Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 21, Issue 11, Pages 962-968Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2899
Keywords
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Funding
- UK Medical Research Council
- Wellcome Trust
- Cancer Research UK
- European Research Council
- Breast Cancer Campaign
- Swiss Bridge
- Louis-Jeantet foundation
- European Molecular Biology Organization Fellowship
- Marie Curie Intra-European Fellowship [MC-IEF-625826]
- Cancer Research UK [11582] Funding Source: researchfish
- Medical Research Council [MR/J001201/1] Funding Source: researchfish
- Wellcome Trust [098412/Z/12/Z] Funding Source: researchfish
- MRC [MR/J001201/1] Funding Source: UKRI
- Wellcome Trust [098412/Z/12/Z] Funding Source: Wellcome Trust
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Mutations in BRCA2 increase susceptibility to breast, ovarian and prostate cancers. The product of human BRCA2, BRCA2 protein, has a key role in the repair of DNA double-strand breaks and interstrand cross-links by RAD51-mediated homologous recombination. Here, we present a biochemical and structural characterization of full-length (3,418 amino acid) BRCA2, alone and in complex with RAD51. We show that BRCA2 facilitates nucleation of RAD51 filaments at multiple sites on single-stranded DNA. Three-dimensional EM reconstructions revealed that BRCA2 exists as a dimer and that two oppositely oriented sets of RAD51 molecules bind the dimer. Single-stranded DNA binds along the long axis of BRCA2, such that only one set of RAD51 monomers can form a productive complex with DNA and establish filament formation. Our data define the molecular mechanism by which this tumor suppressor facilitates RAD51-mediated homologous-recombinational repair.
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