BRCA is an important tumor suppressor for familiar breast and ovarian cancers. Accumulated evidence suggests that BRCA1 participates in DNA damage response including cell cycle checkpoint activation and DNA damage repair. Mutations of BRCA1 abrogate DNA damage response and induce genomic instability under genotoxic stress. Interestingly, recent evidence suggests that PARP inhibitors can specifically suppress BRCA1 mutation-induced breast tumors. Again, the molecular mechanism by which PARP inhibitor selectively kill tumor cells bearing BRCA1 mutations is not clear. It has been shown that BARD1 is a functional partner of BRCA1. Like BRCA1, germline mutations of BARD1 have been found in breast and ovarian cancer patients. Carriers of BARD1 mutations are also predisposed to breast and ovarian cancers, suggesting that like BRCA1, BARD1 is an important tumor suppressor. Unexpectedly, we found that the BRCT domain of BARD1 recognizes poly(ADP-ribose) (PAR). The interaction between the BARD1 BRCT domain and PAR is required for targeting BRCA1 to the sites of DNA damage and facilitates the correlated DNA damage repair. Based on our preliminary study, we hypothesize that the binding between PAR and the BRCA1-BARD1 complex plays a critical role for breast and ovarian tumor suppression. Thus, in this project, we plan to: 1) examine the molecular mechanism by which PAR regulates the BRCA1-BARD1 complex in response to DNA damage;2) characterize the functional defects of the cancer-associated BRCA1 and BARD1 mutations in PAR-dependent DNA damage response;3) study the efficacy of PARP inhibitors in the treatment of BRCA1 mutation-induced mammary tumors. These studies will not only reveal the molecular mechanism of BRCA pathway in DNA damage response, but also translate our basic science research into tumor prevention.

Public Health Relevance

Mutations of BRCA1 are associated with familial breast and ovarian cancers. Accumulated evidence suggests that BRCA1 participates in DNA damage response. However, the molecular mechanism by which BRCA1 in DNA damage response remains elusive. Here, we found that poly(ADP-ribose) mediates the DNA damage repair function of BRCA1. In this proposal, we plan to dissect the role of poly(ADP-ribose) in the BRCA1-dependent DNA damage response. The results will help to understand the role of BRCA pathway in familial breast and ovarian tumor suppression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA187209-01
Application #
8747748
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$322,576
Indirect Cost
$115,076
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Li, M; Yu, X (2015) The role of poly(ADP-ribosyl)ation in DNA damage response and cancer chemotherapy. Oncogene 34:3349-56
Osterman, Michael; Kathawa, Deion; Liu, Diangang et al. (2014) Elevated DNA damage response in pancreatic cancer. Histochem Cell Biol 142:713-20