GENOME MAINTENANCE VIA THE BRCA-PALB2 TUMOR SUPPRESSOR NETWORK

Homologous recombination (HR) is a major chromosome damage repair tool. By eliminating DNA double-strand breaks and other deleterious lesions, HR is indispensable for the maintenance of genome stability.In humans, defects in HR directly lead to cancer. This renewal project focuses on the roles of the tumorsuppressors BRCA1, BARD1, BRCA2, and PALB2 in the HR-mediated repair of damaged chromosomes.Considerable progress has been made during the last funding period, leading to important advances inunderstanding HR mechanism. Capitalizing on our success, a variety of in vitro and in vivo studies will beconducted to delineate the multifaceted roles of the BRCA1-BARD1-BRCA2-PALB2 ensemble in the HRreaction that is catalyzed by the recombinase RAD51. Novel hypotheses regarding how the HR factorsfacilitate the presynaptic stage of the HR reaction and how cancer mutations affect this critical HR step willbe tested. The results from this renewal project will continue to provide insights regarding the functions ofkey HR factors, and will allow us to formulate detailed models of chromosome damage repair and genomemaintenance via the BRCA-PALB2 tumor suppressor network. Our studies have direct relevance to cancerbiology and to the development of chemical compounds to evaluate the potential of HR pathway-targetedtherapeutic strategies. Moreover, the research materials generated during the course of our studiesrepresent an invaluable resource for the DNA repair and cancer biology research communities.