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    Awarded Grants
    Delineation of the role of the tumor suppressor BRCA2 in homologous recombination and DNA repair

    Scientific Abstract:
    Sung, P PDF0503471 Delineation of the role of the tumor suppressor BRCA2 in homologous recombination and DNA repair Mutations in the BRCA2 gene are linked to familial and sporadic breast cancer, yet the molecular function of BRCA2 protein remains largely obscure. BRCA2 protein physically interacts with the Rad51 recombinase, a member of the RAD52 epistasis group of proteins that mediate homologous recombination (HR), a major mechanism that repairs chromosomes damaged by ionizing radiation and genotoxic agents. Accordingly, BRCA2 deficient cell lines exhibit impaired HR and sensitivity to genotoxic agents. A combination of protein biochemistry, recombination enzymology, and electron microscopy will be applied toward validating the hypothesis that BRCA2 influences the Rad51 recombinase activity by nucleating Rad51 onto ssDNA to seed the assembly of the Rad51 presynaptic filament that is central to HR reactions. To achieve our research goal, we will (1) delineate the functional significance of the DSS1 protein in DNA binding by BRCA2 and (2) examine full length BRCA2 and variants containing Rad51-interaction and DNA binding functions for the ability to target Rad51 to HR substrates. As evidence connecting dysfunctional recombination to breast tumor formation emerges, the need for demarcating the interactions between BRCA2 and Rad51 at the mechanistic level becomes more urgent. By deciphering the functional significance of these interactions, we will be able to rationalize how mutations in BRCA2 lead to genome instability and breast cancer.

    Lay Abstract:
    Sung, P PDF0503471 Delineation of the role of the tumor suppressor BRCA2 in homologous recombination and DNA repair Mutations in the BRCA2 gene are linked to familial and sporadic breast cancer, but the molecular function of BRCA2 protein remains to be delineated. BRCA2 protein is thought to be involved in DNA damage repair via interaction with the Rad51 recombinase, a member of the RAD52 group of proteins that mediate homologous recombination, a major mechanism that repairs chromosomes injured by ionizing radiation or genotoxic agents. Consistent with this premise, BRCA2 deficient cell lines have impaired homologous recombination and are highly sensitive to agents that damage DNA. Taken together, the evidence points to the possibility that BRCA2 protein enhances the efficiency of homologous recombination and DNA repair reactions via regulation of the Rad51 recombinase activity. To test this premise, electron microscopy and a variety of biochemical experiments will be conducted to determine the influence of BRCA2 on Rad51 protein functions. Comprehending the manner in which BRCA2 modulates Rad51 activity and the functional integrity of the homologous recombination machinery could very well pave the way for devising new strategies in breast cancer diagnosis, prevention, and treatment.