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 #
5R01CA095175-10
Application #
8433495
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Pelroy, Richard
Project Start
2002-05-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$277,509
Indirect Cost
$114,268
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Willis, Nicholas A; Panday, Arvind; Duffey, Erin E et al. (2018) Rad51 recruitment and exclusion of non-homologous end joining during homologous recombination at a Tus/Ter mammalian replication fork barrier. PLoS Genet 14:e1007486
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
Willis, Nicholas A; Frock, Richard L; Menghi, Francesca et al. (2017) Mechanism of tandem duplication formation in BRCA1-mutant cells. Nature 551:590-595
Nath, Sarmi; Somyajit, Kumar; Mishra, Anup et al. (2017) FANCJ helicase controls the balance between short- and long-tract gene conversions between sister chromatids. Nucleic Acids Res 45:8886-8900
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; 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
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
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
Willis, Nicholas A; Scully, Ralph (2016) DNA Polymerase ?: Duct Tape and Zip Ties for a Fragile Genome. Mol Cell 63:542-544
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

Showing the most recent 10 out of 43 publications