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Entry
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- *604094 - MITOTIC ARREST-DEFICIENT 2 LIKE 2; MAD2L2
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- OMIM
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<p>
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<span class="h4">*604094</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604094">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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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 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=ENSG00000116670;t=ENST00000376692" 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=10459" 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=604094" 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 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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</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=ENSG00000116670;t=ENST00000376692" 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_001127325,NM_006341,XM_047430782" 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_006341" 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=604094" 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=07246&isoform_id=07246_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/MAD2L2" 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/4835900,5305429,6642735,6979208,12643889,15929612,40033440,63021420,119592103,119592104,119592105,187960073,187960079,193786522,193787652,2217263186,2462502186" 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/Q9UI95" 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=10459" 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=ENSG00000116670;t=ENST00000376692" 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=MAD2L2" 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=MAD2L2" 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+10459" 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/MAD2L2" 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:10459" 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/10459" 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=chr1&hgg_gene=ENST00000376692.9&hgg_start=11674480&hgg_end=11691830&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://search.clinicalgenome.org/kb/gene-dosage/HGNC:6764" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604094[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=604094[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://gnomad.broadinstitute.org/gene/ENSG00000116670" 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=MAD2L2" 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=MAD2L2" 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=MAD2L2" 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=MAD2L2&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/PA398" 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:6764" 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/FBgn0037345.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:1919140" 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/MAD2L2#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:1919140" 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/10459/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=10459" 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://zfin.org/ZDB-GENE-050417-61" 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">
|
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<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:10459" 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=MAD2L2&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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</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>
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604094
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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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MITOTIC ARREST-DEFICIENT 2 LIKE 2; MAD2L2
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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">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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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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MITOTIC ARREST-DEFICIENT 2, S. CEREVISIAE, HOMOLOG-LIKE 2<br />
|
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MAD2B<br />
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REV7, S. CEREVISIAE, HOMOLOG OF; REV7
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</span>
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</h4>
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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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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MAD2L2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MAD2L2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/1/154?start=-3&limit=10&highlight=154">1p36.22</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:11674480-11691830&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'})">1:11,674,480-11,691,830</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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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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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover 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="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/1/154?start=-3&limit=10&highlight=154">
|
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1p36.22
|
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</a>
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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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?Fanconi anemia, complementation group V
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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</span>
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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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<a href="/entry/617243"> 617243 </a>
|
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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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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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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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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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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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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/604094" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/604094" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<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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</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="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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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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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The MAD2L2 gene encodes a protein involved in several cellular functions maintaining genomic integrity, including translesion DNA synthesis, mitotic checkpoint regulation, and DNA repair pathway choice. The gene is a subunit of the DNA polymerase-zeta complex, which acts downstream of the Fanconi anemia core proteins in the repair of DNA interstrand-crosslinking lesions (summary by <a href="#1" class="mim-tip-reference" title="Bluteau, D., Masliah-Planchon, J., Clairmont, C., Rousseau, A., Ceccaldi, R., Dubois d'Enghien, C., Bluteau, O., Cuccuini, W., Gachet, S., Peffault de Latour, R., Leblanc, T., Socie, G., Baruchel, A., Stoppa-Lyonnet, D., D'Andrea, A. D., Soulier, J. <strong>Biallelic inactivation of REV7 is associated with Fanconi anemia.</strong> J. Clin. Invest. 126: 3580-3584, 2016. Note: Erratum: J. Clin. Invest. 127: 1117 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27500492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27500492</a>] [<a href="https://doi.org/10.1172/JCI88010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27500492">Bluteau et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27500492" 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>Defects in the mitotic spindle checkpoint have been implicated in the aneuploidy observed in human cancer cells. In S. cerevisiae, members of the MAD (mitotic arrest deficient) and BUB (see BUB1, <a href="/entry/602452">602452</a>) gene families, as well as the Mps1 (see TTK, <a href="/entry/604092">604092</a>) and Cdc20 (see <a href="/entry/603618">603618</a>) genes, encode proteins that play a role in the mitotic spindle checkpoint. To further elucidate the role of mitotic checkpoint genes in human cancers, <a href="#3" class="mim-tip-reference" title="Cahill, D. P., da Costa, L. T., Carson-Walter, E. B., Kinzler, K. W., Vogelstein, B., Lengauer, C. <strong>Characterization of MAD2B and other mitotic spindle checkpoint genes.</strong> Genomics 58: 181-187, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10366450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10366450</a>] [<a href="https://doi.org/10.1006/geno.1999.5831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10366450">Cahill et al. (1999)</a> studied human homologs of these S. cerevisiae genes. By searching an EST database for sequences related to yeast Mad2 and human MAD2L1 (<a href="/entry/601467">601467</a>), they identified cDNAs encoding an additional human Mad2 homolog, which they designated MAD2B. The predicted 211-amino acid MAD2B protein shares 24% and 26% sequence identity with yeast Mad2 and human MAD2L1, respectively, in the conserved regions. RT-PCR analysis revealed that both human MAD2 homologs were expressed at similar high levels in a panel of cell lines. <a href="#3" class="mim-tip-reference" title="Cahill, D. P., da Costa, L. T., Carson-Walter, E. B., Kinzler, K. W., Vogelstein, B., Lengauer, C. <strong>Characterization of MAD2B and other mitotic spindle checkpoint genes.</strong> Genomics 58: 181-187, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10366450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10366450</a>] [<a href="https://doi.org/10.1006/geno.1999.5831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10366450">Cahill et al. (1999)</a> analyzed a panel of 19 aneuploid colorectal tumor cell lines for mutations in MAD2L1, MAD2B, and several other human homologs of yeast mitotic checkpoint genes, but failed to detect any mutations other than those previously identified in the BUB1 and BUBR1 (<a href="/entry/602860">602860</a>) genes. They concluded that these human checkpoint genes account for relatively few of the presumptive spindle checkpoint defects expected in colon cancer lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10366450" 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 a yeast 2-hybrid analysis with the cytoplasmic tails of several a disintegrin and metalloproteinase domain (ADAM) proteins as bait, <a href="#7" class="mim-tip-reference" title="Nelson, K. K., Schlondorff, J., Blobel, C. P. <strong>Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2-beta.</strong> Biochem. J. 343: 673-680, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10527948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10527948</a>]" pmid="10527948">Nelson et al. (1999)</a> found that MAD2L2 interacts with MDC9 (ADAM9; <a href="/entry/602713">602713</a>) and ADAM15 (<a href="/entry/605546">605546</a>) strongly and with ADAM19 (<a href="/entry/603640">603640</a>) weakly, but not with TACE (ADAM17; <a href="/entry/603639">603639</a>), which interacts with MAD2L1. Further binding analyses determined that the interaction of MAD2L2 with ADAM9 is mediated through a proline-rich SH3-ligand domain of ADAM9. Northern blot analysis detected 1.35-kb MAD2L2 transcripts in all tissues tested, with highest expression in testis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10527948" 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="#6" class="mim-tip-reference" title="Murakumo, Y., Ogura, Y., Ishii, H., Numata, S., Ichihara, M., Croce, C. M., Fishel, R., Takahashi, M. <strong>Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7.</strong> J. Biol. Chem. 276: 35644-35651, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11485998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11485998</a>] [<a href="https://doi.org/10.1074/jbc.M102051200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11485998">Murakumo et al. (2001)</a> noted that, in S. cerevisiae, Rev7 is involved with Rev1 (<a href="/entry/606134">606134</a>) and Rev3 (<a href="/entry/602776">602776</a>) in the error-prone translesion synthesis reaction that frequently induces mutations at damaged DNA lesions. They demonstrated direct interaction between human REV7 and REV1 and between REV7 and REV3, as well as homodimerization between REV7 molecules. Residues 21 to 155 of REV7 were involved in all of these interactions. <a href="#6" class="mim-tip-reference" title="Murakumo, Y., Ogura, Y., Ishii, H., Numata, S., Ichihara, M., Croce, C. M., Fishel, R., Takahashi, M. <strong>Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7.</strong> J. Biol. Chem. 276: 35644-35651, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11485998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11485998</a>] [<a href="https://doi.org/10.1074/jbc.M102051200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11485998">Murakumo et al. (2001)</a> hypothesized that REV7 may regulate the enzymatic activities of REV1 and REV3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11485998" 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="Boersma, V., Moatti, N., Segura-Bayona, S., Peuscher, M. H., van der Torre, J., Wevers, B. A., Orthwein, A., Durocher, D., Jacobs, J. J. L. <strong>MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5-prime end resection.</strong> Nature 521: 537-540, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25799990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25799990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25799990[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/nature14216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25799990">Boersma et al. (2015)</a> identified MAD2L2 through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres, and showed that MAD2L2 accumulates at uncapped telomeres and promotes nonhomologous end joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability. MAD2L2 depletion causes elongated 3-prime telomeric overhangs, indicating that MAD2L2 inhibits 5-prime end resection. End resection blocks NHEJ while committing to homology-directed repair, and is under the control of 53BP1 (<a href="/entry/605230">605230</a>), RIF1 (<a href="/entry/608952">608952</a>), and PTIP (<a href="/entry/608254">608254</a>). Consistent with MAD2L2 promoting NHEJ-mediated telomere fusion by inhibiting 5-prime end resection, knockdown of the nucleases CTIP (<a href="/entry/604124">604124</a>) or EXO1 (<a href="/entry/606063">606063</a>) partially restores telomere-driven genomic instability in MAD2L2-depleted cells. Control of DNA repair by MAD2L2 is not limited to telomeres, as MAD2L2 also accumulates and inhibits end resection at irradiation-induced DNA double-strand breaks and promotes end-joining of DNA double-strand breaks in several settings, including during immunoglobulin class switch recombination. These activities of MAD2L2 depend on ATM kinase activity, RNF8 (<a href="/entry/611685">611685</a>), RNF168 (<a href="/entry/612688">612688</a>), 53BP1, and RIF1, but not on PTIP, REV1, and REV3, the latter 2 acting with MAD2L2 in translesion synthesis. <a href="#2" class="mim-tip-reference" title="Boersma, V., Moatti, N., Segura-Bayona, S., Peuscher, M. H., van der Torre, J., Wevers, B. A., Orthwein, A., Durocher, D., Jacobs, J. J. L. <strong>MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5-prime end resection.</strong> Nature 521: 537-540, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25799990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25799990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25799990[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/nature14216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25799990">Boersma et al. (2015)</a> concluded that their data established MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5-prime end resection downstream of RIF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25799990" 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="Xu, G., Chapman, R., Brandsma, I., Yuan, J., Mistrik, M., Bouwman, P., Bartkova, J., Gogola, E., Warmerdam, D., Barazas, M., Jaspers, J. E., Watanabe, K., and 18 others. <strong>REV7 counteracts DNA double-strand break resection and affects PARP inhibition.</strong> Nature 521: 541-544, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25799992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25799992</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25799992[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/nature14328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25799992">Xu et al. (2015)</a> showed that loss of REV7 in mouse and human cell lines reestablishes CTIP-dependent end resection of double-strand breaks in BRCA1 (<a href="/entry/113705">113705</a>)-deficient cells, leading to homologous recombination restoration and PARP (<a href="/entry/173870">173870</a>) inhibitor resistance, which are reversed by ATM kinase (<a href="/entry/607585">607585</a>) inhibition. REV7 is recruited to double-strand breaks in a manner dependent on the H2AX (<a href="/entry/601771">601771</a>)/MDC1 (<a href="/entry/607593">607593</a>)/RNF8/RNF168/53BP1 chromatin pathway, and seems to block homologous recombination and promote end joining in addition to its regulatory role in DNA damage tolerance. <a href="#9" class="mim-tip-reference" title="Xu, G., Chapman, R., Brandsma, I., Yuan, J., Mistrik, M., Bouwman, P., Bartkova, J., Gogola, E., Warmerdam, D., Barazas, M., Jaspers, J. E., Watanabe, K., and 18 others. <strong>REV7 counteracts DNA double-strand break resection and affects PARP inhibition.</strong> Nature 521: 541-544, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25799992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25799992</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25799992[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/nature14328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25799992">Xu et al. (2015)</a> also established that REV7 blocks double-strand break resection to promote NHEJ during immunoglobulin class switch recombination. The authors concluded that their results revealed an unexpectedly crucial function of REV7 downstream of 53BP1 in coordinating pathologic double-strand break repair pathway choices in BRCA1-deficient cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25799992" 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="#8" class="mim-tip-reference" title="Noordermeer, S. M., Adam, S., Setiaputra, D., Barazas, M., Pettitt, S. J., Ling, A. K., Olivieri, M., Alvarez-Quilon, A., Moatti, N., Zimmermann, M., Annunziato, S., Krastev, D. B. <strong>{and 20 others}: The shieldin complex mediates 53BP1-dependent DNA repair.</strong> Nature 560: 117-121, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30022168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30022168</a>] [<a href="https://doi.org/10.1038/s41586-018-0340-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30022168">Noordermeer et al. (2018)</a> identified a 53BP1 effector complex, shieldin, that includes SHLD1 (<a href="/entry/618028">618028</a>), SHLD2 (<a href="/entry/618029">618029</a>), SHLD3 (<a href="/entry/618030">618030</a>), and REV7. Shieldin localizes to double-strand break sites in a 53BP1- and RIF1-dependent manner, and its SHLD2 subunit binds to single-stranded DNA via OB-fold domains that are analogous to those of RPA1 (<a href="/entry/179835">179835</a>) and POT1 (<a href="/entry/606478">606478</a>). Loss of shieldin impairs nonhomologous end joining (NHEJ), leads to defective immunoglobulin class switching, and causes hyperresection. Mutations in genes that encode shieldin subunits also cause resistance to PARP1 inhibition in BRCA1-deficient cells and tumors, owing to restoration of homologous recombination. Finally, <a href="#8" class="mim-tip-reference" title="Noordermeer, S. M., Adam, S., Setiaputra, D., Barazas, M., Pettitt, S. J., Ling, A. K., Olivieri, M., Alvarez-Quilon, A., Moatti, N., Zimmermann, M., Annunziato, S., Krastev, D. B. <strong>{and 20 others}: The shieldin complex mediates 53BP1-dependent DNA repair.</strong> Nature 560: 117-121, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30022168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30022168</a>] [<a href="https://doi.org/10.1038/s41586-018-0340-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30022168">Noordermeer et al. (2018)</a> showed that binding of single-stranded DNA by SHLD2 is critical for shieldin function, consistent with a model in which shieldin protects DNA ends to mediate 53BP1-dependent DNA repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30022168" 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="#5" class="mim-tip-reference" title="Mirman, Z., Lottersberger, F., Takai, H., Kibe, T., Gong, Y., Takai, K., Bianchi, A., Zimmermann, M., Durocher, D., de Lange, T. <strong>53BP1-RIF1-shieldin counteracts DSB resection through CST- and Pol-alpha-dependent fill-in.</strong> Nature 560: 112-116, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30022158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30022158</a>] [<a href="https://doi.org/10.1038/s41586-018-0324-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30022158">Mirman et al. (2018)</a> addressed the mechanism by which 53BP1-RIF1-shieldin regulates the generation of recombinogenic 3-prime overhangs in tumors without BRCA1. <a href="#5" class="mim-tip-reference" title="Mirman, Z., Lottersberger, F., Takai, H., Kibe, T., Gong, Y., Takai, K., Bianchi, A., Zimmermann, M., Durocher, D., de Lange, T. <strong>53BP1-RIF1-shieldin counteracts DSB resection through CST- and Pol-alpha-dependent fill-in.</strong> Nature 560: 112-116, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30022158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30022158</a>] [<a href="https://doi.org/10.1038/s41586-018-0324-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30022158">Mirman et al. (2018)</a> reported that CTC1 (<a href="/entry/613129">613129</a>)-STN1 (<a href="/entry/613128">613128</a>)-TEN1 (<a href="/entry/613130">613130</a>), a complex similar to replication protein A that functions as an accessory factor of polymerase-alpha (see POLA1, <a href="/entry/312040">312040</a>) primase (see <a href="/entry/176635">176635</a>), is a downstream effector in the 53BP1 pathway. CST, the complex of CTC1-STN1-TEN1, interacts with shieldin and localizes with Pol-alpha to sites of DNA damage in a 53BP1- and shieldin-dependent manner. As with loss of 53BP1, RIF1, or shieldin, the depletion of CST leads to increased resection. In BRCA1-deficient cells, CST blocks RAD51 (<a href="/entry/179617">179617</a>) loading and promotes the efficacy of PARP1 inhibitors. In addition, Pol-alpha inhibition diminishes the effect of PARP1 inhibitors. <a href="#5" class="mim-tip-reference" title="Mirman, Z., Lottersberger, F., Takai, H., Kibe, T., Gong, Y., Takai, K., Bianchi, A., Zimmermann, M., Durocher, D., de Lange, T. <strong>53BP1-RIF1-shieldin counteracts DSB resection through CST- and Pol-alpha-dependent fill-in.</strong> Nature 560: 112-116, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30022158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30022158</a>] [<a href="https://doi.org/10.1038/s41586-018-0324-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30022158">Mirman et al. (2018)</a> concluded that CST-Pol-alpha-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1, and shieldin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30022158" 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="Ghezraoui, H., Oliveira, C., Becker, J. R., Bilham, K., Moralli, D., Anzilotti, C., Fischer, R., Deobagkar-Lele, M., Sanchiz-Calvo, M., Fueyo-Marcos, E., Bonham, S., Kessler, B. M., Rottenberg, S., Cornall, R. J., Green, C. M., Chapman, J. R. <strong>53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ.</strong> Nature 560: 122-127, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30046110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30046110</a>] [<a href="https://doi.org/10.1038/s41586-018-0362-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30046110">Ghezraoui et al. (2018)</a> reported that 53BP1 cooperates with its downstream effector protein REV7 to promote NHEJ during class switch recombination, but REV7 is not required for 53BP1-dependent V(D)J recombination. The authors identified the single-stranded DNA-binding complex shieldin as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end protection and NHEJ during class switch recombination, and supports toxic NHEJ in Brca1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link repair. The 53BP1 pathway therefore comprises distinct double-strand break repair activities within chromatin and single-stranded DNA compartments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30046110" 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>By analysis of a radiation hybrid panel, <a href="#3" class="mim-tip-reference" title="Cahill, D. P., da Costa, L. T., Carson-Walter, E. B., Kinzler, K. W., Vogelstein, B., Lengauer, C. <strong>Characterization of MAD2B and other mitotic spindle checkpoint genes.</strong> Genomics 58: 181-187, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10366450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10366450</a>] [<a href="https://doi.org/10.1006/geno.1999.5831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10366450">Cahill et al. (1999)</a> mapped the MAD2B gene to chromosome 1p36, a region that is commonly deleted in a variety of cancers. They identified a MAD2 pseudogene at 14q21-q23. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10366450" 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 girl with Fanconi anemia of complementation group V (FANCV; <a href="/entry/617243">617243</a>), <a href="#1" class="mim-tip-reference" title="Bluteau, D., Masliah-Planchon, J., Clairmont, C., Rousseau, A., Ceccaldi, R., Dubois d'Enghien, C., Bluteau, O., Cuccuini, W., Gachet, S., Peffault de Latour, R., Leblanc, T., Socie, G., Baruchel, A., Stoppa-Lyonnet, D., D'Andrea, A. D., Soulier, J. <strong>Biallelic inactivation of REV7 is associated with Fanconi anemia.</strong> J. Clin. Invest. 126: 3580-3584, 2016. Note: Erratum: J. Clin. Invest. 127: 1117 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27500492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27500492</a>] [<a href="https://doi.org/10.1172/JCI88010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27500492">Bluteau et al. (2016)</a> identified a homozygous missense mutation in the MAD2L2 gene (V85E; <a href="#0001">604094.0001</a>). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro studies demonstrated that the mutation was pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27500492" 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://www.ncbi.nlm.nih.gov/clinvar?term=604094[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">rs1057517674 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057517674;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=rs1057517674" 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=rs1057517674" 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=RCV000412563 OR RCV001194790" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000412563, RCV001194790" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000412563...</a>
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<p>In an 8-year-old girl (patient EGF123) with Fanconi anemia of complementation group V (FANCV; <a href="/entry/617243">617243</a>), <a href="#1" class="mim-tip-reference" title="Bluteau, D., Masliah-Planchon, J., Clairmont, C., Rousseau, A., Ceccaldi, R., Dubois d'Enghien, C., Bluteau, O., Cuccuini, W., Gachet, S., Peffault de Latour, R., Leblanc, T., Socie, G., Baruchel, A., Stoppa-Lyonnet, D., D'Andrea, A. D., Soulier, J. <strong>Biallelic inactivation of REV7 is associated with Fanconi anemia.</strong> J. Clin. Invest. 126: 3580-3584, 2016. Note: Erratum: J. Clin. Invest. 127: 1117 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27500492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27500492</a>] [<a href="https://doi.org/10.1172/JCI88010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27500492">Bluteau et al. (2016)</a> identified a homozygous c.254T-A transversion (c.254T-A, NM_006341.3) in the MAD2L2 gene, resulting in a val85-to-glu (V85E) substitution at a highly conserved residue in the HORMA domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Patient cells showed absence of the REV7 protein despite normal transcript levels, suggesting that the mutation results in destabilization of the protein. Expression of wildtype REV7 rescued the chromosomal breakage, cell cycle arrest, and cell proliferation defects observed in patient cells. Knockdown of the REV7 gene in cultured cells resulted in increased chromosome breaks and cellular sensitivity to mitomycin C, as well as G2/M cell cycle arrest. Knockdown of the Rev7 gene in murine hematopoietic cells impaired their ability to form CFU in vitro, consistent with a DNA damage-mediated mechanism of bone marrow failure. Patient cells and Rev7-null cells showed normal monoubiquitination of FANCD2 (<a href="/entry/613984">613984</a>), suggesting an abnormality downstream of the FA core complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27500492" 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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Bluteau, D., Masliah-Planchon, J., Clairmont, C., Rousseau, A., Ceccaldi, R., Dubois d'Enghien, C., Bluteau, O., Cuccuini, W., Gachet, S., Peffault de Latour, R., Leblanc, T., Socie, G., Baruchel, A., Stoppa-Lyonnet, D., D'Andrea, A. D., Soulier, J.
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<strong>Biallelic inactivation of REV7 is associated with Fanconi anemia.</strong>
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J. Clin. Invest. 126: 3580-3584, 2016. Note: Erratum: J. Clin. Invest. 127: 1117 only, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27500492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27500492</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27500492" 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/10.1172/JCI88010" target="_blank">Full Text</a>]
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Boersma, V., Moatti, N., Segura-Bayona, S., Peuscher, M. H., van der Torre, J., Wevers, B. A., Orthwein, A., Durocher, D., Jacobs, J. J. L.
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<strong>MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5-prime end resection.</strong>
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Nature 521: 537-540, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25799990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25799990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25799990[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=25799990" 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/nature14216" target="_blank">Full Text</a>]
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Cahill, D. P., da Costa, L. T., Carson-Walter, E. B., Kinzler, K. W., Vogelstein, B., Lengauer, C.
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<strong>Characterization of MAD2B and other mitotic spindle checkpoint genes.</strong>
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Genomics 58: 181-187, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10366450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10366450</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10366450" 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/10.1006/geno.1999.5831" target="_blank">Full Text</a>]
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Ghezraoui, H., Oliveira, C., Becker, J. R., Bilham, K., Moralli, D., Anzilotti, C., Fischer, R., Deobagkar-Lele, M., Sanchiz-Calvo, M., Fueyo-Marcos, E., Bonham, S., Kessler, B. M., Rottenberg, S., Cornall, R. J., Green, C. M., Chapman, J. R.
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<strong>53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ.</strong>
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Nature 560: 122-127, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30046110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30046110</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30046110" 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/s41586-018-0362-1" target="_blank">Full Text</a>]
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Mirman, Z., Lottersberger, F., Takai, H., Kibe, T., Gong, Y., Takai, K., Bianchi, A., Zimmermann, M., Durocher, D., de Lange, T.
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<strong>53BP1-RIF1-shieldin counteracts DSB resection through CST- and Pol-alpha-dependent fill-in.</strong>
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Nature 560: 112-116, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30022158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30022158</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30022158" 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/s41586-018-0324-7" target="_blank">Full Text</a>]
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Murakumo, Y., Ogura, Y., Ishii, H., Numata, S., Ichihara, M., Croce, C. M., Fishel, R., Takahashi, M.
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<strong>Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7.</strong>
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J. Biol. Chem. 276: 35644-35651, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11485998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11485998</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11485998" 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.M102051200" target="_blank">Full Text</a>]
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<a id="Nelson1999" class="mim-anchor"></a>
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<p class="mim-text-font">
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Nelson, K. K., Schlondorff, J., Blobel, C. P.
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<strong>Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2-beta.</strong>
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Biochem. J. 343: 673-680, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10527948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10527948</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10527948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Noordermeer2018" class="mim-anchor"></a>
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Noordermeer, S. M., Adam, S., Setiaputra, D., Barazas, M., Pettitt, S. J., Ling, A. K., Olivieri, M., Alvarez-Quilon, A., Moatti, N., Zimmermann, M., Annunziato, S., Krastev, D. B.
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<strong>{and 20 others}: The shieldin complex mediates 53BP1-dependent DNA repair.</strong>
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Nature 560: 117-121, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30022168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30022168</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30022168" 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/s41586-018-0340-7" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Xu2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xu, G., Chapman, R., Brandsma, I., Yuan, J., Mistrik, M., Bouwman, P., Bartkova, J., Gogola, E., Warmerdam, D., Barazas, M., Jaspers, J. E., Watanabe, K., and 18 others.
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<strong>REV7 counteracts DNA double-strand break resection and affects PARP inhibition.</strong>
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Nature 521: 541-544, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25799992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25799992</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25799992[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=25799992" 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/nature14328" 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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Ada Hamosh - updated : 09/19/2018
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/08/2016<br>Ada Hamosh - updated : 06/24/2015<br>Patricia A. Hartz - updated : 3/10/2003<br>Paul J. Converse - updated : 12/11/2000
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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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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Rebekah S. Rasooly : 8/2/1999
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carol : 08/23/2019
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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alopez : 09/19/2018<br>carol : 01/25/2018<br>carol : 01/24/2018<br>carol : 12/19/2016<br>carol : 12/10/2016<br>carol : 12/09/2016<br>ckniffin : 12/08/2016<br>carol : 09/28/2016<br>alopez : 06/24/2015<br>mgross : 3/13/2003<br>terry : 3/10/2003<br>mgross : 1/11/2001<br>mgross : 12/13/2000<br>mgross : 12/13/2000<br>terry : 12/11/2000<br>mgross : 8/2/1999
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<span class="mim-font">
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<strong>*</strong> 604094
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MITOTIC ARREST-DEFICIENT 2 LIKE 2; MAD2L2
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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MITOTIC ARREST-DEFICIENT 2, S. CEREVISIAE, HOMOLOG-LIKE 2<br />
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MAD2B<br />
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REV7, S. CEREVISIAE, HOMOLOG OF; REV7
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MAD2L2</em></strong>
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Cytogenetic location: 1p36.22
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:11,674,480-11,691,830 </span>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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1p36.22
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<span class="mim-font">
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?Fanconi anemia, complementation group V
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<span class="mim-font">
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617243
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<span class="mim-font">
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Autosomal recessive
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<td>
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The MAD2L2 gene encodes a protein involved in several cellular functions maintaining genomic integrity, including translesion DNA synthesis, mitotic checkpoint regulation, and DNA repair pathway choice. The gene is a subunit of the DNA polymerase-zeta complex, which acts downstream of the Fanconi anemia core proteins in the repair of DNA interstrand-crosslinking lesions (summary by Bluteau et al., 2016). </p>
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<strong>Cloning and Expression</strong>
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<p>Defects in the mitotic spindle checkpoint have been implicated in the aneuploidy observed in human cancer cells. In S. cerevisiae, members of the MAD (mitotic arrest deficient) and BUB (see BUB1, 602452) gene families, as well as the Mps1 (see TTK, 604092) and Cdc20 (see 603618) genes, encode proteins that play a role in the mitotic spindle checkpoint. To further elucidate the role of mitotic checkpoint genes in human cancers, Cahill et al. (1999) studied human homologs of these S. cerevisiae genes. By searching an EST database for sequences related to yeast Mad2 and human MAD2L1 (601467), they identified cDNAs encoding an additional human Mad2 homolog, which they designated MAD2B. The predicted 211-amino acid MAD2B protein shares 24% and 26% sequence identity with yeast Mad2 and human MAD2L1, respectively, in the conserved regions. RT-PCR analysis revealed that both human MAD2 homologs were expressed at similar high levels in a panel of cell lines. Cahill et al. (1999) analyzed a panel of 19 aneuploid colorectal tumor cell lines for mutations in MAD2L1, MAD2B, and several other human homologs of yeast mitotic checkpoint genes, but failed to detect any mutations other than those previously identified in the BUB1 and BUBR1 (602860) genes. They concluded that these human checkpoint genes account for relatively few of the presumptive spindle checkpoint defects expected in colon cancer lines. </p>
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Using a yeast 2-hybrid analysis with the cytoplasmic tails of several a disintegrin and metalloproteinase domain (ADAM) proteins as bait, Nelson et al. (1999) found that MAD2L2 interacts with MDC9 (ADAM9; 602713) and ADAM15 (605546) strongly and with ADAM19 (603640) weakly, but not with TACE (ADAM17; 603639), which interacts with MAD2L1. Further binding analyses determined that the interaction of MAD2L2 with ADAM9 is mediated through a proline-rich SH3-ligand domain of ADAM9. Northern blot analysis detected 1.35-kb MAD2L2 transcripts in all tissues tested, with highest expression in testis. </p><p>Murakumo et al. (2001) noted that, in S. cerevisiae, Rev7 is involved with Rev1 (606134) and Rev3 (602776) in the error-prone translesion synthesis reaction that frequently induces mutations at damaged DNA lesions. They demonstrated direct interaction between human REV7 and REV1 and between REV7 and REV3, as well as homodimerization between REV7 molecules. Residues 21 to 155 of REV7 were involved in all of these interactions. Murakumo et al. (2001) hypothesized that REV7 may regulate the enzymatic activities of REV1 and REV3. </p><p>Boersma et al. (2015) identified MAD2L2 through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres, and showed that MAD2L2 accumulates at uncapped telomeres and promotes nonhomologous end joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability. MAD2L2 depletion causes elongated 3-prime telomeric overhangs, indicating that MAD2L2 inhibits 5-prime end resection. End resection blocks NHEJ while committing to homology-directed repair, and is under the control of 53BP1 (605230), RIF1 (608952), and PTIP (608254). Consistent with MAD2L2 promoting NHEJ-mediated telomere fusion by inhibiting 5-prime end resection, knockdown of the nucleases CTIP (604124) or EXO1 (606063) partially restores telomere-driven genomic instability in MAD2L2-depleted cells. Control of DNA repair by MAD2L2 is not limited to telomeres, as MAD2L2 also accumulates and inhibits end resection at irradiation-induced DNA double-strand breaks and promotes end-joining of DNA double-strand breaks in several settings, including during immunoglobulin class switch recombination. These activities of MAD2L2 depend on ATM kinase activity, RNF8 (611685), RNF168 (612688), 53BP1, and RIF1, but not on PTIP, REV1, and REV3, the latter 2 acting with MAD2L2 in translesion synthesis. Boersma et al. (2015) concluded that their data established MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5-prime end resection downstream of RIF1. </p><p>Xu et al. (2015) showed that loss of REV7 in mouse and human cell lines reestablishes CTIP-dependent end resection of double-strand breaks in BRCA1 (113705)-deficient cells, leading to homologous recombination restoration and PARP (173870) inhibitor resistance, which are reversed by ATM kinase (607585) inhibition. REV7 is recruited to double-strand breaks in a manner dependent on the H2AX (601771)/MDC1 (607593)/RNF8/RNF168/53BP1 chromatin pathway, and seems to block homologous recombination and promote end joining in addition to its regulatory role in DNA damage tolerance. Xu et al. (2015) also established that REV7 blocks double-strand break resection to promote NHEJ during immunoglobulin class switch recombination. The authors concluded that their results revealed an unexpectedly crucial function of REV7 downstream of 53BP1 in coordinating pathologic double-strand break repair pathway choices in BRCA1-deficient cells. </p><p>Noordermeer et al. (2018) identified a 53BP1 effector complex, shieldin, that includes SHLD1 (618028), SHLD2 (618029), SHLD3 (618030), and REV7. Shieldin localizes to double-strand break sites in a 53BP1- and RIF1-dependent manner, and its SHLD2 subunit binds to single-stranded DNA via OB-fold domains that are analogous to those of RPA1 (179835) and POT1 (606478). Loss of shieldin impairs nonhomologous end joining (NHEJ), leads to defective immunoglobulin class switching, and causes hyperresection. Mutations in genes that encode shieldin subunits also cause resistance to PARP1 inhibition in BRCA1-deficient cells and tumors, owing to restoration of homologous recombination. Finally, Noordermeer et al. (2018) showed that binding of single-stranded DNA by SHLD2 is critical for shieldin function, consistent with a model in which shieldin protects DNA ends to mediate 53BP1-dependent DNA repair. </p><p>Mirman et al. (2018) addressed the mechanism by which 53BP1-RIF1-shieldin regulates the generation of recombinogenic 3-prime overhangs in tumors without BRCA1. Mirman et al. (2018) reported that CTC1 (613129)-STN1 (613128)-TEN1 (613130), a complex similar to replication protein A that functions as an accessory factor of polymerase-alpha (see POLA1, 312040) primase (see 176635), is a downstream effector in the 53BP1 pathway. CST, the complex of CTC1-STN1-TEN1, interacts with shieldin and localizes with Pol-alpha to sites of DNA damage in a 53BP1- and shieldin-dependent manner. As with loss of 53BP1, RIF1, or shieldin, the depletion of CST leads to increased resection. In BRCA1-deficient cells, CST blocks RAD51 (179617) loading and promotes the efficacy of PARP1 inhibitors. In addition, Pol-alpha inhibition diminishes the effect of PARP1 inhibitors. Mirman et al. (2018) concluded that CST-Pol-alpha-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1, and shieldin. </p><p>Ghezraoui et al. (2018) reported that 53BP1 cooperates with its downstream effector protein REV7 to promote NHEJ during class switch recombination, but REV7 is not required for 53BP1-dependent V(D)J recombination. The authors identified the single-stranded DNA-binding complex shieldin as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end protection and NHEJ during class switch recombination, and supports toxic NHEJ in Brca1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link repair. The 53BP1 pathway therefore comprises distinct double-strand break repair activities within chromatin and single-stranded DNA compartments. </p>
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<div>
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<br />
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>By analysis of a radiation hybrid panel, Cahill et al. (1999) mapped the MAD2B gene to chromosome 1p36, a region that is commonly deleted in a variety of cancers. They identified a MAD2 pseudogene at 14q21-q23. </p>
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<strong>Molecular Genetics</strong>
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<p>In a girl with Fanconi anemia of complementation group V (FANCV; 617243), Bluteau et al. (2016) identified a homozygous missense mutation in the MAD2L2 gene (V85E; 604094.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro studies demonstrated that the mutation was pathogenic. </p>
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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>1 Selected Example):</strong>
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</h4>
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<span class="mim-font">
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<strong>.0001 FANCONI ANEMIA, COMPLEMENTATION GROUP V (1 patient)</strong>
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MAD2L2, VAL85GLU
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<br />
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SNP: rs1057517674,
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ClinVar: RCV000412563, RCV001194790
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<p>In an 8-year-old girl (patient EGF123) with Fanconi anemia of complementation group V (FANCV; 617243), Bluteau et al. (2016) identified a homozygous c.254T-A transversion (c.254T-A, NM_006341.3) in the MAD2L2 gene, resulting in a val85-to-glu (V85E) substitution at a highly conserved residue in the HORMA domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Patient cells showed absence of the REV7 protein despite normal transcript levels, suggesting that the mutation results in destabilization of the protein. Expression of wildtype REV7 rescued the chromosomal breakage, cell cycle arrest, and cell proliferation defects observed in patient cells. Knockdown of the REV7 gene in cultured cells resulted in increased chromosome breaks and cellular sensitivity to mitomycin C, as well as G2/M cell cycle arrest. Knockdown of the Rev7 gene in murine hematopoietic cells impaired their ability to form CFU in vitro, consistent with a DNA damage-mediated mechanism of bone marrow failure. Patient cells and Rev7-null cells showed normal monoubiquitination of FANCD2 (613984), suggesting an abnormality downstream of the FA core complex. </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>REFERENCES</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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<ol>
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<li>
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<p class="mim-text-font">
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Bluteau, D., Masliah-Planchon, J., Clairmont, C., Rousseau, A., Ceccaldi, R., Dubois d'Enghien, C., Bluteau, O., Cuccuini, W., Gachet, S., Peffault de Latour, R., Leblanc, T., Socie, G., Baruchel, A., Stoppa-Lyonnet, D., D'Andrea, A. D., Soulier, J.
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<strong>Biallelic inactivation of REV7 is associated with Fanconi anemia.</strong>
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J. Clin. Invest. 126: 3580-3584, 2016. Note: Erratum: J. Clin. Invest. 127: 1117 only, 2017.
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[PubMed: 27500492]
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[Full Text: https://doi.org/10.1172/JCI88010]
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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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Boersma, V., Moatti, N., Segura-Bayona, S., Peuscher, M. H., van der Torre, J., Wevers, B. A., Orthwein, A., Durocher, D., Jacobs, J. J. L.
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<strong>MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5-prime end resection.</strong>
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Nature 521: 537-540, 2015.
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[PubMed: 25799990]
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[Full Text: https://doi.org/10.1038/nature14216]
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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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Cahill, D. P., da Costa, L. T., Carson-Walter, E. B., Kinzler, K. W., Vogelstein, B., Lengauer, C.
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<strong>Characterization of MAD2B and other mitotic spindle checkpoint genes.</strong>
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Genomics 58: 181-187, 1999.
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[PubMed: 10366450]
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[Full Text: https://doi.org/10.1006/geno.1999.5831]
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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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Ghezraoui, H., Oliveira, C., Becker, J. R., Bilham, K., Moralli, D., Anzilotti, C., Fischer, R., Deobagkar-Lele, M., Sanchiz-Calvo, M., Fueyo-Marcos, E., Bonham, S., Kessler, B. M., Rottenberg, S., Cornall, R. J., Green, C. M., Chapman, J. R.
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<strong>53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ.</strong>
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Nature 560: 122-127, 2018.
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[PubMed: 30046110]
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[Full Text: https://doi.org/10.1038/s41586-018-0362-1]
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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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Mirman, Z., Lottersberger, F., Takai, H., Kibe, T., Gong, Y., Takai, K., Bianchi, A., Zimmermann, M., Durocher, D., de Lange, T.
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<strong>53BP1-RIF1-shieldin counteracts DSB resection through CST- and Pol-alpha-dependent fill-in.</strong>
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Nature 560: 112-116, 2018.
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[PubMed: 30022158]
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[Full Text: https://doi.org/10.1038/s41586-018-0324-7]
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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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Murakumo, Y., Ogura, Y., Ishii, H., Numata, S., Ichihara, M., Croce, C. M., Fishel, R., Takahashi, M.
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<strong>Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7.</strong>
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J. Biol. Chem. 276: 35644-35651, 2001.
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[PubMed: 11485998]
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[Full Text: https://doi.org/10.1074/jbc.M102051200]
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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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Nelson, K. K., Schlondorff, J., Blobel, C. P.
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<strong>Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2-beta.</strong>
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Biochem. J. 343: 673-680, 1999.
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[PubMed: 10527948]
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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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Noordermeer, S. M., Adam, S., Setiaputra, D., Barazas, M., Pettitt, S. J., Ling, A. K., Olivieri, M., Alvarez-Quilon, A., Moatti, N., Zimmermann, M., Annunziato, S., Krastev, D. B.
|
|
<strong>{and 20 others}: The shieldin complex mediates 53BP1-dependent DNA repair.</strong>
|
|
Nature 560: 117-121, 2018.
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[PubMed: 30022168]
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[Full Text: https://doi.org/10.1038/s41586-018-0340-7]
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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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Xu, G., Chapman, R., Brandsma, I., Yuan, J., Mistrik, M., Bouwman, P., Bartkova, J., Gogola, E., Warmerdam, D., Barazas, M., Jaspers, J. E., Watanabe, K., and 18 others.
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<strong>REV7 counteracts DNA double-strand break resection and affects PARP inhibition.</strong>
|
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Nature 521: 541-544, 2015.
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[PubMed: 25799992]
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[Full Text: https://doi.org/10.1038/nature14328]
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</p>
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</li>
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</ol>
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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 class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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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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Ada Hamosh - updated : 09/19/2018<br>Cassandra L. Kniffin - updated : 12/08/2016<br>Ada Hamosh - updated : 06/24/2015<br>Patricia A. Hartz - updated : 3/10/2003<br>Paul J. Converse - updated : 12/11/2000
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</span>
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<br />
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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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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Rebekah S. Rasooly : 8/2/1999
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<span class="text-nowrap mim-text-font">
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Edit History:
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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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carol : 08/23/2019<br>alopez : 09/19/2018<br>carol : 01/25/2018<br>carol : 01/24/2018<br>carol : 12/19/2016<br>carol : 12/10/2016<br>carol : 12/09/2016<br>ckniffin : 12/08/2016<br>carol : 09/28/2016<br>alopez : 06/24/2015<br>mgross : 3/13/2003<br>terry : 3/10/2003<br>mgross : 1/11/2001<br>mgross : 12/13/2000<br>mgross : 12/13/2000<br>terry : 12/11/2000<br>mgross : 8/2/1999
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</span>
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