The major theme of our work is how DNA repair processes are disrupted in human cancers and how this can be exploited therapeutically. The biologically significant DNA damage caused by ionizing radiation and a number of cytotoxic drugs requires double-strand break repair for survival. We have largely focused on the role of double-strand break repair and homologous recombination in particular.
Most DNA repair pathways involve sensing and signaling as well as direct repair proteins, and the upstream signaling to activate homologous recombination may be determined by both double-strand break processing as well as chromatin remodeling. Homologous recombination is often dysregulated in human tumor cells by a variety of mechanisms. Homologous recombination involves many nuclear proteins, including the breast cancer susceptibility genes, BRCA1 and BRCA2, whose function is inactivated in familial breast or ovarian cancers. BRCA1 and BRCA2 both play roles in homologous recombination (HR) although at different steps in the repair pathway. The primary function of homologous recombination may be to restart stalled replication forks, blocked by particular types of DNA damage, or to repair gaps behind the replication fork. There are many vital proteins involved in this DNA repair pathway that are under investigation within the projects of the laboratory.
Impaired HR results in sensitivity to a different spectrum of anticancer drugs, which could significantly impact therapeutic efficacy. Loss of function of the p53 tumor suppressor results in increased frequencies of HR, and inactivation of p53 is almost always found in breast cancers arising in BRCA mutation carriers. Recent work has suggested that p53 interacts with RPA, which may be responsible for the suppression of HR. The functional consequences of loss of both BRCA1/2 and p53 appear to be an important part of the tumor phenotype, and are the subject of ongoing studies. Tests on clinical breast cancer samples have suggested that inactivation of the BRCA1/2 pathway occurs in sporadic breast cancer as well as mutation carriers. We are working on which tumor types are affected in this way. In addition, why BRCA1 and BRCA2 deficiencies predispose to breast and ovarian cancer rather than other tumor types is under investigation.