Please use this identifier to cite or link to this item: https://doi.org/10.1093/nar/gkab308
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dc.titleCancer-causing BRCA2 missense mutations disrupt an intracellular protein assembly mechanism to disable genome maintenance
dc.contributor.authorLee, Miyoung
dc.contributor.authorShorthouse, David
dc.contributor.authorMahen, Robert
dc.contributor.authorHall, Benjamin A.
dc.contributor.authorVenkitaraman, Ashok R.
dc.date.accessioned2022-10-11T07:57:22Z
dc.date.available2022-10-11T07:57:22Z
dc.date.issued2021-05-12
dc.identifier.citationLee, Miyoung, Shorthouse, David, Mahen, Robert, Hall, Benjamin A., Venkitaraman, Ashok R. (2021-05-12). Cancer-causing BRCA2 missense mutations disrupt an intracellular protein assembly mechanism to disable genome maintenance. Nucleic Acids Research 49 (10) : 5588-5604. ScholarBank@NUS Repository. https://doi.org/10.1093/nar/gkab308
dc.identifier.issn0305-1048
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/232066
dc.description.abstractCancer-causing missense mutations in the 3418 amino acid BRCA2 breast and ovarian cancer suppressor protein frequently affect a short (∼340 residue) segment in its carboxyl-terminal domain (DBD). Here, we identify a shared molecular mechanism underlying their pathogenicity. Pathogenic BRCA2 missense mutations cluster in the DBD's helical domain (HD) and OB1-fold motifs, which engage the partner protein DSS1. Pathogenic-but not benign-DBD mutations weaken or abolish DSS1-BRCA2 assembly, provoking mutant BRCA2 oligomers that are excluded from the cell nucleus, and disable DNA repair by homologous DNA recombination (HDR). DSS1 inhibits the intracellular oligomerization of wildtype, but not mutant, forms of BRCA2. Remarkably, DSS1 expression corrects defective HDR in cells bearing pathogenic BRCA2 missense mutants with weakened, but not absent, DSS1 binding. Our findings identify a DSS1-mediated intracellular protein assembly mechanism that is disrupted by cancer-causing BRCA2 missense mutations, and suggest an approach for its therapeutic correction. © 2021 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.
dc.publisherOxford University Press
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceScopus OA2021
dc.typeArticle
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.description.doi10.1093/nar/gkab308
dc.description.sourcetitleNucleic Acids Research
dc.description.volume49
dc.description.issue10
dc.description.page5588-5604
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