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Entry
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- *613984 - FANCD2 GENE; FANCD2
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- OMIM
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<p>
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<span class="h4">*613984</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/613984">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>
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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>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000144554;t=ENST00000675286" 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=2177" 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=613984" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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<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=ENSG00000144554;t=ENST00000675286" 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_001018115,NM_001319984,NM_001374253,NM_001374254,NM_001374255,NM_033084" 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_001018115" 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=613984" 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://www.proteinatlas.org/search/FANCD2" 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/10434106,13183881,13324523,15718476,21361861,34189662,50949457,66528888,84872752,119584459,119584460,119584461,119584462,727863575,987437912,1741710811,1741710849,1741710875" 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/Q9BXW9" 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=2177" 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=ENSG00000144554;t=ENST00000675286" 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=FANCD2" 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=FANCD2" 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+2177" 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/FANCD2" 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:2177" 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/2177" 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=chr3&hgg_gene=ENST00000675286.1&hgg_start=10026437&hgg_end=10101932&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:3585" 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://search.clinicalgenome.org/kb/genes/HGNC:3585" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=613984[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=613984[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/FANCD2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000144554" 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=FANCD2" 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=FANCD2" 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=FANCD2" 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=FANCD2&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/PA27999" 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:3585" 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/FBgn0038827.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:2448480" 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/FANCD2#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:2448480" 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/2177/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=2177" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00012767;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040116-5" 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:2177" 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=FANCD2&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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613984
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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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FANCD2 GENE; FANCD2
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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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<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=FANCD2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FANCD2</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/3/49?start=-3&limit=10&highlight=49">3p25.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:10026437-10101932&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'})">3:10,026,437-10,101,932</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/3/49?start=-3&limit=10&highlight=49">
|
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3p25.3
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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 D2
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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/227646"> 227646 </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">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/613984" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/613984" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="cloning" class="mim-anchor"></a>
|
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>By the study of a panel of somatic cell hybrids constructed using polyethylene glycol as a fusigen, <a href="#17" class="mim-tip-reference" title="Strathdee, C. A., Duncan, A. M. V., Buchwald, M. <strong>Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9.</strong> Nature Genet. 1: 196-198, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303234</a>] [<a href="https://doi.org/10.1038/ng0692-196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303234">Strathdee et al. (1992)</a> identified 4 complementation groups, suggesting that there are at least 4 different FA genes, mutations at any one of which can cause the Fanconi anemia phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1303234" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Timmers, C., Taniguchi, T., Hejna, J., Reifsteck, C., Lucas, L., Bruun, D., Thayer, M., Cox, B., Olson, S., D'Andrea, A. D., Moses, R., Grompe, M. <strong>Positional cloning of a novel Fanconi anemia gene, FANCD2.</strong> Molec. Cell 7: 241-248, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239453</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239453">Timmers et al. (2001)</a> presented evidence that FA complementation group D is heterogeneous, consisting of 2 distinct genes, FANCD1 (<a href="/entry/600185">600185</a>) and FANCD2. They reported positional cloning of the FANCD2 gene, which encodes a 1,451-amino acid nuclear protein, has 2 protein isoforms, and maps to 3p. Similar to other FA proteins, the FANCD2 protein had no known functional domains. However, unlike other FA genes, FANCD2 is highly conserved in A. thaliana, C. elegans, and Drosophila. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Garcia-Higuera, I., Taniguchi, T., Ganesan, S., Meyn, M. S., Timmers, C., Hejna, J., Grompe, M., D'Andrea, A. D. <strong>Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.</strong> Molec. Cell 7: 249-262, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239454</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00173-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239454">Garcia-Higuera et al. (2001)</a> showed that a nuclear complex containing the FANCA (<a href="/entry/607139">607139</a>), FANCC (<a href="/entry/613899">613899</a>), FANCF (<a href="/entry/613897">613897</a>), and FANCG (<a href="/entry/602956">602956</a>) proteins is required for the activation of the FANCD2 protein to a monoubiquitinated isoform. In normal cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with the breast cancer susceptibility protein, BRCA1 (<a href="/entry/113705">113705</a>), in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The authors concluded that the FANCD2 protein therefore provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all subtypes of FA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239454" 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="#18" class="mim-tip-reference" title="Taniguchi, T., Garcia-Higuera, I., Xu, B., Andreassen, P. R., Gregory, R. C., Kim, S.-T., Lane, W. S., Kastan, M. B., D'Andrea, A. D. <strong>Convergence of the Fanconi anemia and ataxia telangiectasia signaling pathways.</strong> Cell 109: 459-472, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12086603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12086603</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00747-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12086603">Taniguchi et al. (2002)</a> identified FANCD2 as a link between the FA and ATM (<a href="/entry/607585">607585</a>) damage response pathways. ATM phosphorylated FANCD2 on ser222 in vitro. This site was also phosphorylated in vivo in an ATM-dependent manner following ionizing radiation. Phosphorylation of FANCD2 was required for activation of an S-phase checkpoint. The authors determined that the ATM-dependent phosphorylation of FANCD2 on ser222 and the FA pathway-dependent monoubiquitination of FANCD2 on lys561 are independent posttranslational modifications regulating discrete cellular signaling pathways. Biallelic disruption of FANCD2 resulted in both mitomycin C (MMC) and ionizing radiation hypersensitivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12086603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By coimmunoprecipitation, <a href="#15" class="mim-tip-reference" title="Nakanishi, K., Taniguchi, T., Ranganathan, V., New, H. V., Moreau, L. A., Stotsky, M., Mathew, C. G., Kastan, M. B., Weaver, D. T., D'Andrea, A. D. <strong>Interaction of FANCD2 and NBS1 in the DNA damage response.</strong> Nature Cell Biol. 4: 913-920, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447395</a>] [<a href="https://doi.org/10.1038/ncb879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447395">Nakanishi et al. (2002)</a> found constitutive interaction between FANCD2 and NBS1 (<a href="/entry/602667">602667</a>), and they provided evidence that these proteins interact in 2 distinct assemblies to mediate S-phase checkpoint and resistance to MMC-induced chromosome damage. NBS1, ATM, and MRE11 (<a href="/entry/600814">600814</a>) were required for FANCD2 phosphorylation in response to radiation-induced S-phase checkpoint. The assembly of NBS1, MRE11, RAD50 (<a href="/entry/604040">604040</a>), and FANCD2 within nuclear foci was required for MMC resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447395" 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="Hussain, S., Wilson, J. B., Medhurst, A. L., Hejna, J., Witt, E., Ananth, S., Davies, A., Masson, J. Y., Moses, R., West, S. C., de Winter, J. P., Ashworth, A., Jones, N. J., Mathew, C. G. <strong>Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways.</strong> Hum. Molec. Genet. 13: 1241-1248, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115758</a>] [<a href="https://doi.org/10.1093/hmg/ddh135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115758">Hussain et al. (2004)</a> used yeast 2-hybrid analysis to test for interaction between FANCD2 and several proteins involved in homologous recombination repair. FANCD2 did not interact with RAD51 (<a href="/entry/179617">179617</a>), the 5 RAD51 paralogs (see <a href="/entry/602774">602774</a>), RAD52 (<a href="/entry/600392">600392</a>), RAD54 (<a href="/entry/600392">600392</a>), or DMC1 (<a href="/entry/602721">602721</a>). However, it bound to a highly conserved C-terminal site in BRCA2 (<a href="/entry/600185">600185</a>) that also bound FANCG/XRCC9 (<a href="/entry/602956">602956</a>). FANCD2 and BRCA2 coimmunoprecipitated from cell extracts of both human and Chinese hamster wildtype cells, thus confirming that the interaction occurs in vivo. Formation of nuclear foci of FANCD2 was normal in the BRCA2 mutant CAPAN-1 cells, suggesting that recruitment of FANCD2 to sites of DNA repair is independent of wildtype BRCA2 function. FANCD2 colocalized with RAD51 in foci following treatment with MMC or hydroxyurea, and colocalized very tightly with PCNA (<a href="/entry/176740">176740</a>) after treatment with hydroxyurea. <a href="#5" class="mim-tip-reference" title="Hussain, S., Wilson, J. B., Medhurst, A. L., Hejna, J., Witt, E., Ananth, S., Davies, A., Masson, J. Y., Moses, R., West, S. C., de Winter, J. P., Ashworth, A., Jones, N. J., Mathew, C. G. <strong>Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways.</strong> Hum. Molec. Genet. 13: 1241-1248, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115758</a>] [<a href="https://doi.org/10.1093/hmg/ddh135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115758">Hussain et al. (2004)</a> suggested that FANCD2 may have a role in the cellular response to stalled replication forks or in the repair of replication-associated double-strand breaks, irrespective of the type of primary DNA lesion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15115758" 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="#23" class="mim-tip-reference" title="Wilson, J. B., Yamamoto, K., Marriott, A. S., Hussain, S., Sung, P., Hoatlin, M. E., Mathew, C. G., Takata, M., Thompson, L. H., Kupfer, G. M., Jones, N. J. <strong>FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3.</strong> Oncogene 27: 3641-3652, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18212739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18212739</a>] [<a href="https://doi.org/10.1038/sj.onc.1211034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18212739">Wilson et al. (2008)</a> found that XRCC3 (<a href="/entry/600675">600675</a>), BRCA2, FANCD2, and FANCG formed a complex via multiple pairwise interactions following phosphorylation of FANCG. They proposed that a complex made up of at least these 4 proteins promotes homologous recombination repair of damaged DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18212739" 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="Howlett, N. G., Taniguchi, T., Durkin, S. G., D'Andrea, A. D., Glover, T. W. <strong>The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability.</strong> Hum. Molec. Genet. 14: 693-701, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15661754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15661754</a>] [<a href="https://doi.org/10.1093/hmg/ddi065" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15661754">Howlett et al. (2005)</a> showed that the FA pathway was strongly activated in response to DNA replicative stress by aphidicolin (APH) and hydroxyurea. Using patient-derived FA cell lines and siRNA targeting FANCD2, the authors demonstrated a functional requirement for the FA pathway in response to low doses of APH. Both the total number of chromosome gaps and breaks and the number of breaks at FRA3B (FHIT; <a href="/entry/601153">601153</a>) and FRA16D (WWOX; <a href="/entry/605131">605131</a>) fragile sites were significantly elevated in the absence of an intact FA pathway. Furthermore, APH activated monoubiquitination of both FANCD2 and PCNA (<a href="/entry/176740">176740</a>) and the phosphorylation of RPA2 (<a href="/entry/179836">179836</a>), signaling processive DNA replication arrest. Following APH treatment, FANCD2-Ub colocalized with PCNA after 4 hours and with RPA2 after 24 hours in discrete nuclear foci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15661754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By covalent modification and expression of recombinant chicken Fancd2 in chicken B-cell lines, <a href="#12" class="mim-tip-reference" title="Matsushita, N., Kitao, H., Ishiai, M., Nagashima, N., Hirano, S., Okawa, K., Ohta, T., Yu, D. S., McHugh, P. J., Hickson, I. D., Venkitaraman, A. R., Kurumizaka, H., Takata, M. <strong>A FancD2-monoubiquitin fusion reveals hidden functions of Fanconi anemia core complex in DNA repair.</strong> Molec. Cell 19: 841-847, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16168378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16168378</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16168378">Matsushita et al. (2005)</a> found that Fancc, Fancg, and Fancl (<a href="/entry/608111">608111</a>) were an integral part of the FA core complex and were necessary for Fancd2 monoubiquitination. These FA core complex proteins were also required for chromatin targeting of monoubiquitinated Fancd2 and for proper function of chromatin-bound Fancd2 in DNA repair. <a href="#12" class="mim-tip-reference" title="Matsushita, N., Kitao, H., Ishiai, M., Nagashima, N., Hirano, S., Okawa, K., Ohta, T., Yu, D. S., McHugh, P. J., Hickson, I. D., Venkitaraman, A. R., Kurumizaka, H., Takata, M. <strong>A FancD2-monoubiquitin fusion reveals hidden functions of Fanconi anemia core complex in DNA repair.</strong> Molec. Cell 19: 841-847, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16168378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16168378</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16168378">Matsushita et al. (2005)</a> suggested that the monoubiquitin moiety on FANCD2 may function primarily as a chromatin targeting signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16168378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using normal human fibroblasts depleted of ERCC1 (<a href="/entry/126380">126380</a>) via small interfering RNA and fibroblasts from FA patients, <a href="#13" class="mim-tip-reference" title="McCabe, K. M., Hemphill, A., Akkari, Y., Jakobs, P. M., Pauw, D., Olson, S. B., Moses, R. E., Grompe, M. <strong>ERCC1 is required for FANCD2 focus formation.</strong> Molec. Genet. Metab. 95: 66-73, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18672388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18672388</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18672388[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2008.06.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18672388">McCabe et al. (2008)</a> showed that ERCC1 was required for both monoubiquitination of FANCD2 and the accumulation of ubiquitinated FANCD2 at sites of DNA damage. ERCC1 was required for FANCD2 foci formation following DNA crosslinking, which can be repaired following the formation of a double-strand break, and on stalled replication forks, which include double-strand breaks. <a href="#13" class="mim-tip-reference" title="McCabe, K. M., Hemphill, A., Akkari, Y., Jakobs, P. M., Pauw, D., Olson, S. B., Moses, R. E., Grompe, M. <strong>ERCC1 is required for FANCD2 focus formation.</strong> Molec. Genet. Metab. 95: 66-73, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18672388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18672388</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18672388[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2008.06.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18672388">McCabe et al. (2008)</a> concluded that ERCC1 is not required for the formation of double-strand breaks but is required for the activation of FANCD2 for their repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18672388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid and coimmunoprecipitation assays, <a href="#20" class="mim-tip-reference" title="Tremblay, C. S., Huang, F. F., Habi, O., Huard, C. C., Godin, C., Levesque, G., Carreau, M. <strong>HES1 is a novel interactor of the Fanconi anemia core complex.</strong> Blood 112: 2062-2070, 2008. Note: Erratum: Blood 114: 3974 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550849[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/10.1182/blood-2008-04-152710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18550849">Tremblay et al. (2008)</a> found that HES1 (<a href="/entry/139605">139605</a>), a NOTCH1 (<a href="/entry/190198">190198</a>) pathway component involved in hematopoietic stem cell self-renewal, interacted directly with several FA core complex components, but not with FANCD2. Depletion of HES1 from HeLa cells resulted in failure of normal interactions between individual FA core components, as well as altered protein levels and mislocalization of some FA core components. Depletion of HES1 also increased cell sensitivity to MMC and reduced MMC-induced monoubiquitination of FANCD2 and localization of FANCD2 to MMC-induced foci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18550849" 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="#7" class="mim-tip-reference" title="Knipscheer, P., Raschle, M., Smogorzewska, A., Enoiu, M., Ho, T. V., Scharer, O. D., Elledge, S. J., Walter, J. C. <strong>The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.</strong> Science 326: 1698-1701, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19965384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19965384</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19965384[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1182372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19965384">Knipscheer et al. (2009)</a> used a cell-free system to demonstrate that FANCI (<a href="/entry/611360">611360</a>)-FANCD2 is required for replication-coupled interstrand crosslink repair in S phase. Removal of FANCD2 from extracts inhibited both nucleolytic incisions near the interstrand crosslink and translesion DNA synthesis past the lesion. Reversal of these defects required ubiquitylated FANCI-FANCD2. <a href="#7" class="mim-tip-reference" title="Knipscheer, P., Raschle, M., Smogorzewska, A., Enoiu, M., Ho, T. V., Scharer, O. D., Elledge, S. J., Walter, J. C. <strong>The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.</strong> Science 326: 1698-1701, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19965384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19965384</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19965384[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1182372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19965384">Knipscheer et al. (2009)</a> concluded that multiple steps of the essential S phase interstrand crosslink repair mechanism fail when the Fanconi anemia pathway is compromised. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19965384" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunohistochemical analysis, <a href="#14" class="mim-tip-reference" title="Naim, V., Rosselli, F. <strong>The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities.</strong> Nature Cell Biol. 11: 761-768, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19465921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19465921</a>] [<a href="https://doi.org/10.1038/ncb1883" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19465921">Naim and Rosselli (2009)</a> found that FANCD2 showed dynamic localization during mitosis in normal human fibroblasts: at the onset of mitosis, FANCD2 was excluded from chromosomes and diffused into the cytoplasm, returning to the nucleus at the end of cell division. FANCD2 was also found at discrete foci on mitotic chromosomes, which appeared to be unresolved foci induced by fork stalling during the previous S phase. APH treatment increased the numbers of FANCD2 and phosphorylated histone H2AX (gamma-H2AX; <a href="/entry/601772">601772</a>) foci on mitotic chromosomes, and these FANCD2 and gamma-H2AX foci showed significant colocalization. Knockdown of FANCD2 and/or BLM (RECQL3; <a href="/entry/604610">604610</a>), a protein involved in completion of sister chromatid separation during mitosis, resulted in a similar increase in noncentromeric anaphase nucleoplasmic bridges and micronuclei following APH exposure. <a href="#14" class="mim-tip-reference" title="Naim, V., Rosselli, F. <strong>The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities.</strong> Nature Cell Biol. 11: 761-768, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19465921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19465921</a>] [<a href="https://doi.org/10.1038/ncb1883" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19465921">Naim and Rosselli (2009)</a> concluded that the FANC pathway facilitates recruitment of BLM to damage-induced nucleoplasmic bridges, and they hypothesized that the FANC and BLM pathways cooperate to resolve abnormal chromatid structures and complete chromatid separation at the end of cell division. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19465921" 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 central event in the Fanconi pathway is monoubiquitylation of the FANCI-FANCD2 protein complex. <a href="#10" class="mim-tip-reference" title="Liu, T., Ghosal, G., Yuan, J., Chen, J., Huang, J. <strong>FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.</strong> Science 329: 693-696, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20671156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20671156</a>] [<a href="https://doi.org/10.1126/science.1192656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20671156">Liu et al. (2010)</a> characterized the Fanconi anemia-associated nuclease FAN1 (<a href="/entry/613534">613534</a>), which promotes interstrand crosslink repair in a manner strictly dependent on its ability to accumulate at or near sites of DNA damage and that relies on monoubiquitylation of the FANCI-FAND2 complex. <a href="#10" class="mim-tip-reference" title="Liu, T., Ghosal, G., Yuan, J., Chen, J., Huang, J. <strong>FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.</strong> Science 329: 693-696, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20671156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20671156</a>] [<a href="https://doi.org/10.1126/science.1192656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20671156">Liu et al. (2010)</a> concluded that the monoubiquitylated complex recruits the downstream repair protein FAN1 and facilitates repair of DNA interstrand crosslinks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20671156" 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="#16" class="mim-tip-reference" title="Pace, P., Mosedale, G., Hodskinson, M. R., Rosado, I. V., Sivasubramaniam, M., Patel, K. J. <strong>Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway.</strong> Science 329: 219-223, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20538911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20538911</a>] [<a href="https://doi.org/10.1126/science.1192277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20538911">Pace et al. (2010)</a> found a genetic interaction between the Fanconi anemia gene FANCC (<a href="/entry/613899">613899</a>) and the nonhomologous end joining (NHEJ) factor Ku70 (<a href="/entry/152690">152690</a>). Disruption of both FANCC and Ku70 suppressed sensitivity to crosslinking agents, diminished chromosome breaks, and reversed defective homologous recombination. Ku70 binds directly to free DNA ends, committing them to NHEJ repair. <a href="#16" class="mim-tip-reference" title="Pace, P., Mosedale, G., Hodskinson, M. R., Rosado, I. V., Sivasubramaniam, M., Patel, K. J. <strong>Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway.</strong> Science 329: 219-223, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20538911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20538911</a>] [<a href="https://doi.org/10.1126/science.1192277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20538911">Pace et al. (2010)</a> showed that purified FANCD2, a downstream effector of the Fanconi anemia pathway, might antagonize Ku70 activity by modifying such DNA substrates. <a href="#16" class="mim-tip-reference" title="Pace, P., Mosedale, G., Hodskinson, M. R., Rosado, I. V., Sivasubramaniam, M., Patel, K. J. <strong>Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway.</strong> Science 329: 219-223, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20538911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20538911</a>] [<a href="https://doi.org/10.1126/science.1192277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20538911">Pace et al. (2010)</a> concluded that these results reveal a function for the Fanconi anemia pathway in processing DNA ends, thereby diverting double-strand break repair from abortive NHEJ and toward homologous recombination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20538911" 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="#11" class="mim-tip-reference" title="Long, D. T., Raschle, M., Joukov, V., Walter, J. C. <strong>Mechanism of RAD51-dependent DNA interstrand cross-link repair.</strong> Science 333: 84-87, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21719678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21719678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21719678[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1204258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21719678">Long et al. (2011)</a> reported that the broken sister chromatid generated by a DNA double-strand break in Xenopus extracts is repaired via RAD51 (<a href="/entry/179617">179617</a>)-dependent strand invasion into the regenerated sister. Recombination acts downstream of FANCI (<a href="/entry/611360">611360</a>)-FANCD2, yet RAD51 binds interstrand crosslinks-stalled replication forks independently of FANCI and FANC2 and before double-strand break formation. <a href="#11" class="mim-tip-reference" title="Long, D. T., Raschle, M., Joukov, V., Walter, J. C. <strong>Mechanism of RAD51-dependent DNA interstrand cross-link repair.</strong> Science 333: 84-87, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21719678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21719678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21719678[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1204258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21719678">Long et al. (2011)</a> concluded that their results elucidated the functional link between the Fanconi anemia pathway and the recombination machinery during interstrand crosslink repair. In addition, their results demonstrated the complete repair of a double-strand break via homologous recombination in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21719678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Zhang, Y., Zhou, X., Zhao, L., Li, C., Zhu, H., Xu, L., Shan, L., Liao, X., Guo, Z., Huang, P. <strong>UBE2W interacts with FANCL and regulates the monoubiquitination of Fanconi anemia protein FANCD2.</strong> Molec. Cells 31: 113-122, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21229326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21229326</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21229326[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/10.1007/s10059-011-0015-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21229326">Zhang et al. (2011)</a> found that mouse ubiquitin-conjugating enzyme-2W (UBE2W; <a href="/entry/614277">614277</a>) monoubiquitinated Fancd2. Downregulation of UBE2W in human cell lines markedly reduced FANCD2 monoubiquitination caused by ultraviolet irradiation, but not FANCD2 monoubiquitination caused by the DNA crosslinking agent mitomycin C or FANCD2 monoubiquitination that occurs normally during S phase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21229326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a series of mutant Fan1 and Fancd2 constructs with wildtype and mutant mouse embryonic fibroblasts, <a href="#8" class="mim-tip-reference" title="Lachaud, C., Moreno, A., Marchesi, F., Toth, R., Blow, J. J., Rouse, J. <strong>Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability.</strong> Science 351: 846-849, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26797144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26797144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26797144[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aad5634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26797144">Lachaud et al. (2016)</a> found that the nuclease activity of Fan1, but not its interaction with ubiquitinated Fancd2, was required for Fan1-dependent repair of DNA interstrand crosslinks. However, both its nuclease activity and its interaction with ubiquitinated Fancd2 were required for Fan1 to restrain stalled forks in DNA and prevent subsequent chromosome abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26797144" 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="#6" class="mim-tip-reference" title="Joo, W., Xu, G., Persky, N. S., Smogorzewska, A., Rudge, D. G., Buzovetsky, O., Elledge, S. J., Pavletich, N. P. <strong>Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway.</strong> Science 333: 312-316, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21764741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21764741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21764741[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1205805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21764741">Joo et al. (2011)</a> determined the crystal structure of the FANCI-FANCD2 (ID) complex at 3.4-angstrom resolution. The structure of the approximate 300-kD ID complex revealed that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8-angstrom electron-density map of FANCI-DNA crystals and in vitro data showed that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an interstrand crosslink. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21764741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Using cryoelectron microscopy, <a href="#21" class="mim-tip-reference" title="Wang, R., Wang, S., Dhar, A., Peralta, C., Pavletich, N. P. <strong>DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex.</strong> Nature 580: 278-282, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32269332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32269332</a>] [<a href="https://doi.org/10.1038/s41586-020-2110-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32269332">Wang et al. (2020)</a> determined the monoubiquitinated human ID complex bound to DNA, and revealed that it forms a closed ring that encircles the DNA. By comparison with the structure of the nonubiquitinated ID complex bound to interstrand crosslinked DNA, they showed that monoubiquitination triggers a complete rearrangement of the open, trough-like ID structure through the ubiquitin of one protomer binding to the other protomer in a reciprocal fashion. These structures, together with biochemical data, indicated that the monoubiquitinated ID complex loses its preference for interstrand crosslinks and related branched DNA structures, and becomes a sliding DNA clamp that can coordinate the subsequent repair reactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32269332" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#19" class="mim-tip-reference" title="Timmers, C., Taniguchi, T., Hejna, J., Reifsteck, C., Lucas, L., Bruun, D., Thayer, M., Cox, B., Olson, S., D'Andrea, A. D., Moses, R., Grompe, M. <strong>Positional cloning of a novel Fanconi anemia gene, FANCD2.</strong> Molec. Cell 7: 241-248, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239453</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239453">Timmers et al. (2001)</a> determined that the FANCD2 gene contains 44 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#22" class="mim-tip-reference" title="Whitney, M., Thayer, M., Reifsteck, C., Olson, S., Smith, L., Jakobs, P. M., Leach, R., Naylor, S., Joenje, H., Grompe, M. <strong>Microcell mediated chromosome transfer maps the Fanconi anaemia group D gene to chromosome 3p.</strong> Nature Genet. 11: 341-343, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581463</a>] [<a href="https://doi.org/10.1038/ng1195-341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581463">Whitney et al. (1995)</a> used microcell-mediated chromosome transfer to map the group D form of Fanconi anemia to 3p. A new immortalized fibroblast cell line from an FACD patient was used as the recipient for chromosome transfer. The cells, referred to as PD20, retained all phenotypic characteristics of FA cells, including sensitivity to mitomycin C and diepoxybutane. Mapping by linkage analysis was impossible because DNA samples were available from only 2 small FACD families. However, the localization of the gene, which they symbolized FAD, to chromosome 3 by functional complementation allowed exclusion mapping to rule out regions of this chromosome, using chromosome 3 microcell hybrids with deletion of various segments. They excluded 28 markers; all 13 markers that were not excluded were located between D3S1619 and D3S1307, a region that spans 3p26-p22 and thus probably contains the FAD gene. They noted that this region spans approximately 50 cM and contains at least 25 genes. Among these, 2 are implicated in DNA repair: XPC (<a href="/entry/613208">613208</a>), located at 3p25, and RAD23B (<a href="/entry/600062">600062</a>), located at 3p25.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7581463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Hejna, J. A., Timmers, C. D., Reifsteck, C., Bruun, D. A., Lucas, L. W., Jakobs, P. M., Toth-Fejel, S., Unsworth, N., Clemens, S. L., Garcia, D. K., Naylor, S. L., Thayer, M. J., Olson, S. B., Grompe, M., Moses, R. E. <strong>Localization of the Fanconi anemia complementation group D gene to a 200-kb region on chromosome 3p25.3.</strong> Am. J. Hum. Genet. 66: 1540-1551, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10762542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10762542</a>] [<a href="https://doi.org/10.1086/302896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10762542">Hejna et al. (2000)</a> refined the localization of the FANCD gene to a 200-kb region on 3p25.3. They used noncomplemented microcell hybrids to identify small overlapping deletions that narrowed the FANCD critical region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10762542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#24" class="mim-tip-reference" title="Zhang, Q.-S., Marquez-Loza, L., Eaton, L., Duncan, A. W., Goldman, D. C., Anur, P., Watanabe-Smith, K., Rathbun, R. K., Fleming, W. H., Bagby, G. C., Grompe, M. <strong>Fancd2-/- mice have hematopoietic defects that can be partially corrected by resveratrol.</strong> Blood 116: 5140-5148, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20826722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20826722</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20826722[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/10.1182/blood-2010-04-278226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20826722">Zhang et al. (2010)</a> found that blood of Fancd2 -/- mice had significantly decreased platelet numbers, but that other hematologic parameters were within normal range, with no sign of anemia. Bone marrow of Fancd2 -/- mice had a 50% reduction in the frequency of Kit (<a href="/entry/164920">164920</a>)- and Sca1 (Ly6a)-positive lineage (KSL) cells, resulting in a smaller hematopoietic stem cell pool and reduced lymphoid progenitor frequency. Fancd2 -/- KSL cells showed a compromised repopulation capacity and formed fewer colonies than wildtype cells when cultured on a normal feeder/stromal layer. Similarly, a Fancd2 -/- bone marrow feeder layer was less supportive of progenitor growth than a wildtype feeder layer. There was nearly twice as many Fancd2 -/- KSL cells with G2 DNA content than wildtype, indicating loss of quiescence. Treatment with the antioxidant resveratrol partially normalized quiescence, colony formation, and cell cycle status in Fancd2 -/- cells, but it had no effect on wildtype cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20826722" 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="Langevin, F., Crossan, G. P., Rosado, I. V., Arends, M. J., Patel, K. J. <strong>Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.</strong> Nature 475: 53-58, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21734703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21734703</a>] [<a href="https://doi.org/10.1038/nature10192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21734703">Langevin et al. (2011)</a> found that the Fanconi anemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Their results showed that the acetaldehyde-catabolizing enzyme Aldh2 (<a href="/entry/100650">100650</a>) is essential for the development of Fancd2-null embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh2 heterozygotes) could support the development of double-mutant Aldh2-null/Fancd2-null mice. However, these embryos were unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitated bone marrow failure. Lastly, Aldh2-null/Fancd2-null mice spontaneously developed acute leukemia. <a href="#9" class="mim-tip-reference" title="Langevin, F., Crossan, G. P., Rosado, I. V., Arends, M. J., Patel, K. J. <strong>Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.</strong> Nature 475: 53-58, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21734703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21734703</a>] [<a href="https://doi.org/10.1038/nature10192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21734703">Langevin et al. (2011)</a> concluded that acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well to normal development, hematopoietic failure, and cancer predisposition in Fanconi anemia patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21734703" 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="#1" class="mim-tip-reference" title="Garaycoechea, J. I., Crossan, G. P., Langevin, F., Daly, M., Arends, M. J., Patel, K. J. <strong>Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function.</strong> Nature 489: 571-575, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22922648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22922648</a>] [<a href="https://doi.org/10.1038/nature11368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22922648">Garaycoechea et al. (2012)</a> reported that aged Aldh2-null/Fancd2-null mutant mice that do not develop leukemia spontaneously develop aplastic anemia, with the concomitant accumulation of damaged DNA within the hematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, they found that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, <a href="#1" class="mim-tip-reference" title="Garaycoechea, J. I., Crossan, G. P., Langevin, F., Daly, M., Arends, M. J., Patel, K. J. <strong>Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function.</strong> Nature 489: 571-575, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22922648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22922648</a>] [<a href="https://doi.org/10.1038/nature11368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22922648">Garaycoechea et al. (2012)</a> concluded that the emergence of bone marrow failure in Fanconi anemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22922648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121917786 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917786;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121917786?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121917786" 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=rs121917786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In the PD20 cell line from a family with Fanconi anemia complementation group D2 (<a href="/entry/227646">227646</a>), <a href="#19" class="mim-tip-reference" title="Timmers, C., Taniguchi, T., Hejna, J., Reifsteck, C., Lucas, L., Bruun, D., Thayer, M., Cox, B., Olson, S., D'Andrea, A. D., Moses, R., Grompe, M. <strong>Positional cloning of a novel Fanconi anemia gene, FANCD2.</strong> Molec. Cell 7: 241-248, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239453</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239453">Timmers et al. (2001)</a> identified a G-to-A transition at nucleotide 3707 of the FANCD2 gene, resulting in an arg1236-to-his (R1236H) substitution. The mutation was not a common polymorphism and was inherited from the father. The maternal mutation identified in this family was an A-to-G transition at nucleotide 376 (<a href="#0002">613984.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239453" 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 the PD20 cell line from a family with Fanconi anemia complementation group D2 (<a href="/entry/227646">227646</a>), <a href="#19" class="mim-tip-reference" title="Timmers, C., Taniguchi, T., Hejna, J., Reifsteck, C., Lucas, L., Bruun, D., Thayer, M., Cox, B., Olson, S., D'Andrea, A. D., Moses, R., Grompe, M. <strong>Positional cloning of a novel Fanconi anemia gene, FANCD2.</strong> Molec. Cell 7: 241-248, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239453</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239453">Timmers et al. (2001)</a> identified an A-to-G transition at nucleotide 376 of the FANCD2 gene, resulting in a ser126-to-gly (S126G) substitution. The mutation also resulted in abnormal splicing and the insertion of 13 bp from intron 5 into the mRNA via the utilization of a cryptic splice site. Forty-three of 43 (100%) independently cloned RT-PCR products with this mutation contained this insertion, whereas only 1 of 31 (3%) control cDNA clones displayed misspliced mRNA. The 13-bp insertion generated a frameshift and predicts a severely truncated protein of 180 amino acids. The mutation was not a common polymorphism and was inherited from the mother. The paternal mutation identified in this family was an arg1236-to-his substitution (<a href="#0001">613984.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121917787 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917787;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121917787?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121917787" 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=rs121917787" 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=RCV000012820 OR RCV000809924" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012820, RCV000809924" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012820...</a>
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<p>In the VU008 cell line from a family with Fanconi anemia complementation group D2 (<a href="/entry/227646">227646</a>), <a href="#19" class="mim-tip-reference" title="Timmers, C., Taniguchi, T., Hejna, J., Reifsteck, C., Lucas, L., Bruun, D., Thayer, M., Cox, B., Olson, S., D'Andrea, A. D., Moses, R., Grompe, M. <strong>Positional cloning of a novel Fanconi anemia gene, FANCD2.</strong> Molec. Cell 7: 241-248, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239453</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239453">Timmers et al. (2001)</a> identified a C-to-T transition at nucleotide 904 of the FANCD2 gene, resulting in an arg302-to-trp (R302W) substitution. This was not a common polymorphism and was inherited from the father. The maternally inherited mutation was a gly320-to-ter substitution (<a href="#0004">613984.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 FANCONI ANEMIA, COMPLEMENTATION GROUP D2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917788 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917788;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=rs121917788" 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=rs121917788" 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=RCV000012821 OR RCV003522920" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012821, RCV003522920" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012821...</a>
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<p>In the VU008 cell line from a family with Fanconi anemia complementation group D2 (<a href="/entry/227646">227646</a>), <a href="#19" class="mim-tip-reference" title="Timmers, C., Taniguchi, T., Hejna, J., Reifsteck, C., Lucas, L., Bruun, D., Thayer, M., Cox, B., Olson, S., D'Andrea, A. D., Moses, R., Grompe, M. <strong>Positional cloning of a novel Fanconi anemia gene, FANCD2.</strong> Molec. Cell 7: 241-248, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239453</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239453">Timmers et al. (2001)</a> identified a C-to-T transition at nucleotide 958 of the FANCD2 gene, resulting in a gln320-to-ter (Q320X) substitution. This was not a common polymorphism and was inherited from the mother. The paternally inherited mutation was an arg302-to-trp substitution (<a href="#0003">613984.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 FANCONI ANEMIA, COMPLEMENTATION GROUP D2</strong>
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FANCD2, EX17 DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012822" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012822" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012822</a>
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<p>In the PD733 cell line from a patient with Fanconi anemia complementation group D2 (<a href="/entry/227646">227646</a>), <a href="#19" class="mim-tip-reference" title="Timmers, C., Taniguchi, T., Hejna, J., Reifsteck, C., Lucas, L., Bruun, D., Thayer, M., Cox, B., Olson, S., D'Andrea, A. D., Moses, R., Grompe, M. <strong>Positional cloning of a novel Fanconi anemia gene, FANCD2.</strong> Molec. Cell 7: 241-248, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239453</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239453">Timmers et al. (2001)</a> identified by RT-PCR the absence of exon 17 of FANCD2 causing an internal deletion of the protein. The genomic alteration in this patient was not found. PD733 did not express any FANCD2 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Garaycoechea2012" class="mim-anchor"></a>
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Garaycoechea, J. I., Crossan, G. P., Langevin, F., Daly, M., Arends, M. J., Patel, K. J.
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<strong>Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function.</strong>
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Nature 489: 571-575, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22922648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22922648</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22922648" 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/nature11368" target="_blank">Full Text</a>]
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Garcia-Higuera, I., Taniguchi, T., Ganesan, S., Meyn, M. S., Timmers, C., Hejna, J., Grompe, M., D'Andrea, A. D.
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<strong>Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.</strong>
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Molec. Cell 7: 249-262, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239454</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(01)00173-3" target="_blank">Full Text</a>]
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Hejna, J. A., Timmers, C. D., Reifsteck, C., Bruun, D. A., Lucas, L. W., Jakobs, P. M., Toth-Fejel, S., Unsworth, N., Clemens, S. L., Garcia, D. K., Naylor, S. L., Thayer, M. J., Olson, S. B., Grompe, M., Moses, R. E.
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<strong>Localization of the Fanconi anemia complementation group D gene to a 200-kb region on chromosome 3p25.3.</strong>
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Am. J. Hum. Genet. 66: 1540-1551, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10762542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10762542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10762542" 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/10.1086/302896" target="_blank">Full Text</a>]
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Howlett, N. G., Taniguchi, T., Durkin, S. G., D'Andrea, A. D., Glover, T. W.
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<strong>The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability.</strong>
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Hum. Molec. Genet. 14: 693-701, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15661754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15661754</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15661754" 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/10.1093/hmg/ddi065" target="_blank">Full Text</a>]
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<a id="Hussain2004" class="mim-anchor"></a>
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Hussain, S., Wilson, J. B., Medhurst, A. L., Hejna, J., Witt, E., Ananth, S., Davies, A., Masson, J. Y., Moses, R., West, S. C., de Winter, J. P., Ashworth, A., Jones, N. J., Mathew, C. G.
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<strong>Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways.</strong>
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Hum. Molec. Genet. 13: 1241-1248, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115758</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15115758" 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/10.1093/hmg/ddh135" target="_blank">Full Text</a>]
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Joo, W., Xu, G., Persky, N. S., Smogorzewska, A., Rudge, D. G., Buzovetsky, O., Elledge, S. J., Pavletich, N. P.
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<strong>Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway.</strong>
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Science 333: 312-316, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21764741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21764741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21764741[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=21764741" 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/10.1126/science.1205805" target="_blank">Full Text</a>]
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Knipscheer, P., Raschle, M., Smogorzewska, A., Enoiu, M., Ho, T. V., Scharer, O. D., Elledge, S. J., Walter, J. C.
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<strong>The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.</strong>
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Science 326: 1698-1701, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19965384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19965384</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19965384[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=19965384" 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/10.1126/science.1182372" target="_blank">Full Text</a>]
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<a id="Lachaud2016" class="mim-anchor"></a>
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Lachaud, C., Moreno, A., Marchesi, F., Toth, R., Blow, J. J., Rouse, J.
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<strong>Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability.</strong>
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Science 351: 846-849, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20826722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20826722</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20826722[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=20826722" 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/10.1182/blood-2010-04-278226" target="_blank">Full Text</a>]
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<a id="Zhang2011" class="mim-anchor"></a>
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Zhang, Y., Zhou, X., Zhao, L., Li, C., Zhu, H., Xu, L., Shan, L., Liao, X., Guo, Z., Huang, P.
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<strong>UBE2W interacts with FANCL and regulates the monoubiquitination of Fanconi anemia protein FANCD2.</strong>
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Molec. Cells 31: 113-122, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21229326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21229326</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21229326[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=21229326" 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/10.1007/s10059-011-0015-9" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 08/10/2020
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Patricia A. Hartz - updated : 08/10/2016<br>Ada Hamosh - updated : 10/9/2012<br>Patricia A. Hartz - updated : 11/2/2011<br>Ada Hamosh - updated : 9/8/2011<br>Ada Hamosh - updated : 9/7/2011<br>Ada Hamosh - updated : 9/1/2011<br>Patricia A. Hartz - updated : 7/11/2011
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Creation Date:
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Anne M. Stumpf : 5/19/2011
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alopez : 08/10/2020
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alopez : 08/10/2016<br>alopez : 10/24/2012<br>terry : 10/9/2012<br>terry : 5/29/2012<br>mgross : 11/2/2011<br>alopez : 9/8/2011<br>alopez : 9/7/2011<br>alopez : 9/6/2011<br>terry : 9/1/2011<br>mgross : 8/16/2011<br>mgross : 8/16/2011<br>terry : 7/11/2011<br>alopez : 5/19/2011
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<strong>*</strong> 613984
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FANCD2 GENE; FANCD2
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<strong><em>HGNC Approved Gene Symbol: FANCD2</em></strong>
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Cytogenetic location: 3p25.3
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<span class="small">(from NCBI)</span>
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Phenotype
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3p25.3
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Fanconi anemia, complementation group D2
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227646
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>Cloning and Expression</strong>
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<p>By the study of a panel of somatic cell hybrids constructed using polyethylene glycol as a fusigen, Strathdee et al. (1992) identified 4 complementation groups, suggesting that there are at least 4 different FA genes, mutations at any one of which can cause the Fanconi anemia phenotype. </p><p>Timmers et al. (2001) presented evidence that FA complementation group D is heterogeneous, consisting of 2 distinct genes, FANCD1 (600185) and FANCD2. They reported positional cloning of the FANCD2 gene, which encodes a 1,451-amino acid nuclear protein, has 2 protein isoforms, and maps to 3p. Similar to other FA proteins, the FANCD2 protein had no known functional domains. However, unlike other FA genes, FANCD2 is highly conserved in A. thaliana, C. elegans, and Drosophila. </p>
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<strong>Gene Function</strong>
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<p>Garcia-Higuera et al. (2001) showed that a nuclear complex containing the FANCA (607139), FANCC (613899), FANCF (613897), and FANCG (602956) proteins is required for the activation of the FANCD2 protein to a monoubiquitinated isoform. In normal cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with the breast cancer susceptibility protein, BRCA1 (113705), in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The authors concluded that the FANCD2 protein therefore provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all subtypes of FA. </p><p>Taniguchi et al. (2002) identified FANCD2 as a link between the FA and ATM (607585) damage response pathways. ATM phosphorylated FANCD2 on ser222 in vitro. This site was also phosphorylated in vivo in an ATM-dependent manner following ionizing radiation. Phosphorylation of FANCD2 was required for activation of an S-phase checkpoint. The authors determined that the ATM-dependent phosphorylation of FANCD2 on ser222 and the FA pathway-dependent monoubiquitination of FANCD2 on lys561 are independent posttranslational modifications regulating discrete cellular signaling pathways. Biallelic disruption of FANCD2 resulted in both mitomycin C (MMC) and ionizing radiation hypersensitivity. </p><p>By coimmunoprecipitation, Nakanishi et al. (2002) found constitutive interaction between FANCD2 and NBS1 (602667), and they provided evidence that these proteins interact in 2 distinct assemblies to mediate S-phase checkpoint and resistance to MMC-induced chromosome damage. NBS1, ATM, and MRE11 (600814) were required for FANCD2 phosphorylation in response to radiation-induced S-phase checkpoint. The assembly of NBS1, MRE11, RAD50 (604040), and FANCD2 within nuclear foci was required for MMC resistance. </p><p>Hussain et al. (2004) used yeast 2-hybrid analysis to test for interaction between FANCD2 and several proteins involved in homologous recombination repair. FANCD2 did not interact with RAD51 (179617), the 5 RAD51 paralogs (see 602774), RAD52 (600392), RAD54 (600392), or DMC1 (602721). However, it bound to a highly conserved C-terminal site in BRCA2 (600185) that also bound FANCG/XRCC9 (602956). FANCD2 and BRCA2 coimmunoprecipitated from cell extracts of both human and Chinese hamster wildtype cells, thus confirming that the interaction occurs in vivo. Formation of nuclear foci of FANCD2 was normal in the BRCA2 mutant CAPAN-1 cells, suggesting that recruitment of FANCD2 to sites of DNA repair is independent of wildtype BRCA2 function. FANCD2 colocalized with RAD51 in foci following treatment with MMC or hydroxyurea, and colocalized very tightly with PCNA (176740) after treatment with hydroxyurea. Hussain et al. (2004) suggested that FANCD2 may have a role in the cellular response to stalled replication forks or in the repair of replication-associated double-strand breaks, irrespective of the type of primary DNA lesion. </p><p>Wilson et al. (2008) found that XRCC3 (600675), BRCA2, FANCD2, and FANCG formed a complex via multiple pairwise interactions following phosphorylation of FANCG. They proposed that a complex made up of at least these 4 proteins promotes homologous recombination repair of damaged DNA. </p><p>Howlett et al. (2005) showed that the FA pathway was strongly activated in response to DNA replicative stress by aphidicolin (APH) and hydroxyurea. Using patient-derived FA cell lines and siRNA targeting FANCD2, the authors demonstrated a functional requirement for the FA pathway in response to low doses of APH. Both the total number of chromosome gaps and breaks and the number of breaks at FRA3B (FHIT; 601153) and FRA16D (WWOX; 605131) fragile sites were significantly elevated in the absence of an intact FA pathway. Furthermore, APH activated monoubiquitination of both FANCD2 and PCNA (176740) and the phosphorylation of RPA2 (179836), signaling processive DNA replication arrest. Following APH treatment, FANCD2-Ub colocalized with PCNA after 4 hours and with RPA2 after 24 hours in discrete nuclear foci. </p><p>By covalent modification and expression of recombinant chicken Fancd2 in chicken B-cell lines, Matsushita et al. (2005) found that Fancc, Fancg, and Fancl (608111) were an integral part of the FA core complex and were necessary for Fancd2 monoubiquitination. These FA core complex proteins were also required for chromatin targeting of monoubiquitinated Fancd2 and for proper function of chromatin-bound Fancd2 in DNA repair. Matsushita et al. (2005) suggested that the monoubiquitin moiety on FANCD2 may function primarily as a chromatin targeting signal. </p><p>Using normal human fibroblasts depleted of ERCC1 (126380) via small interfering RNA and fibroblasts from FA patients, McCabe et al. (2008) showed that ERCC1 was required for both monoubiquitination of FANCD2 and the accumulation of ubiquitinated FANCD2 at sites of DNA damage. ERCC1 was required for FANCD2 foci formation following DNA crosslinking, which can be repaired following the formation of a double-strand break, and on stalled replication forks, which include double-strand breaks. McCabe et al. (2008) concluded that ERCC1 is not required for the formation of double-strand breaks but is required for the activation of FANCD2 for their repair. </p><p>Using yeast 2-hybrid and coimmunoprecipitation assays, Tremblay et al. (2008) found that HES1 (139605), a NOTCH1 (190198) pathway component involved in hematopoietic stem cell self-renewal, interacted directly with several FA core complex components, but not with FANCD2. Depletion of HES1 from HeLa cells resulted in failure of normal interactions between individual FA core components, as well as altered protein levels and mislocalization of some FA core components. Depletion of HES1 also increased cell sensitivity to MMC and reduced MMC-induced monoubiquitination of FANCD2 and localization of FANCD2 to MMC-induced foci. </p><p>Knipscheer et al. (2009) used a cell-free system to demonstrate that FANCI (611360)-FANCD2 is required for replication-coupled interstrand crosslink repair in S phase. Removal of FANCD2 from extracts inhibited both nucleolytic incisions near the interstrand crosslink and translesion DNA synthesis past the lesion. Reversal of these defects required ubiquitylated FANCI-FANCD2. Knipscheer et al. (2009) concluded that multiple steps of the essential S phase interstrand crosslink repair mechanism fail when the Fanconi anemia pathway is compromised. </p><p>Using immunohistochemical analysis, Naim and Rosselli (2009) found that FANCD2 showed dynamic localization during mitosis in normal human fibroblasts: at the onset of mitosis, FANCD2 was excluded from chromosomes and diffused into the cytoplasm, returning to the nucleus at the end of cell division. FANCD2 was also found at discrete foci on mitotic chromosomes, which appeared to be unresolved foci induced by fork stalling during the previous S phase. APH treatment increased the numbers of FANCD2 and phosphorylated histone H2AX (gamma-H2AX; 601772) foci on mitotic chromosomes, and these FANCD2 and gamma-H2AX foci showed significant colocalization. Knockdown of FANCD2 and/or BLM (RECQL3; 604610), a protein involved in completion of sister chromatid separation during mitosis, resulted in a similar increase in noncentromeric anaphase nucleoplasmic bridges and micronuclei following APH exposure. Naim and Rosselli (2009) concluded that the FANC pathway facilitates recruitment of BLM to damage-induced nucleoplasmic bridges, and they hypothesized that the FANC and BLM pathways cooperate to resolve abnormal chromatid structures and complete chromatid separation at the end of cell division. </p><p>A central event in the Fanconi pathway is monoubiquitylation of the FANCI-FANCD2 protein complex. Liu et al. (2010) characterized the Fanconi anemia-associated nuclease FAN1 (613534), which promotes interstrand crosslink repair in a manner strictly dependent on its ability to accumulate at or near sites of DNA damage and that relies on monoubiquitylation of the FANCI-FAND2 complex. Liu et al. (2010) concluded that the monoubiquitylated complex recruits the downstream repair protein FAN1 and facilitates repair of DNA interstrand crosslinks. </p><p>Pace et al. (2010) found a genetic interaction between the Fanconi anemia gene FANCC (613899) and the nonhomologous end joining (NHEJ) factor Ku70 (152690). Disruption of both FANCC and Ku70 suppressed sensitivity to crosslinking agents, diminished chromosome breaks, and reversed defective homologous recombination. Ku70 binds directly to free DNA ends, committing them to NHEJ repair. Pace et al. (2010) showed that purified FANCD2, a downstream effector of the Fanconi anemia pathway, might antagonize Ku70 activity by modifying such DNA substrates. Pace et al. (2010) concluded that these results reveal a function for the Fanconi anemia pathway in processing DNA ends, thereby diverting double-strand break repair from abortive NHEJ and toward homologous recombination. </p><p>Long et al. (2011) reported that the broken sister chromatid generated by a DNA double-strand break in Xenopus extracts is repaired via RAD51 (179617)-dependent strand invasion into the regenerated sister. Recombination acts downstream of FANCI (611360)-FANCD2, yet RAD51 binds interstrand crosslinks-stalled replication forks independently of FANCI and FANC2 and before double-strand break formation. Long et al. (2011) concluded that their results elucidated the functional link between the Fanconi anemia pathway and the recombination machinery during interstrand crosslink repair. In addition, their results demonstrated the complete repair of a double-strand break via homologous recombination in vitro. </p><p>Zhang et al. (2011) found that mouse ubiquitin-conjugating enzyme-2W (UBE2W; 614277) monoubiquitinated Fancd2. Downregulation of UBE2W in human cell lines markedly reduced FANCD2 monoubiquitination caused by ultraviolet irradiation, but not FANCD2 monoubiquitination caused by the DNA crosslinking agent mitomycin C or FANCD2 monoubiquitination that occurs normally during S phase. </p><p>Using a series of mutant Fan1 and Fancd2 constructs with wildtype and mutant mouse embryonic fibroblasts, Lachaud et al. (2016) found that the nuclease activity of Fan1, but not its interaction with ubiquitinated Fancd2, was required for Fan1-dependent repair of DNA interstrand crosslinks. However, both its nuclease activity and its interaction with ubiquitinated Fancd2 were required for Fan1 to restrain stalled forks in DNA and prevent subsequent chromosome abnormalities. </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Joo et al. (2011) determined the crystal structure of the FANCI-FANCD2 (ID) complex at 3.4-angstrom resolution. The structure of the approximate 300-kD ID complex revealed that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8-angstrom electron-density map of FANCI-DNA crystals and in vitro data showed that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an interstrand crosslink. </p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Using cryoelectron microscopy, Wang et al. (2020) determined the monoubiquitinated human ID complex bound to DNA, and revealed that it forms a closed ring that encircles the DNA. By comparison with the structure of the nonubiquitinated ID complex bound to interstrand crosslinked DNA, they showed that monoubiquitination triggers a complete rearrangement of the open, trough-like ID structure through the ubiquitin of one protomer binding to the other protomer in a reciprocal fashion. These structures, together with biochemical data, indicated that the monoubiquitinated ID complex loses its preference for interstrand crosslinks and related branched DNA structures, and becomes a sliding DNA clamp that can coordinate the subsequent repair reactions. </p>
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<strong>Gene Structure</strong>
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<p>Timmers et al. (2001) determined that the FANCD2 gene contains 44 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Whitney et al. (1995) used microcell-mediated chromosome transfer to map the group D form of Fanconi anemia to 3p. A new immortalized fibroblast cell line from an FACD patient was used as the recipient for chromosome transfer. The cells, referred to as PD20, retained all phenotypic characteristics of FA cells, including sensitivity to mitomycin C and diepoxybutane. Mapping by linkage analysis was impossible because DNA samples were available from only 2 small FACD families. However, the localization of the gene, which they symbolized FAD, to chromosome 3 by functional complementation allowed exclusion mapping to rule out regions of this chromosome, using chromosome 3 microcell hybrids with deletion of various segments. They excluded 28 markers; all 13 markers that were not excluded were located between D3S1619 and D3S1307, a region that spans 3p26-p22 and thus probably contains the FAD gene. They noted that this region spans approximately 50 cM and contains at least 25 genes. Among these, 2 are implicated in DNA repair: XPC (613208), located at 3p25, and RAD23B (600062), located at 3p25.1. </p><p>Hejna et al. (2000) refined the localization of the FANCD gene to a 200-kb region on 3p25.3. They used noncomplemented microcell hybrids to identify small overlapping deletions that narrowed the FANCD critical region. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Zhang et al. (2010) found that blood of Fancd2 -/- mice had significantly decreased platelet numbers, but that other hematologic parameters were within normal range, with no sign of anemia. Bone marrow of Fancd2 -/- mice had a 50% reduction in the frequency of Kit (164920)- and Sca1 (Ly6a)-positive lineage (KSL) cells, resulting in a smaller hematopoietic stem cell pool and reduced lymphoid progenitor frequency. Fancd2 -/- KSL cells showed a compromised repopulation capacity and formed fewer colonies than wildtype cells when cultured on a normal feeder/stromal layer. Similarly, a Fancd2 -/- bone marrow feeder layer was less supportive of progenitor growth than a wildtype feeder layer. There was nearly twice as many Fancd2 -/- KSL cells with G2 DNA content than wildtype, indicating loss of quiescence. Treatment with the antioxidant resveratrol partially normalized quiescence, colony formation, and cell cycle status in Fancd2 -/- cells, but it had no effect on wildtype cells. </p><p>Langevin et al. (2011) found that the Fanconi anemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Their results showed that the acetaldehyde-catabolizing enzyme Aldh2 (100650) is essential for the development of Fancd2-null embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh2 heterozygotes) could support the development of double-mutant Aldh2-null/Fancd2-null mice. However, these embryos were unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitated bone marrow failure. Lastly, Aldh2-null/Fancd2-null mice spontaneously developed acute leukemia. Langevin et al. (2011) concluded that acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well to normal development, hematopoietic failure, and cancer predisposition in Fanconi anemia patients. </p><p>Garaycoechea et al. (2012) reported that aged Aldh2-null/Fancd2-null mutant mice that do not develop leukemia spontaneously develop aplastic anemia, with the concomitant accumulation of damaged DNA within the hematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, they found that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, Garaycoechea et al. (2012) concluded that the emergence of bone marrow failure in Fanconi anemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>5 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0001 FANCONI ANEMIA, COMPLEMENTATION GROUP D2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCD2, ARG1236HIS
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<br />
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SNP: rs121917786,
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gnomAD: rs121917786,
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ClinVar: RCV000012818, RCV001265744, RCV002512995
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In the PD20 cell line from a family with Fanconi anemia complementation group D2 (227646), Timmers et al. (2001) identified a G-to-A transition at nucleotide 3707 of the FANCD2 gene, resulting in an arg1236-to-his (R1236H) substitution. The mutation was not a common polymorphism and was inherited from the father. The maternal mutation identified in this family was an A-to-G transition at nucleotide 376 (613984.0002). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0002 FANCONI ANEMIA, COMPLEMENTATION GROUP D2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCD2, 376A-G
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<br />
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SNP: rs764507146,
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gnomAD: rs764507146,
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ClinVar: RCV001194901, RCV003635944
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In the PD20 cell line from a family with Fanconi anemia complementation group D2 (227646), Timmers et al. (2001) identified an A-to-G transition at nucleotide 376 of the FANCD2 gene, resulting in a ser126-to-gly (S126G) substitution. The mutation also resulted in abnormal splicing and the insertion of 13 bp from intron 5 into the mRNA via the utilization of a cryptic splice site. Forty-three of 43 (100%) independently cloned RT-PCR products with this mutation contained this insertion, whereas only 1 of 31 (3%) control cDNA clones displayed misspliced mRNA. The 13-bp insertion generated a frameshift and predicts a severely truncated protein of 180 amino acids. The mutation was not a common polymorphism and was inherited from the mother. The paternal mutation identified in this family was an arg1236-to-his substitution (613984.0001). </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 FANCONI ANEMIA, COMPLEMENTATION GROUP D2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
FANCD2, ARG302TRP
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<br />
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|
|
SNP: rs121917787,
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|
|
gnomAD: rs121917787,
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|
|
|
|
|
ClinVar: RCV000012820, RCV000809924
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the VU008 cell line from a family with Fanconi anemia complementation group D2 (227646), Timmers et al. (2001) identified a C-to-T transition at nucleotide 904 of the FANCD2 gene, resulting in an arg302-to-trp (R302W) substitution. This was not a common polymorphism and was inherited from the father. The maternally inherited mutation was a gly320-to-ter substitution (613984.0004). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 FANCONI ANEMIA, COMPLEMENTATION GROUP D2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FANCD2, GLN320TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121917788,
|
|
|
|
|
|
|
|
ClinVar: RCV000012821, RCV003522920
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the VU008 cell line from a family with Fanconi anemia complementation group D2 (227646), Timmers et al. (2001) identified a C-to-T transition at nucleotide 958 of the FANCD2 gene, resulting in a gln320-to-ter (Q320X) substitution. This was not a common polymorphism and was inherited from the mother. The paternally inherited mutation was an arg302-to-trp substitution (613984.0003). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 FANCONI ANEMIA, COMPLEMENTATION GROUP D2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FANCD2, EX17 DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000012822
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the PD733 cell line from a patient with Fanconi anemia complementation group D2 (227646), Timmers et al. (2001) identified by RT-PCR the absence of exon 17 of FANCD2 causing an internal deletion of the protein. The genomic alteration in this patient was not found. PD733 did not express any FANCD2 protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
</div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Garaycoechea, J. I., Crossan, G. P., Langevin, F., Daly, M., Arends, M. J., Patel, K. J.
|
|
<strong>Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function.</strong>
|
|
Nature 489: 571-575, 2012.
|
|
|
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|
|
[PubMed: 22922648]
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[Full Text: https://doi.org/10.1038/nature11368]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Garcia-Higuera, I., Taniguchi, T., Ganesan, S., Meyn, M. S., Timmers, C., Hejna, J., Grompe, M., D'Andrea, A. D.
|
|
<strong>Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.</strong>
|
|
Molec. Cell 7: 249-262, 2001.
|
|
|
|
|
|
[PubMed: 11239454]
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|
|
[Full Text: https://doi.org/10.1016/s1097-2765(01)00173-3]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Hejna, J. A., Timmers, C. D., Reifsteck, C., Bruun, D. A., Lucas, L. W., Jakobs, P. M., Toth-Fejel, S., Unsworth, N., Clemens, S. L., Garcia, D. K., Naylor, S. L., Thayer, M. J., Olson, S. B., Grompe, M., Moses, R. E.
|
|
<strong>Localization of the Fanconi anemia complementation group D gene to a 200-kb region on chromosome 3p25.3.</strong>
|
|
Am. J. Hum. Genet. 66: 1540-1551, 2000.
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|
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|
|
[PubMed: 10762542]
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[Full Text: https://doi.org/10.1086/302896]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Howlett, N. G., Taniguchi, T., Durkin, S. G., D'Andrea, A. D., Glover, T. W.
|
|
<strong>The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability.</strong>
|
|
Hum. Molec. Genet. 14: 693-701, 2005.
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|
|
[PubMed: 15661754]
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[Full Text: https://doi.org/10.1093/hmg/ddi065]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Hussain, S., Wilson, J. B., Medhurst, A. L., Hejna, J., Witt, E., Ananth, S., Davies, A., Masson, J. Y., Moses, R., West, S. C., de Winter, J. P., Ashworth, A., Jones, N. J., Mathew, C. G.
|
|
<strong>Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways.</strong>
|
|
Hum. Molec. Genet. 13: 1241-1248, 2004.
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|
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[PubMed: 15115758]
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[Full Text: https://doi.org/10.1093/hmg/ddh135]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Joo, W., Xu, G., Persky, N. S., Smogorzewska, A., Rudge, D. G., Buzovetsky, O., Elledge, S. J., Pavletich, N. P.
|
|
<strong>Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway.</strong>
|
|
Science 333: 312-316, 2011.
|
|
|
|
|
|
[PubMed: 21764741]
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[Full Text: https://doi.org/10.1126/science.1205805]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Knipscheer, P., Raschle, M., Smogorzewska, A., Enoiu, M., Ho, T. V., Scharer, O. D., Elledge, S. J., Walter, J. C.
|
|
<strong>The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.</strong>
|
|
Science 326: 1698-1701, 2009.
|
|
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|
|
[PubMed: 19965384]
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[Full Text: https://doi.org/10.1126/science.1182372]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Lachaud, C., Moreno, A., Marchesi, F., Toth, R., Blow, J. J., Rouse, J.
|
|
<strong>Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability.</strong>
|
|
Science 351: 846-849, 2016.
|
|
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|
|
[PubMed: 26797144]
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|
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[Full Text: https://doi.org/10.1126/science.aad5634]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Langevin, F., Crossan, G. P., Rosado, I. V., Arends, M. J., Patel, K. J.
|
|
<strong>Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.</strong>
|
|
Nature 475: 53-58, 2011.
|
|
|
|
|
|
[PubMed: 21734703]
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|
|
|
[Full Text: https://doi.org/10.1038/nature10192]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Liu, T., Ghosal, G., Yuan, J., Chen, J., Huang, J.
|
|
<strong>FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.</strong>
|
|
Science 329: 693-696, 2010.
|
|
|
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|
|
[PubMed: 20671156]
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[Full Text: https://doi.org/10.1126/science.1192656]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Long, D. T., Raschle, M., Joukov, V., Walter, J. C.
|
|
<strong>Mechanism of RAD51-dependent DNA interstrand cross-link repair.</strong>
|
|
Science 333: 84-87, 2011.
|
|
|
|
|
|
[PubMed: 21719678]
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|
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[Full Text: https://doi.org/10.1126/science.1204258]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Matsushita, N., Kitao, H., Ishiai, M., Nagashima, N., Hirano, S., Okawa, K., Ohta, T., Yu, D. S., McHugh, P. J., Hickson, I. D., Venkitaraman, A. R., Kurumizaka, H., Takata, M.
|
|
<strong>A FancD2-monoubiquitin fusion reveals hidden functions of Fanconi anemia core complex in DNA repair.</strong>
|
|
Molec. Cell 19: 841-847, 2005.
|
|
|
|
|
|
[PubMed: 16168378]
|
|
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|
|
[Full Text: https://doi.org/10.1016/j.molcel.2005.08.018]
|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
McCabe, K. M., Hemphill, A., Akkari, Y., Jakobs, P. M., Pauw, D., Olson, S. B., Moses, R. E., Grompe, M.
|
|
<strong>ERCC1 is required for FANCD2 focus formation.</strong>
|
|
Molec. Genet. Metab. 95: 66-73, 2008.
|
|
|
|
|
|
[PubMed: 18672388]
|
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|
|
[Full Text: https://doi.org/10.1016/j.ymgme.2008.06.009]
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</p>
|
|
</li>
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<li>
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