Cancer-causing BRCA2 missense mutations disrupt an intracellular protein assembly mechanism to disable genome maintenance |
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| Authors: | Miyoung Lee David Shorthouse Robert Mahen Benjamin A Hall Ashok
R Venkitaraman |
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| Institution: | Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK;The Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599 & Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove 138648, Singapore |
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| Abstract: | Cancer-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. |
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