Germline missense mutations affecting a single BRCA2 allele predispose humans to cancer. Here we identify a protein-targeting mechanism that is disrupted by the cancer-associated mutation, BRCA2(D2723H), and that controls the nuclear localization of BRCA2 and its cargo, the recombination enzyme RAD51. A nuclear export signal (NES) in BRCA2 is masked by its interaction with a partner protein, DSS1, such that point mutations impairing BRCA2-DSS1 binding render BRCA2 cytoplasmic. In turn, cytoplasmic mislocalization of mutant BRCA2 inhibits the nuclear retention of RAD51 by exposing a similar NES in RAD51 that is usually obscured by the BRCA2-RAD51 interaction. Thus, a series of NES-masking interactions localizes BRCA2 and RAD51 in the nucleus. Notably, BRCA2(D2723H) decreases RAD51 nuclear retention even when wild-type BRCA2 is also present. Our findings suggest a mechanism for the regulation of the nucleocytoplasmic distribution of BRCA2 and RAD51 and its impairment by a heterozygous disease-associated mutation.
Pubmed ID: 24013206 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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