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Your Environment. Your Health.

MECHANISM OF RAD51C FORK PROTECTION AND ENVIRONMENTAL CARCINOGENESIS

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Principal Investigator: Schlacher, Katharina
Institute Receiving Award University Of Tx Md Anderson Can Ctr
Location Houston, TX
Grant Number R01ES029680
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 15 Sep 2018 to 31 May 2023
DESCRIPTION (provided by applicant): 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.
Science Code(s)/Area of Science(s) Primary: 09 - Genome Integrity
Publications See publications associated with this Grant.
Program Officer Leslie Reinlib
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