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
Beck, Carole; Boehler, Christian; Guirouilh Barbat, Josée et al. (2014) PARP3 affects the relative contribution of homologous recombination and nonhomologous end-joining pathways. Nucleic Acids Res 42:5616-32
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
Scully, Ralph; Xie, Anyong (2013) Double strand break repair functions of histone H2AX. Mutat Res 750:5-14
Chandramouly, Gurushankar; Kwok, Amy; Huang, Bin et al. (2013) BRCA1 and CtIP suppress long-tract gene conversion between sister chromatids. Nat Commun 4:2404
Hartlerode, Andrea; Odate, Shobu; Shim, Inbo et al. (2011) Cell cycle-dependent induction of homologous recombination by a tightly regulated I-SceI fusion protein. PLoS One 6:e16501
Dumitrache, Lavinia C; Hu, Lingchuan; Son, Mi Young et al. (2011) Trex2 enables spontaneous sister chromatid exchanges without facilitating DNA double-strand break repair. Genetics 188:787-97
Hu, Yiduo; Scully, Ralph; Sobhian, Bijan et al. (2011) RAP80-directed tuning of BRCA1 homologous recombination function at ionizing radiation-induced nuclear foci. Genes Dev 25:685-700
Scully, Ralph (2010) A histone code for DNA repair. Nat Rev Mol Cell Biol 11:164
Xie, Anyong; Odate, Shobu; Chandramouly, Gurushankar et al. (2010) H2AX post-translational modifications in the ionizing radiation response and homologous recombination. Cell Cycle 9:3602-10
Nagaraju, Ganesh; Hartlerode, Andrea; Kwok, Amy et al. (2009) XRCC2 and XRCC3 regulate the balance between short- and long-tract gene conversions between sister chromatids. Mol Cell Biol 29:4283-94

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