Friday, December 12, 2025 12/12/2025

Mechanism of RAD51C fork protection and environmental carcinogenesis

Award Number: R01ES029680
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2025

Group Awards By:

View Award Description

Mechanism of RAD51C fork protection and environmental carcinogenesis - SUMMARY Environmental carcinogens generate DNA damage that stalls DNA replication. This jeopardizes genomic integrity critical to diverse disease-suppression. Accumulating reports show that individuals with mutations in breast cancer predisposition genes (BRCA) (found in more than 1 in 150 people) have increased cancer rates upon exposure to environmental carcinogens. The underlying cause for this has recently come under debate. In this application, we will determine the molecular mechanism of DNA replication fork protection (FP) mediated by BRCA3/RAD51C and how RAD51C and FP suppress carcinogen-induced tumorigenesis. RAD51C is the newest and perhaps least understood member of the BRCA disease suppressor family. Because of sequence homology to RAD51, which is regulated by BRCA1/2 during homology-directed double- strand (DSB) break repair, RAD51C studies have focused on its repair function. However, patient data suggests an additional tumor suppression function; 8 out of 10 disease-linked RAD51C patient mutations initially identified, do not cause DSB-repair deficiencies and based on this were designated unclassified. Yet, multiple subsequent independent breast cancer population studies identified the same alleles, suggesting significance for disease penetrance. BRCA genes have cellular functions besides DNA repair. Importantly, this includes the protection of stalled DNA replication forks from degradation by MRE11 nuclease, a new functional pathway that we have recently defined. Excitingly, our preliminary data shows many of the unclassified cancer- associated RAD51C mutations compromise FP, irrespective of DSB-repair. FP prevents genome instability ubiquitously at stalled DNA replication forks as induced by virtually all environmental carcinogens. We thus hypothesize that BRCA3/RAD51C safeguards against environmental carcinogens through protection of stalled DNA replication forks. In Aim 1) we will define the mechanism of RAD51C mediated fork stability, enabled by our discovery and understanding of new BRCA gene functions in FP, by our development of a single-cell assay for protein-DNA replication fork interactions (SIRF), by our structural understanding of the RAD51C DNA binding and ATPase domains and by having established CRISPR/CAS9 knock-in mutant RAD51C human cell lines. In Aim 2) we will determine if FP defects promote environmental carcinogen-induced mammary tumorigenesis in vivo, enabled by our having established a viable mutant RAD51C mouse model with FP defects, but no apparent DSB-repair defects, and by our understanding of genetic control of FP and DSBs by PTIP and 53BP1, that allows us to genetically test and distinguish FP from DSB repair contributions to carcinogen-induced mammary carcinogenesis. Collectively the proposed research will provide fundamental knowledge of how RAD51C-mediated FP suppresses environmentally induced genome instability and tumors. As many genes besides BRCA genes are now known to control FP, the outcome of our studies can have important broad implications for accurate and efficient disease-risk assessment for a large group of people.


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 = -$19,936 )
2026	2022	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Environmental Health	000	5	12/3/2025	NON-COMPETING CONTINUATION	-$19,936
														Subtotal = -$19,936

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Environmental Health	000	5	5/31/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $360,000 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Environmental Health	000	5	6/8/2022	NON-COMPETING CONTINUATION	$360,000
														Subtotal = $360,000

Issue Date FY: 2021 ( Subtotal = $360,000 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Environmental Health	000	4	5/17/2021	NON-COMPETING CONTINUATION	$360,000
														Subtotal = $360,000

Issue Date FY: 2020 ( Subtotal = $360,000 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Environmental Health	000	3	6/15/2020	NON-COMPETING CONTINUATION	$360,000
														Subtotal = $360,000

Issue Date FY: 2019 ( Subtotal = $360,000 )
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Environmental Health	000	2	5/2/2019	NON-COMPETING CONTINUATION	$360,000
														Subtotal = $360,000

Issue Date FY: 2018 ( Subtotal = $360,000 )
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Environmental Health	000	1	9/10/2018	NEW	$360,000
														Subtotal = $360,000

Grand Total All Awards = $1,780,064

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanism of RAD51C fork protection and environmental carcinogenesis

Award Number: R01ES029680

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer