BRCA1 and BRCA2 are nuclear polypeptides to suppress familial breast and ovarian cancers. Accumulated evidence suggests that both BRCA1 and BRCA2 participate in DNA damage response and maintain genomic stability. Mutations of BRCA1 and BRCA2 abrogate DNA damage repair and cause genomic instability under genotoxic stress, which eventually induces tumorigenesis. However, the molecular mechanism by which BRCA1 and BRCA2 participate in DNA damage response remain elusive, which impairs the irradiation of familial breast and ovarian cancers. Recently, we and others identified that PALB2 is an important adaptor that links BRCA1 and BRCA2 in a linear DNA damage repair pathway. Moreover, like BRCA1 and BRCA2, germline mutations of PALB2 are associated with familial breast and ovarian cancers, suggesting that PALB2 is a bona fide tumor suppressor. To elucidate the function of this BRCA pathway in DNA damage response and tumor suppression, our research focuses on the molecular mechanism of PALB2. Using unbiased protein affinity purification approach, we identified several PALB2 partners. Our preliminary study indicates that PALB2 is a double-strand DNA binding protein and plays an important role in DNA damage-induced histone acetylation and chromatin remodeling. In this project, we plan to: 1) dissect the molecular mechanism of PALB2 in DNA damage-induced chromatin remodeling;2) examine the functional defects of cancer-associated PALB2 mutations;3) explore novel therapeutic strategies to prevent PALB2 deficiency-induced tumorigenesis. These studies will not only reveal the molecular mechanism of BRCA pathway in DNA damage response, but also translate our knowledge from basic science research into tumor prevention.

Public Health Relevance

Mutations of BRCA1 and BRCA2 associate with familial breast and ovarian cancers. Accumulated evidence suggests that both BRCA1 and BRCA2 participate in DNA damage response. However, the molecular mechanism of BRCA1 and BRCA2 in DNA damage response remains elusive. Recently, we and others found that PALB2 is an important adaptor that links BRCA1 and BRCA2 in DNA damage repair. In this proposal, we plan to dissect the molecular mechanism of PALB2 in DNA damage repair. This study is likely to reveal the novel function of the BRCA pathway in DNA damage response. The results may also lead to design novel strategies for tumor prevention.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01CA132755-06A1
Application #
8628417
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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