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Synergistic DNA repair genes and sensitivity to radiation therapy in prostate cancer

Award Number: R15CA263784
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Synergistic DNA repair genes and sensitivity to radiation therapy in prostate cancer - PROJECT SUMMARY/ABSTRACT In the U.S, over 33,000 patients die yearly from prostate cancer (PCa), and an estimated 190,000 new cases are diagnosed. 10-20% of these patients are diagnosed with metastatic PCa (mPCa). mPCa and metastatic castration-resistant prostate cancer (mCRPC) acquire resistance to established treatments and progress with profound effects on patient quality of life. mCRPC remains fatal. Our group was the first to describe the new DNA repair gene FAM35A whose status may greatly affect tumor sensitivity to radiation treatment in a large proportion of PCa patients. This R15 project will determine a new mechanism of FAM35A-related treatment resistance/sensitization in PCa. Our central hypothesis is that 1) FAM35A regulates resection inhibition and 2) FAM35A and DNA polymerase theta (POLQ) antagonize the homologous recombination (HR) pathway. We will investigate through the following two specific aims: AIM 1: Determine the mechanism of FAM35A-mediated resection inhibition. Although our FAM35A-complex data includes BLM as a binding partner, it remains unclear how FAM35A blocks activity of resection enzymes (BLM-DNA2 and BLM-EXO1) and/or prevents the interaction of BLM with DNA2 or EXO1. We will test our working hypothesis that FAM35A prevents nuclease activity by binding to DNA and/or by binding to BLM. Our experimental approach will incorporate biochemical and cell biology methods to determine FAM35A’s resection inhibition activity. First, we will a) confirm in vitro DNA-binding activity of the two FAM35A isoforms, and b) determine the BLM binding site in FAM35A. Using FAM35A knockout cell lines complemented with mutant FAM35A, we will then assess DNA damage sensitivity using clonogenic assays; monitor the DNA damage response using confocal microscopy; and measure resection using DNA fiber assays. AIM 2: Elucidate the mechanism by which FAM35A contributes to the DNA damage response in POLQ KO PCa. My working hypothesis is that depletion of FAM35A/POLQ causes complete dysfunction of both c- and alt- NHEJ pathways, resulting in HR hyperactivation. 1) To test how FAM35A deficiency affects DNA damaging agents with and without POLQ, we will perform clonogenic assays using three FAM35A-depleted PCa cell lines of varying POLQ status. 2) To determine DNA repair activity in FAM35A-depleted POLQ KO PCa cells treated with DNA damaging agents, we will use confocal microscopy and immunoblotting to monitor the DNA damage response with DNA damage inducing agents. We will perform DSB-induced HR assays to measure HR activity. Results are expected to clarify the role of DNA repair dysfunction in resistance/sensitization in PCa and facilitate discovery of therapeutic and prognostic targets for radiation. The primary positive impact will be clarification of roles of DNA repair pathway between FAM35A and Polq. This AREA project will enable the research training of undergraduate and graduate students pursuing careers in health and basic sciences.


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 = -$190 )
2026	2021	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Cancer Cause and Prevention Research	000	1	11/18/2025	NEW	-$190
														Subtotal = -$190

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Cancer Cause and Prevention Research	000	1	7/17/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $446,505 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Cancer Cause and Prevention Research	000	1	6/22/2021	NEW	$446,505
														Subtotal = $446,505

Grand Total All Awards = $446,315

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Synergistic DNA repair genes and sensitivity to radiation therapy in prostate cancer

Award Number: R15CA263784

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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