More than 50 percent of familial breast and ovarian cancer are due to mutations of BRCA1 or BRCA2 genes. The long-term goal of research in my laboratory is to reveal the molecular mechanisms by which BRCA1 and BRCA2 operate as tumor suppressors. Increasing evidences suggest that BRCA1 and BRCA2 exert their tumor suppressor functions, at least in part, by participating in certain DNA damage responsive pathways and controlling genome integrity. Cells carrying mutant BRCA1 or BRCA2 are hypersensitive to DNA damage and show increased genomic instability. In support of their functions in DNA repair, the phosphorylation status and sub-nuclear localization of BRCA1 and BRCA2 are tightly regulated by DNA damage. Moreover, BRCA1 and BRCA2 interact with several DNA repair proteins. BRCA1 and BRCA2 form a stable complex in mitotic and meiotic cells, suggesting that they may function as a protein complex. Indeed, recent studies suggest the existence of a large protein complex containing BRCA1 and BRCA2. To begin to understand the functions of this complex, the following experiments will be performed: 1. Examine the sensitivity of cells carrying mutant BRCA1 to various types of DNA damage, and determine the regulation of BRCA1 in cells treated with these types of DNA-damaging agents. These studies will reveal the DNA repair and/or DNA damage responsive pathways in which BRCAI participates. 2. Examine whether the damage-induced phosphorylation status of BRCA1 determines its localization and function following DNA damage. 3. Study whether the proper S-phase localization of BRCA1 is important for its function in DNA repair. 4. We have recently identified a BRCA 1-associated protein. This protein interacts with BRCA1 and co-localizes with BRCA1 following DNA damage. Here, we will explore the biological significance of its interaction with BRCA1. Collectively, these studies will not only provide better understanding of normal function of the BRCA1IBRCA2 complex, but also provide insights into the mechanisms by which disruption of this complex, by mutations in either BRCA1 or BRCA2, leads to accelerated development of familial breast and ovarian cancer.
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