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Mechanisms and Functional Roles of PARP1 Hyperactivation in Cancer

Award Number: R01CA307676
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/20/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Mechanisms and Functional Roles of PARP1 Hyperactivation in Cancer - PROJECT SUMMARY 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $639,707 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Cause and Prevention Research	000	1	6/26/2026	NEW	$639,707
														Subtotal = $639,707

Grand Total All Awards = $639,707

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Mechanisms and Functional Roles of PARP1 Hyperactivation in Cancer

Award Number: R01CA307676

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/20/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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