Mechanisms and Functional Roles of PARP1 Hyperactivation in Cancer

Genomic integrity is constantly challenged by endogenous and exogenous factors such as replication stress, APOBEC enzymes, UV radiation, and chemical agents that induce DNA damage. The DNA Damage Response (DDR) serves as a critical safeguard, detecting lesions and activating repair pathways to maintain genome stability. While most DNA lesions are repaired, excessive damage can lead to mutations and chromosomal rearrangements that contribute to cancer. Poly(ADP-ribose) polymerase 1 (PARP1) plays a central role in the early detection of DNA damage by recognizing DNA strand breaks and coordinating chromatin remodeling, DNA repair, and cell death pathways. Despite its essential function, the extent of PARP1 activation varies significantly depending on the type of DNA lesion, suggesting an additional layer of regulation that remains poorly understood. ATR kinase, a master regulator of replication stress response, ensures the stability of stalled replication forks and facilitates DNA repair. Given its essential role in genome maintenance, ATR inhibitors (ATRi) are currently being evaluated in clinical trials as promising cancer therapeutics. Notably, cancer cells treated with ATRi exhibit hypersensitivity to PARP inhibitors (PARPi), yet the underlying mechanism driving this synthetic lethality remains unclear. The goal of this proposal is to elucidate the mechanism by which ATR inhibitors enhance cancer cell sensitivity to PARP inhibitors. Our preliminary data reveal that DNA replication fork cleavage by APE1 is the key step leading to PARP1 hyperactivation after ATRi treatment. We propose to explain (1) why DNA cleavage by APE1 is the essential step leading to PARP1 hyperactivation regardless of the type of DNA lesion, (2) identify the factors driving cell sensitivity to ATR inhibition, and (3) determine the consequences of PARP1 hyperactivation for the cells. Together, this proposal will reveal how cells regulate PARP1 activation in response to different types of DNA lesions and explain why the type of DNA damage caused by ATR inhibition renders cells hypersensitive to PARP inhibitors. Project Number: 1R01CA307676-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Remi Buisson | Institution: UNIVERSITY OF CALIFORNIA-IRVINE, IRVINE, CA | Award Amount: $639,707 | Activity Code: R01 | Study Section: Biochemical and Cellular Oncogenesis Study Section[BCO] View on NIH RePORTER: https://reporter.nih.gov/project-details/11447336