Double-stranded DNA breaks (DSB)s are repaired by two major mechanistically distinct pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). The relative contribution of the competing DSB repair pathways differs in the different cell types and in different phases of the cell cycle, and this balance is critical for maintaining genomic stability. The major focus of my research is to decipher the molecular mechanism of the cellular response to DSBs. Epithelial ovarian cancer (EOC) is characterized by enhanced sensitivity to platinum analogs and PARP inhibitors (PARPi) due to defects in HR-mediated DSB repair, characterized primarily by BRCA1/2 alterations. However, de novo and acquired resistance to these agents is common and poses a significant and unsolved clinical challenge. Here, we focus on a newly discovered factor, DYNLL1, and the well-established DSB repair factor, 53BP1. The initial step of DNA end resection is critical for the choice of DSB repair pathways and, thereby, response to PARPi and platinum-based therapy. In a systematic effort to overcome resistance to these agents, we plan to investigate the underlying biology of PARPi and platinum resistance of BRCA-mutant EOCs in the context of manipulating the DYNLL1/53BP1 axes.
