Grant: Project Grant

Poly(ADP-ribose) polymerases (PARPs) are a diverse class of medically relevant human enzymes, with regulatory roles in virtually all aspects of cell biology. The enzyme PARP1 is a principal component of the cellular response to DNA damage. PARP1 rapidly detects DNA strand breaks and then creates the molecule poly(ADP-ribose) to signal the presence and location of the DNA break. Poly(ADP-ribose) recruits other cellular factors to the site of DNA breaks so that the damage can be repaired in a timely and efficient manner. Certain cancers have inherent deficiencies in the repair of DNA strand breaks, and the survival of these cancer cells is dependent on PARP1 activity. PARP inhibitor (PARPi) compounds block PARP1 activity and are thus toxic to these cancer cells with defective DNA repair, whereas normal cells are able to withstand PARPi treatment. The proposed research will provide fundamental insights into the control of PARP1 activity in cells that will improve our ability to regulate PARP1 activity for cancer treatment. PARP1 hyperactivity is associated with other diseases, such as cardiovascular and neurodegenerative disorders, thus our findings will also impact our understanding of PARP1 regulation in other areas of biology that are important for human health.