The long-term objective of this proposal is to determine the tumor suppressor functions of the hereditary breast/ovarian cancer susceptibility gene, BRCA1. BRCA1 and its associated proteins are known to contribute to homologous recombination (HR), a potentially error-free form of double strand break repair. However, the precise steps in HR that are regulated by BRCA1 are not well understood. Nor is it understood to what extent BRCA1's role in HR accounts for its function as a tumor suppressor gene. We propose that BRCA1 acts as a tumor suppressor by controlling sister chromatid recombination (SCR), an HR process that operates during S and G2 phases of the cell cycle to repair replication-associated DNA damage in an error free manner. To test this hypothesis, we have developed novel SCR reporters that deliver an unprecedented degree of detailed molecular information regarding SCR, and will use them to study BRCA1's role in this process. Our data suggest that cells lacking wild-type BRCA1 have a specific defect in SCR. In work proposed here, we will explore this observation in depth and attempt to relate it to BRCA1's function as a tumor suppressor.
Our specific aims are: 1. To define SCR functions of BRCA1. 2. To determine whether clinically described mutant BRCA1 alleles are defective for SCR control. 3. To identify steps during DSB processing and SCR that are regulated by BRCA1.

Public Health Relevance

If a woman inherits an error in a vital anti-cancer gene, BRCA1, she will have a greatly (~10-fold) increased risk of breast and ovarian cancer throughout her life;however, we do not understand precisely how the loss of BRCA1 function leads to cancer. New discoveries in our laboratory suggest that BRCA1 is needed for a process called """"""""sister chromatid recombination"""""""" - a way of accurately repairing DNA breaks that arise as cells grow and divide. In this proposal, we will conduct experiments to find out whether BRCA1's tumor suppressor function is linked to its ability to repair broken DNA by sister chromatid recombination.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095175-09
Application #
8213647
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Pelroy, Richard
Project Start
2002-05-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$295,223
Indirect Cost
$121,562
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Willis, Nicholas A; Rass, Emilie; Scully, Ralph (2015) Deciphering the Code of the Cancer Genome: Mechanisms of Chromosome Rearrangement. Trends Cancer 1:217-230
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Liu, Pengda; Gan, Wenjian; Guo, Chunguang et al. (2015) Akt-mediated phosphorylation of XLF impairs non-homologous end-joining DNA repair. Mol Cell 57:648-61
Liu, Xue-Song; Chandramouly, Gurushankar; Rass, Emilie et al. (2015) LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair. Nat Commun 6:8325
Willis, Nicholas A; Chandramouly, Gurushankar; Huang, Bin et al. (2014) BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks. Nature 510:556-9
Liu, Yan; Marks, Kevin; Cowley, Glenn S et al. (2013) Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. Cancer Discov 3:870-9
Somyajit, Kumar; Basavaraju, Shivakumar; Scully, Ralph et al. (2013) ATM- and ATR-mediated phosphorylation of XRCC3 regulates DNA double-strand break-induced checkpoint activation and repair. Mol Cell Biol 33:1830-44
Chandramouly, Gurushankar; Kwok, Amy; Huang, Bin et al. (2013) BRCA1 and CtIP suppress long-tract gene conversion between sister chromatids. Nat Commun 4:2404
Scully, Ralph; Xie, Anyong (2013) Double strand break repair functions of histone H2AX. Mutat Res 750:5-14
Hartlerode, Andrea J; Guan, Yinghua; Rajendran, Anbazhagan et al. (2012) Impact of histone H4 lysine 20 methylation on 53BP1 responses to chromosomal double strand breaks. PLoS One 7:e49211

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