidics, <a href="#32" class="mim-tip-reference" title="van Mameren, J., Modesti, M., Kanaar, R., Wyman, C., Peterman, E. J. G., Wuite, G. J. L. <strong>Counting RAD51 proteins disassembling from nucleoprotein filaments under tension.</strong> Nature 457: 745-748, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19060884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19060884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19060884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19060884">van Mameren et al. (2009)</a> demonstrated that disassembly of human RAD51 nucleoprotein filaments results from the interplay between ATP hydrolysis and the release of the tension stored in the filament. By applying external tension to the DNA, they found that disassembly slows down and can even be stalled. The authors quantified the fluorescence of RAD51 patches and found that disassembly occurs in bursts interspersed by long pauses. After relaxation of a stalled complex, pauses were suppressed resulting in a large burst. <a href="#32" class="mim-tip-reference" title="van Mameren, J., Modesti, M., Kanaar, R., Wyman, C., Peterman, E. J. G., Wuite, G. J. L. <strong>Counting RAD51 proteins disassembling from nucleoprotein filaments under tension.</strong> Nature 457: 745-748, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19060884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19060884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19060884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19060884">Van Mameren et al. (2009)</a> concluded that tension-dependent disassembly takes place only from filament ends, after tension-independent ATP hydrolysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19060884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using purified recombinant proteins, <a href="#29" class="mim-tip-reference" title="Tombline, G., Fishel, R. <strong>Biochemical characterization of the human RAD51 protein: I. ATP hydrolysis.</strong> J. Biol. Chem. 277: 14417-14425, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11839739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11839739</a>] [<a href="https://doi.org/10.1074/jbc.M109915200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11839739">Tombline and Fishel (2002)</a> showed that human RAD51 had a 50-fold reduction in catalytic efficiency compared to bacterial RecA and lacked the magnitude of ATP-induced cooperativity that is a hallmark of RecA. Altering the ratio of DNA/RAD51 and including salts that stimulate DNA strand exchange, such as ammonium sulfate, were found to increase RAD51 catalytic efficiency. RAD51 and RecA differed in the ability of ssDNA and dsDNA to induce their ATPase activity and also showed differences in DNA site size. RAD51 had a minimal site size of 3 nucleotides, but 6 to 8 nucleotides of ssDNA per RAD51 monomer provoked optimal ATPase efficiency, whereas RecA has a site size of 3 nucleotides for ssDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11839739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Park, J.-Y., Yoo, H.-W., Kim, B.-R., Park, R., Choi, S.-Y., Kim, Y. <strong>Identification of a novel human Rad51 variant that promotes DNA strand exchange.</strong> Nucleic Acids Res. 36: 3226-3234, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18417535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18417535</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18417535[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/nar/gkn171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18417535">Park et al. (2008)</a> showed that RAD51-delta-ex9 showed approximately the same DNA strand exchange activity as full-length RAD51 in vitro, although it had significantly higher activity than RAD51 in homologous DNA repair. Mutation analysis revealed that the unique C termini of RAD51 and RAD51-delta-ex9 independently directed their nuclear localization in transfected COS-7 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18417535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Western blot analysis, <a href="#24" class="mim-tip-reference" title="Sage, J. M., Gildemeister, O. S., Knight, K. L. <strong>Discovery of a novel function for human Rad51: maintenance of the mitochondrial genome.</strong> J. Biol. Chem. 285: 18984-18990, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20413593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20413593</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20413593[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M109.099846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20413593">Sage et al. (2010)</a> found that mitochondrial levels of RAD51, RAD51C, and XRCC3 in human cell lines increased in response to oxidative stress and weak ionizing radiation. Immunoprecipitation analysis showed that oxidative stress increased the interaction of RAD51 with mitochondrial DNA (mtDNA), and knockdown of RAD51, via small interfering RNA, increased mtDNA copy number, apparently due to general inhibition of cell cycle progression. Oxidative stress normally increases mtDNA copy number; however, knockdown of RAD51, RAD51C, or XRCC3 suppressed this stress response and resulted in decreased mtDNA copy number. <a href="#24" class="mim-tip-reference" title="Sage, J. M., Gildemeister, O. S., Knight, K. L. <strong>Discovery of a novel function for human Rad51: maintenance of the mitochondrial genome.</strong> J. Biol. Chem. 285: 18984-18990, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20413593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20413593</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20413593[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M109.099846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20413593">Sage et al. (2010)</a> concluded that proteins of the homologous recombination pathway are required to maintain the mitochondrial genome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20413593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Jensen, R. B., Carreira, A., Kowalczykowski, S. C. <strong>Purified human BRCA2 stimulates RAD51-mediated recombination.</strong> Nature 467: 678-683, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20729832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20729832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20729832[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20729832">Jensen et al. (2010)</a> reported the purification of BRCA2 and showed that it both binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto ssDNA. BRCA2 acts by targeting RAD51 to ssDNA over dsDNA, enabling RAD51 to displace replication protein-A (RPA; <a href="/entry/179835">179835</a>) from ssDNA and stabilizing RAD51 ssDNA filaments by blocking ATP hydrolysis. BRCA2 does not anneal ssDNA complexed with RPA, implying it does not directly function in repair processes that involve ssDNA annealing. The findings of <a href="#14" class="mim-tip-reference" title="Jensen, R. B., Carreira, A., Kowalczykowski, S. C. <strong>Purified human BRCA2 stimulates RAD51-mediated recombination.</strong> Nature 467: 678-683, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20729832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20729832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20729832[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20729832">Jensen et al. (2010)</a> showed that BRCA2 is a key mediator of homologous recombination and provided a molecular basis for understanding how this DNA repair process is disrupted by BRCA2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20729832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For additional information on RAD51 and the BRCC protein complex that performs DNA repair and recombination, see BRCA2 (<a href="/entry/600185">600185</a>).</p><p><a href="#15" class="mim-tip-reference" title="Jirawatnotai, S., Hu, Y., Michowski, W., Elias, J. E., Becks, L., Bienvenu, F., Zagozdzon, A., Goswami, T., Wang, Y. E., Clark, A. B., Kunkel, T. A., van Harn, T., Xia, B., Correll, M., Quackenbush, J., Livingston, D. M., Gygi, S. P., Sicinski, P. <strong>A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers.</strong> Nature 474: 230-234, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21654808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21654808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21654808[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21654808">Jirawatnotai et al. (2011)</a> performed a series of proteomic screens for cyclin D1 (<a href="/entry/168461">168461</a>) protein partners in several types of human tumors and found that cyclin D1 directly binds RAD51 and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein (<a href="/entry/614041">614041</a>), which do not require D-cyclins for proliferation. <a href="#15" class="mim-tip-reference" title="Jirawatnotai, S., Hu, Y., Michowski, W., Elias, J. E., Becks, L., Bienvenu, F., Zagozdzon, A., Goswami, T., Wang, Y. E., Clark, A. B., Kunkel, T. A., van Harn, T., Xia, B., Correll, M., Quackenbush, J., Livingston, D. M., Gygi, S. P., Sicinski, P. <strong>A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers.</strong> Nature 474: 230-234, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21654808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21654808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21654808[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21654808">Jirawatnotai et al. (2011)</a> concluded that their findings revealed an unexpected function of a core cell-cycle protein in DNA repair and suggested that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers, which were thought to be unaffected by cyclin D1 inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21654808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Long, D. T., Raschle, M., Joukov, V., Walter, J. C. <strong>Mechanism of RAD51-dependent DNA interstrand cross-link repair.</strong> Science 333: 84-87, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21719678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21719678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21719678[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1204258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21719678">Long et al. (2011)</a> reported that the broken sister chromatid generated by a DNA double-strand break in Xenopus extracts is repaired via RAD51-dependent strand invasion into the regenerated sister. Recombination acts downstream of FANCI (<a href="/entry/611360">611360</a>)-FANCD2 (<a href="/entry/613984">613984</a>), yet RAD51 binds interstrand crosslinks-stalled replication forks independently of FANCI and FANC2 and before double-strand break formation. <a href="#19" class="mim-tip-reference" title="Long, D. T., Raschle, M., Joukov, V., Walter, J. C. <strong>Mechanism of RAD51-dependent DNA interstrand cross-link repair.</strong> Science 333: 84-87, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21719678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21719678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21719678[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1204258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21719678">Long et al. (2011)</a> concluded that their results elucidated the functional link between the Fanconi anemia pathway and the recombination machinery during interstrand crosslink repair. In addition, their results demonstrated the complete repair of a double-strand break via homologous recombination in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21719678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the developing mouse cortex, <a href="#7" class="mim-tip-reference" title="Depienne, C., Bouteiller, D., Meneret, A., Billot, S., Groppa, S., Klebe, S., Charbonnier-Beaupel, F., Corvol, J.-C., Saraiva, J.-P., Brueggemann, N., Bhatia, K., Cincotta, M., and 13 others. <strong>RAD51 haploinsufficiency causes congenital mirror movements in humans.</strong> Am. J. Hum. Genet. 90: 301-307, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22305526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22305526</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22305526[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.12.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22305526">Depienne et al. (2012)</a> found that expression of the Rad51 gene was highest at embryonic day 12 (E12), and was mostly detected in the cortical ventricular proliferative zone. The Dcc gene (<a href="/entry/120470">120470</a>) was also expressed at this time, but in a different location in the preplate postmitotic zone. In the cortex of newborn mice, Rad51 was mainly present in the subplate and, in lesser amounts, in layer V, whereas Dcc was selectively located in axons innervating the cortex. Rad51 was also detected in a subpopulation of corticospinal axons at the pyramidal decussation in 2-day-old mice. The subcellular location of Rad51 also changes with development: at E12, it was mostly detected in the nucleus of progenitor cells, whereas after birth, it was mainly localized in the cell soma. The results suggested that Rrad51 could have several functions related to different cellular localizations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22305526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>With use of a separation-of-function mutant form of Rad51 that retains filament-forming but not joint molecule (JM)-forming activity in S. cerevisiae,, <a href="#6" class="mim-tip-reference" title="Cloud, V., Chan, Y.-L., Grubb, J., Budke, B., Bishop, D. K. <strong>Rad51 is an accessory factor for Dmc1-mediated joint molecule formation during meiosis.</strong> Science 337: 1222-1225, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22955832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22955832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22955832[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1219379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22955832">Cloud et al. (2012)</a> showed that the JM activity of Rad51 is fully dispensable for meiotic recombination. The corresponding mutation in Dmc1 (<a href="/entry/602721">602721</a>) causes a profound recombination defect, demonstrating that Dmc1's JM activity alone is responsible for meiotic recombination. <a href="#6" class="mim-tip-reference" title="Cloud, V., Chan, Y.-L., Grubb, J., Budke, B., Bishop, D. K. <strong>Rad51 is an accessory factor for Dmc1-mediated joint molecule formation during meiosis.</strong> Science 337: 1222-1225, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22955832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22955832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22955832[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1219379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22955832">Cloud et al. (2012)</a> further provided biochemical evidence that Rad51 acts with Mei5-Sae3 as a Dmc1 accessory factor. Thus, Rad51 is a multifunctional protein that catalyzes recombination directly in mitosis and indirectly, via Dmc1, during meiosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22955832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Ceccaldi, R., Liu, J. C., Amunugama, R., Hajdu, I., Primack, B., Petalcorin, M. I. R., O'Connor, K. W., Konstantinopoulos, P. A., Elledge, S. J., Boulton, S. J., Yusufzai, T., D'Andrea, A. D. <strong>Homologous-recombination- deficient tumours are dependent on Pol(theta)-mediated repair.</strong> Nature 518: 258-262, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25642963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25642963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25642963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature14184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25642963">Ceccaldi et al. (2015)</a> reported an inverse correlation between homologous recombination (HR) activity and polymerase theta (POLQ; <a href="/entry/604419">604419</a>) expression in epithelial ovarian cancers. Knockdown of POLQ in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of POLQ in HR-deficient epithelial ovarian cancers enhances cell death. Consistent with these results, genetic inactivation of the HR gene Fancd2 and Polq in mice resulted in embryonic lethality. Moreover, POLQ contains RAD51 binding motifs and blocks RAD51-mediated recombination. <a href="#3" class="mim-tip-reference" title="Ceccaldi, R., Liu, J. C., Amunugama, R., Hajdu, I., Primack, B., Petalcorin, M. I. R., O'Connor, K. W., Konstantinopoulos, P. A., Elledge, S. J., Boulton, S. J., Yusufzai, T., D'Andrea, A. D. <strong>Homologous-recombination- deficient tumours are dependent on Pol(theta)-mediated repair.</strong> Nature 518: 258-262, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25642963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25642963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25642963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature14184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25642963">Ceccaldi et al. (2015)</a> concluded that their results revealed a synthetic lethal relationship between the homologous recombination pathway and POLQ-mediated repair in epithelial ovarian cancers, and identified POLQ as a novel druggable target. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25642963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By examining purified wildtype and mutant BRCA1 (<a href="/entry/113705">113705</a>)-BARD1 (<a href="/entry/601593">601593</a>), <a href="#37" class="mim-tip-reference" title="Zhao, W., Steinfeld, J. B., Liang, F., Chen, X., Maranon, D. G., Ma, C. J., Kwon, Y., Rao, T., Wang, W., Sheng, C., Song, X., Deng, Y., Jimenez-Sainz, J., Lu, L., Jensen, R. B., Xiong, Y., Kupfer, G. M., Wiese, C., Greene, E. C., Sung, P. <strong>BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing.</strong> Nature 550: 360-36, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28976962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28976962</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28976962[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature24060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28976962">Zhao et al. (2017)</a> showed that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1-BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. <a href="#37" class="mim-tip-reference" title="Zhao, W., Steinfeld, J. B., Liang, F., Chen, X., Maranon, D. G., Ma, C. J., Kwon, Y., Rao, T., Wang, W., Sheng, C., Song, X., Deng, Y., Jimenez-Sainz, J., Lu, L., Jensen, R. B., Xiong, Y., Kupfer, G. M., Wiese, C., Greene, E. C., Sung, P. <strong>BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing.</strong> Nature 550: 360-36, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28976962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28976962</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28976962[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature24060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28976962">Zhao et al. (2017)</a> provided evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1-BARD1 mutants with weakened RAD51 interactions showed compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28976962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Telomeric repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from chromosome ends and regulate telomeric chromatin structure and telomere maintenance through telomerase (see <a href="/entry/187270">187270</a>). <a href="#11" class="mim-tip-reference" title="Feretzaki, M., Pospisilova, M., Valador Fernandes, R., Lunardi, T., Krejci, L., Lingner, J. <strong>RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops.</strong> Nature 587: 303-308, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33057192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33057192</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33057192[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2815-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33057192">Feretzaki et al. (2020)</a> showed that the UUAGGG repeats of human TERRA were both necessary and sufficient to target TERRA to chromosome ends. TERRA preferentially associated with short telomeres through formation of telomeric DNA-RNA hybrid (R-loop) structures that could form in trans. Telomere association and R-loop formation triggered telomere fragility and were promoted by RAD51 and its interacting partner BRCA2, but were counteracted by the RNA-surveillance factors RNASEH1 (<a href="/entry/604123">604123</a>) and TRF1 (TERF1; <a href="/entry/600951">600951</a>). RAD51 physically interacted with TERRA and catalyzed R-loop formation with TERRA in vitro, suggesting direct involvement of this DNA recombinase in recruitment of TERRA by strand invasion. <a href="#11" class="mim-tip-reference" title="Feretzaki, M., Pospisilova, M., Valador Fernandes, R., Lunardi, T., Krejci, L., Lingner, J. <strong>RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops.</strong> Nature 587: 303-308, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33057192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33057192</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33057192[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2815-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33057192">Feretzaki et al. (2020)</a> concluded that a RAD51-dependent pathway governs TERRA-mediated R-loop formation after transcription, providing a mechanism for recruitment of lncRNAs to new loci in trans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33057192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Susceptibility to Breast Cancer</em></strong></p><p>
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RAD51, a homolog of RecA of E. coli, functions in recombination and in DNA repair. The BRCA1 and BRCA2 proteins, implicated in familial breast cancer, form a complex with RAD51, and these genes are thought to participate in a common DNA damage response pathway associated with the activation of homologous recombination and DSB repair. To investigate the possibility that the RAD51 gene may be involved in the development of hereditary breast cancer, <a href="#16" class="mim-tip-reference" title="Kato, M., Yano, K., Matsuo, F., Saito, H., Katagiri, T., Kurumizaka, H., Yoshimoto, M., Kasumi, F., Akiyama, F., Sakamoto, G., Nagawa, H., Nakamura, Y., Miki, Y. <strong>Identification of Rad51 alteration in patients with bilateral breast cancer.</strong> J. Hum. Genet. 45: 133-137, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807537</a>] [<a href="https://doi.org/10.1007/s100380050199" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10807537">Kato et al. (2000)</a> screened Japanese patients with hereditary breast cancer for RAD51 mutations and found a single alteration in exon 6 (<a href="#0001">179617.0001</a>). This was determined to be present in the germline in 2 patients with bilateral breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10807537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Mirror Movements 2</em></strong></p><p>
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By exome sequencing of a large French family with congenital mirror movements-2 (MRMV2; <a href="/entry/614508">614508</a>), originally reported by <a href="#8" class="mim-tip-reference" title="Depienne, C., Cincotta, M., Billot, S., Bouteiller, D., Groppa, S., Brochard, V., Flamand, C., Hubsch, C., Meunier, S., Giovannelli, F., Klebe, S., Corvol, J. C., Vidailhet, M., Brice, A., Roze, E. <strong>A novel DCC mutation and genetic heterogeneity in congenital mirror movements.</strong> Neurology 76: 260-264, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21242494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21242494</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318207b1e0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21242494">Depienne et al. (2011)</a>, <a href="#7" class="mim-tip-reference" title="Depienne, C., Bouteiller, D., Meneret, A., Billot, S., Groppa, S., Klebe, S., Charbonnier-Beaupel, F., Corvol, J.-C., Saraiva, J.-P., Brueggemann, N., Bhatia, K., Cincotta, M., and 13 others. <strong>RAD51 haploinsufficiency causes congenital mirror movements in humans.</strong> Am. J. Hum. Genet. 90: 301-307, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22305526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22305526</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22305526[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.12.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22305526">Depienne et al. (2012)</a> identified a heterozygous truncating mutation in the RAD51 gene (<a href="#0003">179617.0003</a>). The mutation was found in 8 affected individuals and in 8 unaffected individuals, indicating significant incomplete penetrance (50%). A second truncating mutation in the RAD51 gene (<a href="#0004">179617.0004</a>) was identified in a German family with the disorder. The authors concluded that haploinsufficiency was the pathogenic mechanism. The mechanism linking RAD1 deficiency to the disorder was unclear: insufficient RAD51-related DNA repair during early corticogenesis might lead to excessive apoptosis and altered central nervous system development; however, the authors noted that RAD51 may have a direct or indirect role in axonal guidance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22305526+21242494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Trouillard, O., Koht, J., Gerstner, T., Moland, S., Depienne, C., Dusart, I., Meneret, A., Ruiz, M., Dubacq, C., Roze, E. <strong>Congenital mirror movements due to RAD51: cosegregation with a nonsense mutation in a Norwegian pedigree and review of the literature.</strong> Tremor Other Hyperkinet. Mov. (N.Y.) 6: 424, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27830107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27830107</a>] [<a href="https://doi.org/10.7916/D8BK1CNF" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27830107">Trouillard et al. (2016)</a> identified a heterozygous R254X mutation in the RAD51 gene in 8 members of a Norwegian family with MRMV2. The mutation, which was found by direct sequencing of the RAD51 gene, segregated with the disorder in the family. Four mutation carriers had obvious mirror movements in the hands that disturbed activities of daily living, whereas the other 4 mutation carriers had no complaints despite mild mirror movements. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27830107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated patients with sporadic MRMV2 (female probands from families 3 and 16), <a href="#21" class="mim-tip-reference" title="Meneret, A., Depienne, C., Riant, F., Trouillard, O., Bouteiller, D., Cincotta, M., Bitoun, P., Wickert, J., Lagroua, I., Westenberger, A., Borgheresi, A., Doummar, D., and 18 others. <strong>Congenital mirror movements: mutational analysis of RAD51 and DCC in 26 cases.</strong> Neurology 82: 1999-2002, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24808016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24808016</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24808016[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24808016">Meneret et al. (2014)</a> identified heterozygous missense variants in the RAD51 gene (H47R and I137F) by direct Sanger sequencing. Both variants were inherited from the patients' unaffected mothers, and 1 of them (H47R) was also present in an unaffected brother. Functional studies and studies of patient cells were not performed. The patients were ascertained from a cohort of 6 familial and 20 simplex cases of congenital mirror movements who were specifically screened for mutations in the DCC (<a href="/entry/120470">120470</a>) and RAD51 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24808016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 9 individuals spanning 2 generations of a family (family A) with MRMV2, <a href="#12" class="mim-tip-reference" title="Franz, E. A., Chiaroni-Clarke, R., Woodrow, S., Glendining, K. A., Jasoni, C. L., Robertson, S. P., Gardner, R. J. M., Markie, D. <strong>Congenital mirror movements: phenotypes associated with DCC and RAD51 mutations.</strong> J. Neurol. Sci. 351: 140-145, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25813273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25813273</a>] [<a href="https://doi.org/10.1016/j.jns.2015.03.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25813273">Franz et al. (2015)</a> identified a heterozygous missense mutation in the RAD51 gene (R250Q; <a href="#0006">179617.0006</a>). The variant, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Functional studies of the RAD51 variant and studies of patient cells were not performed. One variant carrier (patient IV.6) did not have overt mirror movements, but did show subtle mirror movements detected by an accelerometer glove. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25813273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Fanconi Anemia, Complementation Group R</em></strong></p><p>
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In a patient with an atypical form of Fanconi anemia (FANCR; <a href="/entry/617244">617244</a>), <a href="#1" class="mim-tip-reference" title="Ameziane, N., May, P., Haitjema, A., van de Vrugt, H. J., van Rossum-Fikket, S. E., Ristc, D., Williams, G. J., Balk, J., Rockx, D., Li, H., Rooimans, M. A., Oostra, A. B., and 17 others. <strong>A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51.</strong> Nature Commun. 6: 8829, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26681308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26681308</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26681308[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ncomms9829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26681308">Ameziane et al. (2015)</a> identified a de novo heterozygous missense mutation in the RAD51 gene (A293T; <a href="#0005">179617.0005</a>). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. In vitro functional expression assays and biochemical studies showed that the mutation impairs the binding of RAD51 to single- and double-stranded DNA, and attenuates the DNA-stimulated ATPase activity of RAD51 in a dominant-negative manner when coexpressed with the wildtype protein. Patient cells showed increased sensitivity to DNA crosslinking agents due to defective DNA repair, with normal monoubiquitination of FANCD2 (<a href="/entry/613984">613984</a>), suggesting a defect downstream of the core FA complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26681308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a girl with FANCR, <a href="#34" class="mim-tip-reference" title="Wang, A. T., Kim, T., Wagner, J. E., Conti, B. A., Lach, F. P., Huang, A. L., Molina, H., Sanborn, E. M., Zierhut, H., Cornes, B. K., Abhyankar, A., Sougnez, C., Gabriel, S. B., Auerbach, A. D., Kowalczykowski, S. C., Smogorzewska, A. <strong>A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination.</strong> Molec. Cell 59: 478-490, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26253028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26253028</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26253028[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2015.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26253028">Wang et al. (2015)</a> identified a de novo heterozygous missense mutation in the RAD51 gene (T131P; <a href="#0007">179617.0007</a>). The mutation was found by whole-exome sequencing. Analysis of patient cells showed that the mutant allele was expressed at the mRNA and protein levels, although protein levels were lower compared with wildtype. Patient cells showed increased chromosomal breakage in response to crosslinking agents DEB and MMC. The mutant appeared to act in a dominant-negative manner. In contrast, patient cells were not more sensitive to ionizing radiation compared with controls, indicating that the homologous recombination pathway was intact. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26253028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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<a href="#20" class="mim-tip-reference" title="Luo, W., Guo, T., Li, G., Liu, R., Zhao, S., Song, M., Zhang, L., Wang, S., Chen, Z.-J., Qin, Y. <strong>Variants in homologous recombination genes EXO1 and RAD51 related with premature ovarian insufficiency.</strong> J. Clin. Endocr. Metab. 105: dgaa505, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32772095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32772095</a>] [<a href="https://doi.org/10.1210/clinem/dgaa505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32772095">Luo et al. (2020)</a> studied 50 Chinese women with premature ovarian insufficiency (see POF1, <a href="/entry/311360">311360</a>), who had no spontaneous menstruation, elevated serum FSH (see <a href="/entry/136530">136530</a>) and low estradiol levels, and no ovarian follicles seen on ultrasound. By whole-exome sequencing, they identified a 33-year-old woman (patient 1) with a potentially pathogenic missense mutation in the RAD51 gene (E68G), which was not found in 200 Chinese female controls. Analysis of transfected HEK293 cells demonstrated impaired efficiency of homologous recombination repair for DNA double-stranded breaks with the mutant compared to wildtype EXO1, and evidence of a dominant-negative effect was observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32772095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using targeted gene mutation in embryonic stem (ES) cells, <a href="#31" class="mim-tip-reference" title="Tsuzuki, T., Fujii, Y., Sakumi, K., Tominaga, Y., Nakao, K., Sekiguchi, M., Matsushiro, A., Yoshimura, Y., Morita, T. <strong>Targeted disruption of the Rad51 gene leads to lethality in embryonic mice.</strong> Proc. Nat. Acad. Sci. 93: 6236-2640, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8692798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8692798</a>] [<a href="https://doi.org/10.1073/pnas.93.13.6236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8692798">Tsuzuki et al. (1996)</a> introduced a small deletion into an essential region of the mouse Rad51 gene and transmitted the mutation through mouse germ-cell lines. Mice heterozygous for the mutation were viable and fertile. The authors identified no Rad51 -/- pups among 148 neonates examined. However, a few Rad51 -/- embryos were identified when examined during the early stages of embryonic development. No Rad51 -/- ES cells were detected under selective growth conditions. <a href="#31" class="mim-tip-reference" title="Tsuzuki, T., Fujii, Y., Sakumi, K., Tominaga, Y., Nakao, K., Sekiguchi, M., Matsushiro, A., Yoshimura, Y., Morita, T. <strong>Targeted disruption of the Rad51 gene leads to lethality in embryonic mice.</strong> Proc. Nat. Acad. Sci. 93: 6236-2640, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8692798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8692798</a>] [<a href="https://doi.org/10.1073/pnas.93.13.6236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8692798">Tsuzuki et al. (1996)</a> concluded that the Rad51 protein plays an essential role in the proliferation of cells and that a basic molecular defect present in the Rad51 -/- embryos interferes with cell viability, leading to pre-implantation lethality. The homozygous Rad51 null mutation can be characterized as a preimplantational lethal mutation that disrupts basic molecular functions of cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8692798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>7 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=179617[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121917739 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917739;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121917739?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121917739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121917739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In studies of 20 patients from breast cancer (<a href="/entry/114480">114480</a>) families and 25 patients with breast cancer that was early-onset, bilateral, or accompanied by a history of primary cancer(s) of other organs, <a href="#16" class="mim-tip-reference" title="Kato, M., Yano, K., Matsuo, F., Saito, H., Katagiri, T., Kurumizaka, H., Yoshimoto, M., Kasumi, F., Akiyama, F., Sakamoto, G., Nagawa, H., Nakamura, Y., Miki, Y. <strong>Identification of Rad51 alteration in patients with bilateral breast cancer.</strong> J. Hum. Genet. 45: 133-137, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807537</a>] [<a href="https://doi.org/10.1007/s100380050199" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10807537">Kato et al. (2000)</a> found a missense mutation in 2 patients with familial breast cancer: a G-to-A transition converting codon 150 from CGG (arg) to CAG (gln). Both patients had bilateral breast cancer, one with synchronous bilateral breast cancer and the other with synchronous bilateral multiple breast cancer. The patients were presumed to be unrelated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10807537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1801320 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1801320;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1801320?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1801320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1801320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014008 OR RCV001642223" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014008, RCV001642223" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014008...</a>
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<p><a href="#35" class="mim-tip-reference" title="Wang, W., Tucker, M. A., Doody, M. M., Tarone, R. E., Struewing, J. P. <strong>A single nucleotide polymorphism in the 5-prime-UTR of RAD51 is associated with the risk of breast cancer among BRCA1/2 mutation carriers. (Abstract)</strong> Am. J. Hum. Genet. 65: A22 only, 1999."None>Wang et al. (1999)</a> presented evidence that a single nucleotide polymorphism (SNP) in the 5-prime untranslated region of RAD51 is associated with increased breast cancer risk in BRCA1 (<a href="/entry/113705">113705</a>) and BRCA2 (<a href="/entry/600185">600185</a>) carriers but does not influence breast cancer risk in women who are not BRCA1 or BRCA2 carriers. This SNP, designated 135g/c, is a substitution of C for G at position 135 in the RAD51 cDNA. <a href="#18" class="mim-tip-reference" title="Levy-Lahad, E., Lahad, A., Eisenberg, S., Dagan, E., Paperna, T., Kasinetz, L., Catane, R., Kaufman, B., Beller, U., Renbaum, P., Gershoni-Baruch, R. <strong>A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers.</strong> Proc. Nat. Acad. Sci. 98: 3232-3236, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11248061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11248061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11248061[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.051624098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11248061">Levy-Lahad et al. (2001)</a> studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG; <a href="/entry/113705#0003">113705.0003</a>, or 5382insC; <a href="/entry/113705#0018">113705.0018</a>) or BRCA2 (6174delT; <a href="/entry/600185#0009">600185.0009</a>) mutations. They found that the 135 SNP modified cancer risk in BRCA2 carriers but not in BRCA1 carriers. Survival analysis in BRCA2 carriers showed that 135C increased risk of breast and/or ovarian cancer with a hazard ratio (HR) of 4.0. This effect was largely due to increased breast cancer risk with an HR of 3.46 for breast cancer in BRCA2 carriers who were 135C heterozygotes. RAD51 status did not affect ovarian cancer risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11248061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Antoniou, A. C., Sinilnikova, O. M., Simard, J., Leone, M., Dumont, M., Neuhausen, S. L., Struewing, J. P., Stoppa-Lyonnet, D., Barjhoux, L., Hughes, D. J., Coupier, I., Belotti, M., and 71 others. <strong>RAD51 135G-C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.</strong> Am. J. Hum. Genet. 81: 1186-1200, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17999359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17999359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17999359[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/522611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17999359">Antoniou et al. (2007)</a> pooled genotype data for 8,512 female carriers from 19 studies for the RAD51 135G-C SNP. They found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio 1.92; 95% confidence interval 1.25-2.94) but not in heterozygotes. When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom they observed hazard ratios of 1.17 (95% confidence interval 0.91-1.51) among heterozygotes and 3.18 (95% confidence interval 1.39-7.27) among rare homozygotes. In addition, they determined that the 135G-C variant affects RAD51 splicing within the 5-prime untranslated region. Thus, 135G-C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. <a href="#2" class="mim-tip-reference" title="Antoniou, A. C., Sinilnikova, O. M., Simard, J., Leone, M., Dumont, M., Neuhausen, S. L., Struewing, J. P., Stoppa-Lyonnet, D., Barjhoux, L., Hughes, D. J., Coupier, I., Belotti, M., and 71 others. <strong>RAD51 135G-C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.</strong> Am. J. Hum. Genet. 81: 1186-1200, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17999359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17999359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17999359[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/522611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17999359">Antoniou et al. (2007)</a> stated that RAD51 was the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17999359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199925463 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199925463;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199925463?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199925463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199925463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022747 OR RCV003322592" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022747, RCV003322592" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022747...</a>
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<p>In 8 affected members of a large 4-generation French family with congenital mirror movements-2 (MRMV2; <a href="/entry/614508">614508</a>), originally reported by <a href="#8" class="mim-tip-reference" title="Depienne, C., Cincotta, M., Billot, S., Bouteiller, D., Groppa, S., Brochard, V., Flamand, C., Hubsch, C., Meunier, S., Giovannelli, F., Klebe, S., Corvol, J. C., Vidailhet, M., Brice, A., Roze, E. <strong>A novel DCC mutation and genetic heterogeneity in congenital mirror movements.</strong> Neurology 76: 260-264, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21242494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21242494</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318207b1e0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21242494">Depienne et al. (2011)</a>, <a href="#7" class="mim-tip-reference" title="Depienne, C., Bouteiller, D., Meneret, A., Billot, S., Groppa, S., Klebe, S., Charbonnier-Beaupel, F., Corvol, J.-C., Saraiva, J.-P., Brueggemann, N., Bhatia, K., Cincotta, M., and 13 others. <strong>RAD51 haploinsufficiency causes congenital mirror movements in humans.</strong> Am. J. Hum. Genet. 90: 301-307, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22305526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22305526</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22305526[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.12.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22305526">Depienne et al. (2012)</a> identified a heterozygous 760C-T transition in exon 8 of the RAD51 gene, resulting in an arg254-to-ter (R254X) substitution. The mutation was not found in 644 controls, but it was found in 8 unaffected family members, indicating striking incomplete penetrance (50%). The mutation was found by exome sequencing. RAD51 mRNA was significantly downregulated due to nonsense-mediated mRNA decay, indicating haploinsufficiency as the pathogenic mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22305526+21242494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Trouillard, O., Koht, J., Gerstner, T., Moland, S., Depienne, C., Dusart, I., Meneret, A., Ruiz, M., Dubacq, C., Roze, E. <strong>Congenital mirror movements due to RAD51: cosegregation with a nonsense mutation in a Norwegian pedigree and review of the literature.</strong> Tremor Other Hyperkinet. Mov. (N.Y.) 6: 424, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27830107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27830107</a>] [<a href="https://doi.org/10.7916/D8BK1CNF" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27830107">Trouillard et al. (2016)</a> identified a heterozygous R254X mutation (c.760C-T, NM_002875.4) in 8 members of a Norwegian family with MRMV2. The mutation, which was found by direct sequencing of the RAD51 gene, segregated with the disorder in the family. Four mutation carriers had obvious mirror movements in the hands that disturbed activities of daily living, whereas the other 4 mutation carriers had no complaints despite mild mirror movements. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27830107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a German mother and son with congenital mirror movements-2 (MRMV2; <a href="/entry/614508">614508</a>), originally reported by <a href="#8" class="mim-tip-reference" title="Depienne, C., Cincotta, M., Billot, S., Bouteiller, D., Groppa, S., Brochard, V., Flamand, C., Hubsch, C., Meunier, S., Giovannelli, F., Klebe, S., Corvol, J. C., Vidailhet, M., Brice, A., Roze, E. <strong>A novel DCC mutation and genetic heterogeneity in congenital mirror movements.</strong> Neurology 76: 260-264, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21242494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21242494</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318207b1e0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21242494">Depienne et al. (2011)</a>, <a href="#7" class="mim-tip-reference" title="Depienne, C., Bouteiller, D., Meneret, A., Billot, S., Groppa, S., Klebe, S., Charbonnier-Beaupel, F., Corvol, J.-C., Saraiva, J.-P., Brueggemann, N., Bhatia, K., Cincotta, M., and 13 others. <strong>RAD51 haploinsufficiency causes congenital mirror movements in humans.</strong> Am. J. Hum. Genet. 90: 301-307, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22305526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22305526</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22305526[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.12.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22305526">Depienne et al. (2012)</a> identified a heterozygous 1-bp duplication (855dupA) in exon 9 of the RAD51 gene, resulting in a frameshift and premature termination. The mutation was not found in 644 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22305526+21242494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519413 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519413;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1057519413" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1057519413" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000412566 OR RCV000622620 OR RCV001194792 OR RCV001731668" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000412566, RCV000622620, RCV001194792, RCV001731668" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000412566...</a>
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<p>In a 23-year-old man with Fanconi anemia of complementation group R (FANCR; <a href="/entry/617244">617244</a>), <a href="#1" class="mim-tip-reference" title="Ameziane, N., May, P., Haitjema, A., van de Vrugt, H. J., van Rossum-Fikket, S. E., Ristc, D., Williams, G. J., Balk, J., Rockx, D., Li, H., Rooimans, M. A., Oostra, A. B., and 17 others. <strong>A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51.</strong> Nature Commun. 6: 8829, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26681308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26681308</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26681308[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ncomms9829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26681308">Ameziane et al. (2015)</a> identified a de novo heterozygous c.877G-A transition (c.877G-A, NM_002875) in the RAD51 gene, resulting in an ala293-to-thr (A293T) substitution at a conserved residue in a region involved in monomer-monomer interactions. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases. In vitro studies showed that the mutant protein was expressed and was associated with increased spontaneous and MMC-induced chromosomal breaks as well as increased cellular sensitivity to MMC. In vitro functional expression assays showed that the mutant protein reduced the formation of D-loop intermediates, which measures homology-dependent joint molecule formation during DNA repair by homologous recombination. Biochemical studies showed that the mutation impairs the binding of RAD51 to single- and double-stranded DNA, and attenuates the DNA-stimulated ATPase activity of RAD51. The mutant protein was unable to form proper and functional nucleoprotein filaments, and acted in a dominant-negative manner when coexpressed with the wildtype protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26681308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555429623 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555429623;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1555429623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1555429623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000542570" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000542570" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000542570</a>
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<p>In 9 individuals spanning 2 generations of a family (family A) with congenital mirror movements-2 (MRMV2; <a href="/entry/614508">614508</a>), <a href="#12" class="mim-tip-reference" title="Franz, E. A., Chiaroni-Clarke, R., Woodrow, S., Glendining, K. A., Jasoni, C. L., Robertson, S. P., Gardner, R. J. M., Markie, D. <strong>Congenital mirror movements: phenotypes associated with DCC and RAD51 mutations.</strong> J. Neurol. Sci. 351: 140-145, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25813273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25813273</a>] [<a href="https://doi.org/10.1016/j.jns.2015.03.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25813273">Franz et al. (2015)</a> identified a heterozygous c.749G-A transition (c.749G-A, NM_002875.4) in the RAD51 gene, resulting in an arg250-to-gln (R250Q) substitution at a conserved residue. The variant, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. It was not found in the Exome Sequencing Project database. Exome sequencing also identified 3 additional missense variants that segregated with the disorder in the family; details of these variants were not provided. Functional studies of the RAD51 variant and studies of patient cells were not performed. One variant carrier (patient IV.6) did not have overt mirror movements, but did show subtle mirror movements detected by an accelerometer glove. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25813273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1895530875 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1895530875;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1895530875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1895530875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001172541 OR RCV001194791" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001172541, RCV001194791" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001172541...</a>
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<p>In a 13-year-old girl with Fanconi anemia complementation group R (FANCR; <a href="/entry/617244">617244</a>), <a href="#34" class="mim-tip-reference" title="Wang, A. T., Kim, T., Wagner, J. E., Conti, B. A., Lach, F. P., Huang, A. L., Molina, H., Sanborn, E. M., Zierhut, H., Cornes, B. K., Abhyankar, A., Sougnez, C., Gabriel, S. B., Auerbach, A. D., Kowalczykowski, S. C., Smogorzewska, A. <strong>A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination.</strong> Molec. Cell 59: 478-490, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26253028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26253028</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26253028[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2015.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26253028">Wang et al. (2015)</a> identified a de novo heterozygous c.391A-C transversion in the RAD51 gene, resulting in a thr131-to-pro (T131P) substitution at a conserved residue in the Walker A domain, which is important for ATP binding and hydrolysis. The mutation was found by whole-exome sequencing. Analysis of patient cells showed that the mutant allele was expressed at the mRNA and protein levels, although protein levels were lower compared to wildtype. Patient cells showed increased chromosomal breakage in response to crosslinking agents DEB and MMC. In contrast, patient cells were not more sensitive to ionizing radiation compared with controls, indicating that the homologous recombination pathway was intact. Primary fibroblasts (RA2630) from the patient showed defective DNA interstrand crosslink (ICL) repair with DNA2 (<a href="/entry/601810">601810</a>)- and WRN (<a href="/entry/604611">604611</a>)-dependent hyperactivation of RPA (<a href="/entry/179835">179835</a>), resulting in DNA degradation after treatment with MMC. Abolishing the RAD51 mutant allele by genetic disruption and keeping the wildtype allele only in RA2630 cells reverted the cellular abnormalities and restored the normal phenotype, demonstrating that T131P was causative for the defect in ICL repair. Analysis of purified RAD51 T131P protein revealed that the mutant protein had constitutive ATPase activity comparable to wildtype RAD51, but this activity was independent of ssDNA. The mutant protein could bind ssDNA and dsDNA, but it could not function as a homologous DNA-pairing and strand-exchange protein. When a mixture of wildtype and mutant RAD51 was present in RA2630 cells, the mutant protein showed dominant-negative behavior and disrupted DNA strand-exchange reactions, causing defective ICL repair and RPA hyperactivation. However, with an optimal amount of wildtype RAD51 present in the mixture, DNA-pairing functions were largely unaffected, thereby keeping homologous recombination proficient in RA2630 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26253028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1038/nature06971" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1219379" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M506506200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg266" target="_blank">Full Text</a>]
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Tombline, G., Fishel, R.
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<strong>Biochemical characterization of the human RAD51 protein: I. ATP hydrolysis.</strong>
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J. Biol. Chem. 277: 14417-14425, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11839739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11839739</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11839739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M109915200" target="_blank">Full Text</a>]
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<a id="30" class="mim-anchor"></a>
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<a id="Trouillard2016" class="mim-anchor"></a>
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<div class="">
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Trouillard, O., Koht, J., Gerstner, T., Moland, S., Depienne, C., Dusart, I., Meneret, A., Ruiz, M., Dubacq, C., Roze, E.
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<strong>Congenital mirror movements due to RAD51: cosegregation with a nonsense mutation in a Norwegian pedigree and review of the literature.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27830107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27830107</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27830107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.7916/D8BK1CNF" target="_blank">Full Text</a>]
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<a id="31" class="mim-anchor"></a>
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<a id="Tsuzuki1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tsuzuki, T., Fujii, Y., Sakumi, K., Tominaga, Y., Nakao, K., Sekiguchi, M., Matsushiro, A., Yoshimura, Y., Morita, T.
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<strong>Targeted disruption of the Rad51 gene leads to lethality in embryonic mice.</strong>
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Proc. Nat. Acad. Sci. 93: 6236-2640, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8692798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8692798</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8692798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.93.13.6236" target="_blank">Full Text</a>]
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<a id="32" class="mim-anchor"></a>
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<a id="van Mameren2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van Mameren, J., Modesti, M., Kanaar, R., Wyman, C., Peterman, E. J. G., Wuite, G. J. L.
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<strong>Counting RAD51 proteins disassembling from nucleoprotein filaments under tension.</strong>
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Nature 457: 745-748, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19060884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19060884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19060884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19060884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature07581" target="_blank">Full Text</a>]
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<a id="Veaute2003" class="mim-anchor"></a>
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<div class="">
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Veaute, X., Jeusset, J., Soustelle, C., Kowalczykowski, S. C., Le Cam, E., Fabre, F.
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<strong>The Srs2 helicase prevents recombination by disrupting Rad51 nucleoprotein filaments.</strong>
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Nature 423: 309-312, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12748645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12748645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12748645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature01585" target="_blank">Full Text</a>]
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<a id="Wang2015" class="mim-anchor"></a>
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Wang, A. T., Kim, T., Wagner, J. E., Conti, B. A., Lach, F. P., Huang, A. L., Molina, H., Sanborn, E. M., Zierhut, H., Cornes, B. K., Abhyankar, A., Sougnez, C., Gabriel, S. B., Auerbach, A. D., Kowalczykowski, S. C., Smogorzewska, A.
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<strong>A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination.</strong>
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Molec. Cell 59: 478-490, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26253028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26253028</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26253028[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26253028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2015.07.009" target="_blank">Full Text</a>]
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<a id="35" class="mim-anchor"></a>
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<a id="Wang1999" class="mim-anchor"></a>
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Wang, W., Tucker, M. A., Doody, M. M., Tarone, R. E., Struewing, J. P.
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<strong>A single nucleotide polymorphism in the 5-prime-UTR of RAD51 is associated with the risk of breast cancer among BRCA1/2 mutation carriers. (Abstract)</strong>
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Am. J. Hum. Genet. 65: A22 only, 1999.
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Yang, H., Li, Q., Fan, J., Holloman, W. K., Pavletich, N. P.
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<strong>The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction.</strong>
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Nature 433: 653-657, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703751</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature03234" target="_blank">Full Text</a>]
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<a id="Zhao2017" class="mim-anchor"></a>
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Zhao, W., Steinfeld, J. B., Liang, F., Chen, X., Maranon, D. G., Ma, C. J., Kwon, Y., Rao, T., Wang, W., Sheng, C., Song, X., Deng, Y., Jimenez-Sainz, J., Lu, L., Jensen, R. B., Xiong, Y., Kupfer, G. M., Wiese, C., Greene, E. C., Sung, P.
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<strong>BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing.</strong>
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Nature 550: 360-36, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28976962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28976962</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28976962[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28976962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature24060" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 06/03/2022
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Ada Hamosh - updated : 01/26/2021<br>Bao Lige - updated : 08/07/2020<br>Cassandra L. Kniffin - updated : 06/07/2020<br>Ada Hamosh - updated : 02/22/2018<br>Cassandra L. Kniffin - updated : 12/18/2017<br>Cassandra L. Kniffin - updated : 12/08/2016<br>Ada Hamosh - updated : 03/04/2015<br>Ada Hamosh - updated : 10/31/2012<br>Cassandra L. Kniffin - updated : 3/2/2012<br>Ada Hamosh - updated : 9/1/2011<br>Ada Hamosh - updated : 7/26/2011<br>Ada Hamosh - updated : 10/22/2010<br>Patricia A. Hartz - updated : 8/12/2010<br>Ada Hamosh - updated : 2/18/2009<br>Ada Hamosh - updated : 6/3/2008<br>Victor A. McKusick - updated : 11/28/2007<br>Patricia A. Hartz - updated : 8/23/2007<br>Patricia A. Hartz - updated : 10/16/2006<br>George E. Tiller - updated : 9/12/2005<br>Ada Hamosh - updated : 4/15/2005<br>Ada Hamosh - updated : 5/29/2003<br>Stylianos E. Antonarakis - updated : 5/5/2003<br>Ada Hamosh - updated : 11/12/2002<br>Stylianos E. Antonarakis - updated : 11/13/2001<br>Victor A. McKusick - updated : 4/11/2001<br>Victor A. McKusick - updated : 6/12/2000<br>Moyra Smith - updated : 8/30/1996
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 9/28/1993
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alopez : 06/03/2022
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mgross : 02/09/2021<br>mgross : 01/26/2021<br>mgross : 08/07/2020<br>carol : 06/10/2020<br>ckniffin : 06/07/2020<br>carol : 08/21/2019<br>alopez : 02/22/2018<br>alopez : 12/20/2017<br>ckniffin : 12/18/2017<br>carol : 12/09/2016<br>ckniffin : 12/08/2016<br>alopez : 03/04/2015<br>carol : 1/8/2015<br>carol : 9/17/2013<br>alopez : 11/5/2012<br>terry : 10/31/2012<br>terry : 8/17/2012<br>terry : 4/12/2012<br>carol : 3/2/2012<br>carol : 3/2/2012<br>terry : 3/2/2012<br>ckniffin : 3/1/2012<br>alopez : 9/6/2011<br>terry : 9/1/2011<br>alopez : 8/8/2011<br>terry : 7/26/2011<br>alopez : 10/22/2010<br>wwang : 9/21/2010<br>terry : 8/12/2010<br>alopez : 2/24/2009<br>terry : 2/18/2009<br>alopez : 9/24/2008<br>alopez : 6/4/2008<br>terry : 6/3/2008<br>alopez : 11/29/2007<br>terry : 11/28/2007<br>alopez : 9/11/2007<br>terry : 8/23/2007<br>wwang : 10/16/2006<br>alopez : 10/20/2005<br>terry : 9/12/2005<br>alopez : 4/22/2005<br>terry : 4/15/2005<br>alopez : 5/29/2003<br>alopez : 5/29/2003<br>terry : 5/29/2003<br>mgross : 5/5/2003<br>alopez : 12/3/2002<br>alopez : 11/13/2002<br>terry : 11/12/2002<br>terry : 11/12/2002<br>mgross : 11/13/2001<br>mgross : 11/13/2001<br>carol : 8/23/2001<br>cwells : 5/2/2001<br>cwells : 5/2/2001<br>mcapotos : 4/18/2001<br>terry : 4/11/2001<br>mcapotos : 6/28/2000<br>mcapotos : 6/27/2000<br>terry : 6/12/2000<br>alopez : 8/6/1998<br>psherman : 7/30/1998<br>carol : 7/6/1998<br>psherman : 6/15/1998<br>terry : 11/20/1996<br>terry : 11/12/1996<br>terry : 11/1/1996<br>terry : 8/30/1996<br>carol : 2/10/1995<br>carol : 11/4/1993<br>carol : 9/28/1993
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<strong>*</strong> 179617
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<h3>
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RAD51 RECOMBINASE; RAD51
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RAD51, S. CEREVISIAE, HOMOLOG OF<br />
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RAD51, S. CEREVISIAE, HOMOLOG OF, A; RAD51A<br />
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RECOMBINATION PROTEIN A; RECA<br />
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RECA, E. COLI, HOMOLOG OF
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<strong><em>HGNC Approved Gene Symbol: RAD51</em></strong>
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<strong>SNOMEDCT:</strong> 254843006;
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<strong>
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<em>
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Cytogenetic location: 15q15.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:40,694,733-40,732,340 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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15q15.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Breast cancer, susceptibility to}
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</span>
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</td>
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<td>
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<span class="mim-font">
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114480
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Somatic mutation
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Fanconi anemia, complementation group R
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</span>
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</td>
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<td>
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<span class="mim-font">
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617244
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Mirror movements 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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614508
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>RAD51 has a critical role in the maintenance of genomic integrity by functioning in the repair of DNA double-strand breaks (DSBs). RAD51 mediates homologous pairing and strand exchange in recombinatory structures known as RAD51 foci in the nucleus (summary by Park et al., 2008). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In Escherichia coli, the RecA protein searches for homologous regions between 2 double-stranded DNA molecules and promotes strand exchange. It is also involved in recombinational repair of DSBs. In Saccharomyces cerevisiae, the protein encoded by rad51 is required for repair of DSBs that occur in mitosis or meiosis. By searching for orthologs of E. coli RecA, Shinohara et al. (1993) cloned genes from human, mouse, and Schizosaccharomyces pombe (fission yeast) that are homologous to rad51. Human and mouse RAD51 are identical 339-amino acid proteins and are highly homologous (83%) with the yeast rad51 proteins. The mouse gene was transcribed at a high level in thymus, spleen, testis, and ovary and at a lower level in brain. </p><p>By screening a testis cDNA library with a RAD51 probe, Park et al. (2008) cloned a RAD51 splice variant lacking exon 9, which they called RAD51-delta-ex9. The deduced 280-amino acid protein is identical to full-length RAD51 for the first 259 amino acids, which includes an N-terminal basic motif followed by the Walker A and B ATP-binding motifs. The 2 proteins diverge at their C termini, but both C termini contain basic motifs predicted to function as nuclear localization signals. PCR analysis detected high expression of full-length RAD51 in testis, with moderate expression detected in placenta, thymus, pancreas, and colon, and weaker expression detected in lung, liver, skeletal muscle, kidney, and ovary. RAD51-delta-ex9 was highly expressed in testis, with much weaker expression only in skeletal muscle, pancreas, thymus, and ovary. Western blot analysis of human testis detected RAD51 and RAD51-delta-ex9 at apparent molecular masses of 37 and 31 kD, respectively. RAD51, but not RAD51-delta-ex9, was also detected at a lower level in placenta, lung, and small intestine. Fluorescence-tagged RAD51 and RAD51-delta-ex9 proteins both localized to the nucleus of transfected COS-7 cells, with exclusion from nucleoli. </p><p>Using Western blot analysis, Sage et al. (2010) showed that a part of the cytoplasmic pool of RAD51 in human cell lines fractionated with mitochondria. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Park et al. (2008) determined that the RAD51 gene contains 10 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Slupianek et al. (2001) demonstrated that RAD51 is important for resistance to cisplatin and mitomycin C in cells expressing the BCR (151410)/ABL (189980) oncogenic tyrosine kinase. BCR/ABL significantly enhanced the expression of RAD51 and several RAD51 paralogs. RAD51 overexpression was mediated by STAT5 (601511)-dependent transcription as well as by inhibition of caspase-3 (600636)-dependent cleavage. Phosphorylation of the RAD51 tyr315 residue by BCR/ABL appeared essential for enhanced DSB repair and drug resistance. </p><p><strong><em>Crystal Structure</em></strong></p><p>
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Pellegrini et al. (2002) reported the 1.7-angstrom crystal structure of a complex between the BRC repeat, which is an evolutionarily conserved sequence in BRCA2, and the RecA-homology domain of RAD51. The BRC repeat mimics a motif in RAD51 that serves as an interface for oligomerization between individual RAD51 monomers, thus enabling BRCA2 to control the assembly of the RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. The RAD51 oligomerization motif is highly conserved among RecA-like recombinases, highlighting a common evolutionarily origin for the mechanism of nucleoprotein filament formation, mirrored in the BRC repeat. Pellegrini et al. (2002) showed that cancer-associated mutations that affect the BRC repeat disrupt its predicted interaction with RAD51, yielding structural insight into mechanisms for cancer susceptibility. </p><p>Chen et al. (2008) solved the crystal structures of the E. coli RecA-ssDNA and RecA heteroduplex filaments. They showed that ssDNA and ATP bind to RecA-RecA interfaces cooperatively, explaining the ATP dependency of DNA binding. The ATP gamma-phosphate is sensed across the RecA-RecA interface by 2 lysine residues that also stimulate ATP hydrolysis, providing a mechanism for DNA release. The DNA is underwound and stretched globally, but locally it adopts a B-DNA-like conformation that restricts the homology search to Watson-Crick-type basepairing. The complementary strand interacts primarily through basepairing, making heteroduplex formation strictly dependent on complementarity. The underwound, stretched filament conformation probably evolved to destabilize the donor duplex, freeing the complementary strand for homology sampling. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Shinohara et al. (1993) mapped the RAD51 gene to chromosome 15 by analysis of a somatic cell hybrid panel and localized the mouse gene to chromosome 2F1 by fluorescence in situ hybridization. </p><p>By FISH analysis, Takahashi et al. (1994) assigned the RAD51 gene to chromosome 15q15.1 and the mouse gene to chromosome 2F1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Solinger et al. (2002) showed that RAD54 (603615) protein dissociates RAD51 from nucleoprotein filaments formed on double-stranded DNA (dsDNA). Addition of RAD54 protein overcame inhibition of DNA strand exchange by RAD51 protein bound to substrate dsDNA. Species preference in the RAD51 dissociation and DNA strand exchange assays underlined the importance of specific RAD54-RAD51 protein interactions. RAD51 protein was unable to release dsDNA upon ATP hydrolysis, leaving it stuck on the heteroduplex DNA product after DNA strand exchange. The authors suggested that RAD54 protein is involved in the turnover of RAD51-dsDNA filaments. </p><p>In S. cerevisiae, the Srs2 helicase negatively modulates recombination, and later experiments have suggested that it reverses intermediate recombination structures. Veaute et al. (2003) demonstrated that DNA strand exchange mediated in vitro by RAD51 is inhibited by Srs2, and that Srs2 disrupts RAD51 filaments formed on single-stranded DNA. Veaute et al. (2003) concluded that their data provided an explanation for the antirecombinogenic role of Srs2 in vivo and highlighted a theretofore unknown mechanism for recombination control. </p><p>Krejci et al. (2003) clarified the role of Srs2 in recombination modulation by purifying its encoded product and examining its interactions with the RAD51 recombinase. Srs2 has a robust ATPase activity that is dependent on single-stranded DNA and binds RAD51, but the addition of a catalytic quantity of Srs2 to RAD51-mediated recombination reactions causes severe inhibition of these reactions. Krejci et al. (2003) showed that Srs2 acts by dislodging RAD51 from single-stranded DNA. Thus, the attenuation of recombination efficiency by Srs2 stems primarily from its ability to dismantle the RAD51 presynaptic filament efficiently. Krejci et al. (2003) suggested that their findings have implications for the basis of Bloom (210900) and Werner (277700) syndromes, which are caused by mutations in DNA helicases and are characterized by increased frequencies of recombination and a predisposition to cancers and accelerated aging. </p><p>Hussain et al. (2003) found that the FANCG protein (602956) colocalized in nuclear foci with both BRCA2 (600185) and RAD51 following DNA damage with mitomycin C. The authors concluded that BRCA2 is directly connected to a pathway deficient in interstrand crosslink repair, and that at least 1 other Fanconi anemia protein is closely associated with the homologous recombination DNA repair machinery. </p><p>Dong et al. (2003) isolated a holoenzyme complex containing BRCA1 (113705), BRCA2, BARD1 (610593), and RAD51, which they called the BRCA1- and BRCA2-containing complex (BRCC). The complex showed UBC5 (see UBE2D1; 602961)-dependent ubiquitin E3 ligase activity. Inclusion of BRE (610497) and BRCC3 (300617) enhanced ubiquitination by the complex, and cancer-associated truncations in BRCA1 reduced the association of BRE and BRCC3 with the complex. RNA interference of BRE and BRCC3 in HeLa cells increased cell sensitivity to ionizing radiation and resulted in a defect in G2/M checkpoint arrest. Dong et al. (2003) concluded that the BRCC is a ubiquitin E3 ligase that enhances cellular survival following DNA damage. </p><p>Yang et al. (2005) showed that a full-length Brca2 homolog (Brh2, from the fungus Ustilago maydis) stimulates Rad51-mediated recombination at substoichiometric concentrations relative to Rad51. Brh2 recruits Rad51 to DNA and facilitates the nucleation of the filament, which is then elongated by the pool of free Rad51. Brh2 acts preferentially at a junction between double-stranded DNA and single-stranded DNA, with strict specificity for the 3-prime overhang polarity of a resected double-stranded break. Yang et al. (2005) concluded that their results established a BRCA2 function in RAD51-mediated double-stranded break repair and explained the loss of this repair capacity in BRCA2-associated cancers. </p><p>Enomoto et al. (2006) demonstrated that coexpression of human MND1 (611422) and HOP2 (608665) in E. coli resulted in the formation of stable heterodimers that stimulated DMC1- and RAD51-mediated DNA strand exchange. Chi et al. (2007) found that the Hop2 component of the mouse recombinant Hop2-Mnd1 complex was the major DNA-binding subunit, and that Mnd1 was the Rad51-interacting entity. Hop2-Mnd1 stabilized the Rad51-single-stranded DNA (ssDNA) nucleoprotein filament, and enhanced the ability of the Rad51-ssDNA nucleoprotein filament to capture duplex DNA, which is an obligatory step in the formation of the synaptic complex critical for DNA joint formation. </p><p>By combining optical tweezers with single-molecule fluorescence microscopy and microfluidics, van Mameren et al. (2009) demonstrated that disassembly of human RAD51 nucleoprotein filaments results from the interplay between ATP hydrolysis and the release of the tension stored in the filament. By applying external tension to the DNA, they found that disassembly slows down and can even be stalled. The authors quantified the fluorescence of RAD51 patches and found that disassembly occurs in bursts interspersed by long pauses. After relaxation of a stalled complex, pauses were suppressed resulting in a large burst. Van Mameren et al. (2009) concluded that tension-dependent disassembly takes place only from filament ends, after tension-independent ATP hydrolysis. </p><p>Using purified recombinant proteins, Tombline and Fishel (2002) showed that human RAD51 had a 50-fold reduction in catalytic efficiency compared to bacterial RecA and lacked the magnitude of ATP-induced cooperativity that is a hallmark of RecA. Altering the ratio of DNA/RAD51 and including salts that stimulate DNA strand exchange, such as ammonium sulfate, were found to increase RAD51 catalytic efficiency. RAD51 and RecA differed in the ability of ssDNA and dsDNA to induce their ATPase activity and also showed differences in DNA site size. RAD51 had a minimal site size of 3 nucleotides, but 6 to 8 nucleotides of ssDNA per RAD51 monomer provoked optimal ATPase efficiency, whereas RecA has a site size of 3 nucleotides for ssDNA. </p><p>Park et al. (2008) showed that RAD51-delta-ex9 showed approximately the same DNA strand exchange activity as full-length RAD51 in vitro, although it had significantly higher activity than RAD51 in homologous DNA repair. Mutation analysis revealed that the unique C termini of RAD51 and RAD51-delta-ex9 independently directed their nuclear localization in transfected COS-7 cells. </p><p>Using Western blot analysis, Sage et al. (2010) found that mitochondrial levels of RAD51, RAD51C, and XRCC3 in human cell lines increased in response to oxidative stress and weak ionizing radiation. Immunoprecipitation analysis showed that oxidative stress increased the interaction of RAD51 with mitochondrial DNA (mtDNA), and knockdown of RAD51, via small interfering RNA, increased mtDNA copy number, apparently due to general inhibition of cell cycle progression. Oxidative stress normally increases mtDNA copy number; however, knockdown of RAD51, RAD51C, or XRCC3 suppressed this stress response and resulted in decreased mtDNA copy number. Sage et al. (2010) concluded that proteins of the homologous recombination pathway are required to maintain the mitochondrial genome. </p><p>Jensen et al. (2010) reported the purification of BRCA2 and showed that it both binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto ssDNA. BRCA2 acts by targeting RAD51 to ssDNA over dsDNA, enabling RAD51 to displace replication protein-A (RPA; 179835) from ssDNA and stabilizing RAD51 ssDNA filaments by blocking ATP hydrolysis. BRCA2 does not anneal ssDNA complexed with RPA, implying it does not directly function in repair processes that involve ssDNA annealing. The findings of Jensen et al. (2010) showed that BRCA2 is a key mediator of homologous recombination and provided a molecular basis for understanding how this DNA repair process is disrupted by BRCA2 mutations. </p><p>For additional information on RAD51 and the BRCC protein complex that performs DNA repair and recombination, see BRCA2 (600185).</p><p>Jirawatnotai et al. (2011) performed a series of proteomic screens for cyclin D1 (168461) protein partners in several types of human tumors and found that cyclin D1 directly binds RAD51 and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein (614041), which do not require D-cyclins for proliferation. Jirawatnotai et al. (2011) concluded that their findings revealed an unexpected function of a core cell-cycle protein in DNA repair and suggested that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers, which were thought to be unaffected by cyclin D1 inhibition. </p><p>Long et al. (2011) reported that the broken sister chromatid generated by a DNA double-strand break in Xenopus extracts is repaired via RAD51-dependent strand invasion into the regenerated sister. Recombination acts downstream of FANCI (611360)-FANCD2 (613984), yet RAD51 binds interstrand crosslinks-stalled replication forks independently of FANCI and FANC2 and before double-strand break formation. Long et al. (2011) concluded that their results elucidated the functional link between the Fanconi anemia pathway and the recombination machinery during interstrand crosslink repair. In addition, their results demonstrated the complete repair of a double-strand break via homologous recombination in vitro. </p><p>In the developing mouse cortex, Depienne et al. (2012) found that expression of the Rad51 gene was highest at embryonic day 12 (E12), and was mostly detected in the cortical ventricular proliferative zone. The Dcc gene (120470) was also expressed at this time, but in a different location in the preplate postmitotic zone. In the cortex of newborn mice, Rad51 was mainly present in the subplate and, in lesser amounts, in layer V, whereas Dcc was selectively located in axons innervating the cortex. Rad51 was also detected in a subpopulation of corticospinal axons at the pyramidal decussation in 2-day-old mice. The subcellular location of Rad51 also changes with development: at E12, it was mostly detected in the nucleus of progenitor cells, whereas after birth, it was mainly localized in the cell soma. The results suggested that Rrad51 could have several functions related to different cellular localizations. </p><p>With use of a separation-of-function mutant form of Rad51 that retains filament-forming but not joint molecule (JM)-forming activity in S. cerevisiae,, Cloud et al. (2012) showed that the JM activity of Rad51 is fully dispensable for meiotic recombination. The corresponding mutation in Dmc1 (602721) causes a profound recombination defect, demonstrating that Dmc1's JM activity alone is responsible for meiotic recombination. Cloud et al. (2012) further provided biochemical evidence that Rad51 acts with Mei5-Sae3 as a Dmc1 accessory factor. Thus, Rad51 is a multifunctional protein that catalyzes recombination directly in mitosis and indirectly, via Dmc1, during meiosis. </p><p>Ceccaldi et al. (2015) reported an inverse correlation between homologous recombination (HR) activity and polymerase theta (POLQ; 604419) expression in epithelial ovarian cancers. Knockdown of POLQ in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of POLQ in HR-deficient epithelial ovarian cancers enhances cell death. Consistent with these results, genetic inactivation of the HR gene Fancd2 and Polq in mice resulted in embryonic lethality. Moreover, POLQ contains RAD51 binding motifs and blocks RAD51-mediated recombination. Ceccaldi et al. (2015) concluded that their results revealed a synthetic lethal relationship between the homologous recombination pathway and POLQ-mediated repair in epithelial ovarian cancers, and identified POLQ as a novel druggable target. </p><p>By examining purified wildtype and mutant BRCA1 (113705)-BARD1 (601593), Zhao et al. (2017) showed that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1-BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. Zhao et al. (2017) provided evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1-BARD1 mutants with weakened RAD51 interactions showed compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells. </p><p>Telomeric repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from chromosome ends and regulate telomeric chromatin structure and telomere maintenance through telomerase (see 187270). Feretzaki et al. (2020) showed that the UUAGGG repeats of human TERRA were both necessary and sufficient to target TERRA to chromosome ends. TERRA preferentially associated with short telomeres through formation of telomeric DNA-RNA hybrid (R-loop) structures that could form in trans. Telomere association and R-loop formation triggered telomere fragility and were promoted by RAD51 and its interacting partner BRCA2, but were counteracted by the RNA-surveillance factors RNASEH1 (604123) and TRF1 (TERF1; 600951). RAD51 physically interacted with TERRA and catalyzed R-loop formation with TERRA in vitro, suggesting direct involvement of this DNA recombinase in recruitment of TERRA by strand invasion. Feretzaki et al. (2020) concluded that a RAD51-dependent pathway governs TERRA-mediated R-loop formation after transcription, providing a mechanism for recruitment of lncRNAs to new loci in trans. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Susceptibility to Breast Cancer</em></strong></p><p>
|
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RAD51, a homolog of RecA of E. coli, functions in recombination and in DNA repair. The BRCA1 and BRCA2 proteins, implicated in familial breast cancer, form a complex with RAD51, and these genes are thought to participate in a common DNA damage response pathway associated with the activation of homologous recombination and DSB repair. To investigate the possibility that the RAD51 gene may be involved in the development of hereditary breast cancer, Kato et al. (2000) screened Japanese patients with hereditary breast cancer for RAD51 mutations and found a single alteration in exon 6 (179617.0001). This was determined to be present in the germline in 2 patients with bilateral breast cancer. </p><p><strong><em>Mirror Movements 2</em></strong></p><p>
|
|
By exome sequencing of a large French family with congenital mirror movements-2 (MRMV2; 614508), originally reported by Depienne et al. (2011), Depienne et al. (2012) identified a heterozygous truncating mutation in the RAD51 gene (179617.0003). The mutation was found in 8 affected individuals and in 8 unaffected individuals, indicating significant incomplete penetrance (50%). A second truncating mutation in the RAD51 gene (179617.0004) was identified in a German family with the disorder. The authors concluded that haploinsufficiency was the pathogenic mechanism. The mechanism linking RAD1 deficiency to the disorder was unclear: insufficient RAD51-related DNA repair during early corticogenesis might lead to excessive apoptosis and altered central nervous system development; however, the authors noted that RAD51 may have a direct or indirect role in axonal guidance. </p><p>Trouillard et al. (2016) identified a heterozygous R254X mutation in the RAD51 gene in 8 members of a Norwegian family with MRMV2. The mutation, which was found by direct sequencing of the RAD51 gene, segregated with the disorder in the family. Four mutation carriers had obvious mirror movements in the hands that disturbed activities of daily living, whereas the other 4 mutation carriers had no complaints despite mild mirror movements. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 2 unrelated patients with sporadic MRMV2 (female probands from families 3 and 16), Meneret et al. (2014) identified heterozygous missense variants in the RAD51 gene (H47R and I137F) by direct Sanger sequencing. Both variants were inherited from the patients' unaffected mothers, and 1 of them (H47R) was also present in an unaffected brother. Functional studies and studies of patient cells were not performed. The patients were ascertained from a cohort of 6 familial and 20 simplex cases of congenital mirror movements who were specifically screened for mutations in the DCC (120470) and RAD51 genes. </p><p>In 9 individuals spanning 2 generations of a family (family A) with MRMV2, Franz et al. (2015) identified a heterozygous missense mutation in the RAD51 gene (R250Q; 179617.0006). The variant, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Functional studies of the RAD51 variant and studies of patient cells were not performed. One variant carrier (patient IV.6) did not have overt mirror movements, but did show subtle mirror movements detected by an accelerometer glove. </p><p><strong><em>Fanconi Anemia, Complementation Group R</em></strong></p><p>
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In a patient with an atypical form of Fanconi anemia (FANCR; 617244), Ameziane et al. (2015) identified a de novo heterozygous missense mutation in the RAD51 gene (A293T; 179617.0005). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. In vitro functional expression assays and biochemical studies showed that the mutation impairs the binding of RAD51 to single- and double-stranded DNA, and attenuates the DNA-stimulated ATPase activity of RAD51 in a dominant-negative manner when coexpressed with the wildtype protein. Patient cells showed increased sensitivity to DNA crosslinking agents due to defective DNA repair, with normal monoubiquitination of FANCD2 (613984), suggesting a defect downstream of the core FA complex. </p><p>In a girl with FANCR, Wang et al. (2015) identified a de novo heterozygous missense mutation in the RAD51 gene (T131P; 179617.0007). The mutation was found by whole-exome sequencing. Analysis of patient cells showed that the mutant allele was expressed at the mRNA and protein levels, although protein levels were lower compared with wildtype. Patient cells showed increased chromosomal breakage in response to crosslinking agents DEB and MMC. The mutant appeared to act in a dominant-negative manner. In contrast, patient cells were not more sensitive to ionizing radiation compared with controls, indicating that the homologous recombination pathway was intact. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Luo et al. (2020) studied 50 Chinese women with premature ovarian insufficiency (see POF1, 311360), who had no spontaneous menstruation, elevated serum FSH (see 136530) and low estradiol levels, and no ovarian follicles seen on ultrasound. By whole-exome sequencing, they identified a 33-year-old woman (patient 1) with a potentially pathogenic missense mutation in the RAD51 gene (E68G), which was not found in 200 Chinese female controls. Analysis of transfected HEK293 cells demonstrated impaired efficiency of homologous recombination repair for DNA double-stranded breaks with the mutant compared to wildtype EXO1, and evidence of a dominant-negative effect was observed. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using targeted gene mutation in embryonic stem (ES) cells, Tsuzuki et al. (1996) introduced a small deletion into an essential region of the mouse Rad51 gene and transmitted the mutation through mouse germ-cell lines. Mice heterozygous for the mutation were viable and fertile. The authors identified no Rad51 -/- pups among 148 neonates examined. However, a few Rad51 -/- embryos were identified when examined during the early stages of embryonic development. No Rad51 -/- ES cells were detected under selective growth conditions. Tsuzuki et al. (1996) concluded that the Rad51 protein plays an essential role in the proliferation of cells and that a basic molecular defect present in the Rad51 -/- embryos interferes with cell viability, leading to pre-implantation lethality. The homozygous Rad51 null mutation can be characterized as a preimplantational lethal mutation that disrupts basic molecular functions of cells. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>7 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 BREAST CANCER, FAMILIAL</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RAD51, ARG150GLN
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<br />
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SNP: rs121917739,
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gnomAD: rs121917739,
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ClinVar: RCV000014007, RCV000889052, RCV001777137, RCV003492294, RCV004541001
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In studies of 20 patients from breast cancer (114480) families and 25 patients with breast cancer that was early-onset, bilateral, or accompanied by a history of primary cancer(s) of other organs, Kato et al. (2000) found a missense mutation in 2 patients with familial breast cancer: a G-to-A transition converting codon 150 from CGG (arg) to CAG (gln). Both patients had bilateral breast cancer, one with synchronous bilateral breast cancer and the other with synchronous bilateral multiple breast cancer. The patients were presumed to be unrelated. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 BREAST CANCER, SUSCEPTIBILITY TO, IN BRCA1 AND BRCA2 CARRIERS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RAD51, 135G-C
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<br />
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SNP: rs1801320,
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gnomAD: rs1801320,
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ClinVar: RCV000014008, RCV001642223
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Wang et al. (1999) presented evidence that a single nucleotide polymorphism (SNP) in the 5-prime untranslated region of RAD51 is associated with increased breast cancer risk in BRCA1 (113705) and BRCA2 (600185) carriers but does not influence breast cancer risk in women who are not BRCA1 or BRCA2 carriers. This SNP, designated 135g/c, is a substitution of C for G at position 135 in the RAD51 cDNA. Levy-Lahad et al. (2001) studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG; 113705.0003, or 5382insC; 113705.0018) or BRCA2 (6174delT; 600185.0009) mutations. They found that the 135 SNP modified cancer risk in BRCA2 carriers but not in BRCA1 carriers. Survival analysis in BRCA2 carriers showed that 135C increased risk of breast and/or ovarian cancer with a hazard ratio (HR) of 4.0. This effect was largely due to increased breast cancer risk with an HR of 3.46 for breast cancer in BRCA2 carriers who were 135C heterozygotes. RAD51 status did not affect ovarian cancer risk. </p><p>Antoniou et al. (2007) pooled genotype data for 8,512 female carriers from 19 studies for the RAD51 135G-C SNP. They found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio 1.92; 95% confidence interval 1.25-2.94) but not in heterozygotes. When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom they observed hazard ratios of 1.17 (95% confidence interval 0.91-1.51) among heterozygotes and 3.18 (95% confidence interval 1.39-7.27) among rare homozygotes. In addition, they determined that the 135G-C variant affects RAD51 splicing within the 5-prime untranslated region. Thus, 135G-C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. Antoniou et al. (2007) stated that RAD51 was the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 MIRROR MOVEMENTS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RAD51, ARG254TER
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<br />
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SNP: rs199925463,
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gnomAD: rs199925463,
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ClinVar: RCV000022747, RCV003322592
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 8 affected members of a large 4-generation French family with congenital mirror movements-2 (MRMV2; 614508), originally reported by Depienne et al. (2011), Depienne et al. (2012) identified a heterozygous 760C-T transition in exon 8 of the RAD51 gene, resulting in an arg254-to-ter (R254X) substitution. The mutation was not found in 644 controls, but it was found in 8 unaffected family members, indicating striking incomplete penetrance (50%). The mutation was found by exome sequencing. RAD51 mRNA was significantly downregulated due to nonsense-mediated mRNA decay, indicating haploinsufficiency as the pathogenic mechanism. </p><p>Trouillard et al. (2016) identified a heterozygous R254X mutation (c.760C-T, NM_002875.4) in 8 members of a Norwegian family with MRMV2. The mutation, which was found by direct sequencing of the RAD51 gene, segregated with the disorder in the family. Four mutation carriers had obvious mirror movements in the hands that disturbed activities of daily living, whereas the other 4 mutation carriers had no complaints despite mild mirror movements. Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MIRROR MOVEMENTS 2</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
RAD51, 1-BP DUP, 855A
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<br />
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|
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SNP: rs34091239,
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|
|
ClinVar: RCV000022748
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a German mother and son with congenital mirror movements-2 (MRMV2; 614508), originally reported by Depienne et al. (2011), Depienne et al. (2012) identified a heterozygous 1-bp duplication (855dupA) in exon 9 of the RAD51 gene, resulting in a frameshift and premature termination. The mutation was not found in 644 controls. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 FANCONI ANEMIA, COMPLEMENTATION GROUP R</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
RAD51, ALA293THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057519413,
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|
|
|
|
|
|
|
ClinVar: RCV000412566, RCV000622620, RCV001194792, RCV001731668
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 23-year-old man with Fanconi anemia of complementation group R (FANCR; 617244), Ameziane et al. (2015) identified a de novo heterozygous c.877G-A transition (c.877G-A, NM_002875) in the RAD51 gene, resulting in an ala293-to-thr (A293T) substitution at a conserved residue in a region involved in monomer-monomer interactions. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases. In vitro studies showed that the mutant protein was expressed and was associated with increased spontaneous and MMC-induced chromosomal breaks as well as increased cellular sensitivity to MMC. In vitro functional expression assays showed that the mutant protein reduced the formation of D-loop intermediates, which measures homology-dependent joint molecule formation during DNA repair by homologous recombination. Biochemical studies showed that the mutation impairs the binding of RAD51 to single- and double-stranded DNA, and attenuates the DNA-stimulated ATPase activity of RAD51. The mutant protein was unable to form proper and functional nucleoprotein filaments, and acted in a dominant-negative manner when coexpressed with the wildtype protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MIRROR MOVEMENTS 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RAD51, ARG250GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555429623,
|
|
|
|
|
|
|
|
ClinVar: RCV000542570
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 9 individuals spanning 2 generations of a family (family A) with congenital mirror movements-2 (MRMV2; 614508), Franz et al. (2015) identified a heterozygous c.749G-A transition (c.749G-A, NM_002875.4) in the RAD51 gene, resulting in an arg250-to-gln (R250Q) substitution at a conserved residue. The variant, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. It was not found in the Exome Sequencing Project database. Exome sequencing also identified 3 additional missense variants that segregated with the disorder in the family; details of these variants were not provided. Functional studies of the RAD51 variant and studies of patient cells were not performed. One variant carrier (patient IV.6) did not have overt mirror movements, but did show subtle mirror movements detected by an accelerometer glove. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 FANCONI ANEMIA, COMPLEMENTATION GROUP R</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RAD51, THR131PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1895530875,
|
|
|
|
|
|
|
|
ClinVar: RCV001172541, RCV001194791
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 13-year-old girl with Fanconi anemia complementation group R (FANCR; 617244), Wang et al. (2015) identified a de novo heterozygous c.391A-C transversion in the RAD51 gene, resulting in a thr131-to-pro (T131P) substitution at a conserved residue in the Walker A domain, which is important for ATP binding and hydrolysis. The mutation was found by whole-exome sequencing. Analysis of patient cells showed that the mutant allele was expressed at the mRNA and protein levels, although protein levels were lower compared to wildtype. Patient cells showed increased chromosomal breakage in response to crosslinking agents DEB and MMC. In contrast, patient cells were not more sensitive to ionizing radiation compared with controls, indicating that the homologous recombination pathway was intact. Primary fibroblasts (RA2630) from the patient showed defective DNA interstrand crosslink (ICL) repair with DNA2 (601810)- and WRN (604611)-dependent hyperactivation of RPA (179835), resulting in DNA degradation after treatment with MMC. Abolishing the RAD51 mutant allele by genetic disruption and keeping the wildtype allele only in RA2630 cells reverted the cellular abnormalities and restored the normal phenotype, demonstrating that T131P was causative for the defect in ICL repair. Analysis of purified RAD51 T131P protein revealed that the mutant protein had constitutive ATPase activity comparable to wildtype RAD51, but this activity was independent of ssDNA. The mutant protein could bind ssDNA and dsDNA, but it could not function as a homologous DNA-pairing and strand-exchange protein. When a mixture of wildtype and mutant RAD51 was present in RA2630 cells, the mutant protein showed dominant-negative behavior and disrupted DNA strand-exchange reactions, causing defective ICL repair and RPA hyperactivation. However, with an optimal amount of wildtype RAD51 present in the mixture, DNA-pairing functions were largely unaffected, thereby keeping homologous recombination proficient in RA2630 cells. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<br />
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|
</div>
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
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|
|
<div>
|
|
<ol>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ameziane, N., May, P., Haitjema, A., van de Vrugt, H. J., van Rossum-Fikket, S. E., Ristc, D., Williams, G. J., Balk, J., Rockx, D., Li, H., Rooimans, M. A., Oostra, A. B., and 17 others.
|
|
<strong>A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51.</strong>
|
|
Nature Commun. 6: 8829, 2015. Note: Electronic Article.
|
|
|
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|
|
[PubMed: 26681308]
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|
|
[Full Text: https://doi.org/10.1038/ncomms9829]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Antoniou, A. C., Sinilnikova, O. M., Simard, J., Leone, M., Dumont, M., Neuhausen, S. L., Struewing, J. P., Stoppa-Lyonnet, D., Barjhoux, L., Hughes, D. J., Coupier, I., Belotti, M., and 71 others.
|
|
<strong>RAD51 135G-C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.</strong>
|
|
Am. J. Hum. Genet. 81: 1186-1200, 2007.
|
|
|
|
|
|
[PubMed: 17999359]
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|
|
[Full Text: https://doi.org/10.1086/522611]
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</p>
|
|
</li>
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<li>
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<p class="mim-text-font">
|
|
Ceccaldi, R., Liu, J. C., Amunugama, R., Hajdu, I., Primack, B., Petalcorin, M. I. R., O'Connor, K. W., Konstantinopoulos, P. A., Elledge, S. J., Boulton, S. J., Yusufzai, T., D'Andrea, A. D.
|
|
<strong>Homologous-recombination- deficient tumours are dependent on Pol(theta)-mediated repair.</strong>
|
|
Nature 518: 258-262, 2015.
|
|
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|
|
[PubMed: 25642963]
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|
[Full Text: https://doi.org/10.1038/nature14184]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Chen, Z., Yang, H., Pavletich, N. P.
|
|
<strong>Mechanism of homologous recombination from the RecA-ssDNA/dsDNA structures.</strong>
|
|
Nature 453: 489-494, 2008.
|
|
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|
|
[PubMed: 18497818]
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[Full Text: https://doi.org/10.1038/nature06971]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Chi, P., San Filippo, J., Sehorn, M. G., Petukhova, G. V., Sung, P.
|
|
<strong>Bipartite stimulatory action of the Hop2-Mnd1 complex on the Rad51 recombinase.</strong>
|
|
Genes Dev. 21: 1747-1757, 2007.
|
|
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|
|
[PubMed: 17639080]
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[Full Text: https://doi.org/10.1101/gad.1563007]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Cloud, V., Chan, Y.-L., Grubb, J., Budke, B., Bishop, D. K.
|
|
<strong>Rad51 is an accessory factor for Dmc1-mediated joint molecule formation during meiosis.</strong>
|
|
Science 337: 1222-1225, 2012.
|
|
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|
|
[PubMed: 22955832]
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|
|
[Full Text: https://doi.org/10.1126/science.1219379]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Marla J. F. O'Neill - updated : 06/03/2022<br>Ada Hamosh - updated : 01/26/2021<br>Bao Lige - updated : 08/07/2020<br>Cassandra L. Kniffin - updated : 06/07/2020<br>Ada Hamosh - updated : 02/22/2018<br>Cassandra L. Kniffin - updated : 12/18/2017<br>Cassandra L. Kniffin - updated : 12/08/2016<br>Ada Hamosh - updated : 03/04/2015<br>Ada Hamosh - updated : 10/31/2012<br>Cassandra L. Kniffin - updated : 3/2/2012<br>Ada Hamosh - updated : 9/1/2011<br>Ada Hamosh - updated : 7/26/2011<br>Ada Hamosh - updated : 10/22/2010<br>Patricia A. Hartz - updated : 8/12/2010<br>Ada Hamosh - updated : 2/18/2009<br>Ada Hamosh - updated : 6/3/2008<br>Victor A. McKusick - updated : 11/28/2007<br>Patricia A. Hartz - updated : 8/23/2007<br>Patricia A. Hartz - updated : 10/16/2006<br>George E. Tiller - updated : 9/12/2005<br>Ada Hamosh - updated : 4/15/2005<br>Ada Hamosh - updated : 5/29/2003<br>Stylianos E. Antonarakis - updated : 5/5/2003<br>Ada Hamosh - updated : 11/12/2002<br>Stylianos E. Antonarakis - updated : 11/13/2001<br>Victor A. McKusick - updated : 4/11/2001<br>Victor A. McKusick - updated : 6/12/2000<br>Moyra Smith - updated : 8/30/1996
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Victor A. McKusick : 9/28/1993
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