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    Awarded Grants
    Role of BRCA2 in Homology-Directed Repair of DNA Breaks

    Scientific Abstract:
    The BRCA2-encoded product physically interacts with the Rad51 recombinase, a member of the RAD52 group of proteins that mediate homologous recombination and the recombinational repair of damaged chromosomes. Consistent with this observation, BRCA2 deficient cell lines are sensitive to DNA damaging agents and impaired for HR. BRCA2 binds Rad51 through a series of conserved modules called the BRC repeats and possesses three oligonucleotide and oligosaccharide binding (OB) folds concerned with DNA binding. This research project will use a variety of molecular approaches to decipher the functional significance of the BRCA2-Rad51 complex. We propose to accomplish our research goals by applying a combination of biochemistry, electron microscopy, and genetics. We have already developed several methods to study the biochemical functions of the human Rad51 protein and are able to visualize the filamentous, catalytically active form of this recombinase on DNA by electron microscopy. Portions of the human BRCA2 protein important for homologous recombination function have been expressed and purified to a high degree. We will characterize these BRCA2 domains for DNA binding by biochemical techniques and use electron microscopy to examine their functional interactions with Rad51 in the context of assembly of the Rad51-DNA filament. We are in the process of generating the complete BRCA2 protein. When available, full length BRCA2 will be similarly characterized. In addition to the studies involving purified protein factors, we will introduce mutations into the BRCA2 protein to attenuate its DNA binding activity. The effects of these mutations will be defined using our biochemical assays and electron microscopy. How these mutations affect BRCA2 function in cells will be assessed by genetic methods. The results from our research will for the first time elucidate the biological function of the BRCA2 protein and should illuminate the link between defective homologous recombination and breast tumor formation. It is anticipated that the knowledge gained from this research project will make a major contribution toward breast cancer prevention and treatment. In addition, the research material that we generate will greatly facilitate the efforts of other investigators in the breast cancer field.

    Lay Abstract:
    A significant proportion of familial breast cancers are caused by mutations in the BRCA2 gene. Despite the prevalence of the BRCA2 gene in breast cancer etiology, relatively little is known about the molecular function of its encoded protein. Importantly, recent studies have found interactions between BRCA2 and Rad51, which is a key member of the RAD52 group of proteins that mediate homologous recombination and the repair of damaged chromosomes. This research project will use a variety of molecular approaches to decipher the functional significance of the BRCA2-Rad51 complex. We propose to accomplish our research goals by applying a combination of biochemistry, electron microscopy, cytology, and genetics. The results from our research will for the first time elucidate the biological function of the BRCA2 protein and should illuminate the link between defective homologous recombination and breast tumor formation. It is anticipated that the knowledge garnered from this research project will make a major contribution toward breast cancer prevention and treatment. In addition, the research material that we generate will facilitate the efforts of other investigators.