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The breast cancer susceptibility protein, BRCA2, is essential for recombinational DNA repair. BRCA2 delivers RAD51 to double-stranded DNA (dsDNA) breaks through interaction with eight conserved, approximately 35 amino acid motifs, the BRC repeats. Here we show that the solitary BRC4 promotes assembly of RAD51 onto single-stranded DNA (ssDNA), but not dsDNA, to stimulate DNA strand exchange. BRC4 acts by blocking ATP hydrolysis and thereby maintaining the active ATP-bound form of the RAD51-ssDNA filament. Single-molecule visualization shows that BRC4 does not disassemble RAD51-dsDNA filaments but rather blocks nucleation of RAD51 onto dsDNA. Furthermore, this behavior is manifested by a domain of BRCA2 comprising all eight BRC repeats. These results establish that the BRC repeats modulate RAD51-DNA interaction in two opposing but functionally reinforcing ways: targeting active RAD51 to ssDNA and prohibiting RAD51 nucleation onto dsDNA. Thus, BRCA2 recruits RAD51 to DNA breaks and, we propose, the BRC repeats regulate DNA-binding selectivity.
Pubmed ID: 19303847 RIS Download
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When the BRCA1 gene was cloned, a Steering Committee was initiated to help coordinate the formation of a Breast Cancer Information Core (BIC) that could act as such a central repository. NHGRI has chosen as the most accessible format for the BIC this World Wide Web site. The recent identification of mutations in breast cancer susceptibility genes has provided the exciting opportunity to help identify women who are at high risk to develop breast cancer. One of the serious impediments to achieving clinical benefits from this information however, is finding and assessing the significance of mutations in these new susceptibility genes. It is imperative that the detection and interpretation of these mutations is coordinated and that this information is made available to as many qualified investigators as possible. There are many sites on the web that contain general as well as scientific information relevant to breast cancer. A partial list of these can be found here. Having participated in the poorly coordinated analysis of other cancer susceptibility genes, we consider it important to create and maintain a central repository for information regarding mutations and polymorphisms. NHGRI also think it critical to make available the reagents necessary to carry out many different techniques for the detection of such mutations. Sponsors: This resource is supported by the National Human Genome Research Institute (NHGRI). Keywords: Breast, Cancer, Mutation, Clincial, Polymorphism, Gene, Scientific,
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