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)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132755-12
Application #
9687676
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
2008-04-01
Project End
2020-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
12
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Chen, Qian; Kassab, Muzaffer Ahmad; Dantzer, Fran├žoise et al. (2018) PARP2 mediates branched poly ADP-ribosylation in response to DNA damage. Nat Commun 9:3233
Wang, Jiaxu; Yuan, Zenglin; Cui, Yaqi et al. (2018) Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR. Nat Commun 9:2689
Wang, Mengxi; Yuan, Zenglin; Xie, Rong et al. (2018) Structure-function analyses reveal the mechanism of the ARH3-dependent hydrolysis of ADP-ribosylation. J Biol Chem 293:14470-14480
Liu, Yidan; Zhang, Bin; Meng, Xiaoyu et al. (2017) UHRF2 regulates local 5-methylcytosine and suppresses spontaneous seizures. Epigenetics 12:551-560
Li, Mo; Chen, Qian; Ma, Teng et al. (2017) Targeting reactive nitrogen species suppresses hereditary pancreatic cancer. Proc Natl Acad Sci U S A 114:7106-7111
Liu, Chao; Vyas, Aditi; Kassab, Muzaffer A et al. (2017) The role of poly ADP-ribosylation in the first wave of DNA damage response. Nucleic Acids Res 45:8129-8141
Han, Deqiang; Chen, Qian; Shi, Jiazhong et al. (2017) CTCF participates in DNA damage response via poly(ADP-ribosyl)ation. Sci Rep 7:43530
Li, Mo; Chen, Qian; Yu, Xiaochun (2017) Chemopreventive Effects of ROS Targeting in a Murine Model of BRCA1-Deficient Breast Cancer. Cancer Res 77:448-458
Evans, Joseph R; Zhao, Shuang G; Chang, S Laura et al. (2016) Patient-Level DNA Damage and Repair Pathway Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer. JAMA Oncol 2:471-80
Yu, Xiaochun (2016) A special issue on the DNA damage response and genomic instability. Acta Biochim Biophys Sin (Shanghai) 48:593

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