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 #
5R01CA095175-07
Application #
7790609
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Pelroy, Richard
Project Start
2002-05-01
Project End
2014-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
7
Fiscal Year
2010
Total Cost
$304,354
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Hwang, Yung; Futran, Melinda; Hidalgo, Daniel et al. (2017) Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch. Sci Adv 3:e1700298
Smith, Eric A; Gole, Boris; Willis, Nicholas A et al. (2017) DEK is required for homologous recombination repair of DNA breaks. Sci Rep 7:44662
Willis, Nicholas A; Frock, Richard L; Menghi, Francesca et al. (2017) Mechanism of tandem duplication formation in BRCA1-mutant cells. Nature 551:590-595
Juvekar, Ashish; Hu, Hai; Yadegarynia, Sina et al. (2016) Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion. Proc Natl Acad Sci U S A 113:E4338-47
Willis, Nicholas A; Scully, Ralph (2016) DNA Polymerase ?: Duct Tape and Zip Ties for a Fragile Genome. Mol Cell 63:542-544
Menghi, Francesca; Inaki, Koichiro; Woo, XingYi et al. (2016) The tandem duplicator phenotype as a distinct genomic configuration in cancer. Proc Natl Acad Sci U S A 113:E2373-82
Hartlerode, Andrea J; Willis, Nicholas A; Rajendran, Anbazhagan et al. (2016) Complex Breakpoints and Template Switching Associated with Non-canonical Termination of Homologous Recombination in Mammalian Cells. PLoS Genet 12:e1006410
Guirouilh-Barbat, Josée; Gelot, Camille; Xie, Anyong et al. (2016) 53BP1 Protects against CtIP-Dependent Capture of Ectopic Chromosomal Sequences at the Junction of Distant Double-Strand Breaks. PLoS Genet 12:e1006230
Willis, Nicholas A; Scully, Ralph (2016) Spatial separation of replisome arrest sites influences homologous recombination quality at a Tus/Ter-mediated replication fork barrier. Cell Cycle 15:1812-20
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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