Cancer occurs as a result of mutations, or abnormal changes, in the genes responsible for regulating the growth of cells and keeping them healthy. Normal cells encounter numerous DNA damages induced by environmental and internal hazards. A gene named BRCA1 exists in the cells of ovarian and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired. If BRCA1 itself is mutated, the damaged DNA won’t be repaired properly, which significantly increases risks for cancers. Ovarian cancer cases are often attributed to germline mutations of BRCA1 gene, conferring lifetime risks of up to 50% in the mutation carriers for developing ovarian cancer.
Recent studies suggest that PARP inhibitors could be the prevalent anticancer drug for ovarian cancer chemotherapeutics. However, how PARP inhibitors kill ovarian tumor cells is far from clear. Particularly, it is not clear whether PARP inhibitors could kill all the ovarian tumors bearing BRCA1 mutations or just selectively kill a set of ovarian tumor cells with specific BRCA1 mutations. Following DNA damage, PARPs catalyze poly-ADP-ribose (PAR), a kind of small molecule polymers, at DNA lesions, which is important for DNA damage repair without elucidated mechanism. Here, we found that PAR recruited the BRCA1 complex to DNA damage sites to fulfill its DNA repair function. Suppression PAR synthesis at DNA damage sites by PARPs inhibitor abrogates partial of BRCA1’s function. Since BRCA1 is essential for cell viability and most ovarian cancer-associated BRCA1 mutations also abolish partial of BRCA1’s function, PARPs inhibitors could easily kill ovarian tumor cells bearing cancer-associated BRCA1 mutations by aggravating the loss of BRCA1-dependent function in cells. However, based on our preliminary results, PARPs inhibitors treatment could not aggravate the loss of BRCA1-dependent function on a small subset of BRCA1 mutations.
In this application, we plan to examine which BRCA1 mutations are sensitive to PARPs inhibitor treatment. These results may have major impact on the design of future ovarian cancer chemotherapeutics to improve the survival rate of ovarian cancer patients.