Grant: Operating Grant

The DNA that composes our genetic information is susceptible to damage that must be repaired in order to maintain the integrity of the genome and the health of an organism. Correspondingly, cells have extensive DNA repair mechanisms that detect and correct the damage that arises from environmental agents such as ultraviolet radiation and through normal cellular processes such as DNA replication. Several human deficiencies in DNA repair are associated with genomic instability and cellular transformations that can lead to cancer, thus underscoring the need to understand at a detailed molecular level the mechanisms of DNA repair. Our research focuses on a family of proteins called poly(ADP-ribose) polymerases, or PARPs. Several PARP family members are integral to the DNA damage response, where they detect damage and facilitate repair. PARP inhibitors are under clinical development to treat various cancers. An exciting aspect of PARP inhibition is the ability to selectively target cancer cells with known DNA repair deficiencies (e.g. BRCA1/2 deficient cancers). Our research group uses a structural biology approach to study how the PARP proteins recognize DNA breaks and how binding to these breaks turns on their catalytic activity to coordinate DNA repair. In particular, we use x-ray crystallography and other structural biology techniques to obtain detailed three-dimensional structures of PARPs that allow us to understand their function and mechanism at the molecular level. We further use cell biological and biochemical analysis to advance our understanding of PARP contribution to DNA repair, and to identify novel ways of inhibiting PARPs for cancer treatment.