Loss of function of either BRCA1 or BRCA2 results in genomic instability and breast cancer predisposition, although the precise mechanism from a heterozygous mutant germline to homozygous inactivation in breast cancers is unknown. BRCA1 and to a lesser extent BRCA2 have been implicated in a wide variety of cellular processes, but a property shared by both proteins is an involvement in homologous recombination (HR). HR can be utilized for the error-free repair of DNA double-strand breaks (DSBs) or for the restart of stalled or damaged DNA replication forks. If error-free HR is defective, error-prone homologous and non-homologous repair becomes more prevalent, which may result in genomic instability. Thus, defining the roles of BRCA1 and BRCA2 in HR may be the key to understanding the cancer-prone phenotype of BRCA mutation carriers. This study has two main aims, which are related to the view that BRCA1 plays a proximal and extensive role in the cellular response to DNA damage, where it links sensing and signaling of damage to effector components. (1) We will test the hypothesis that BRCA1 controls several pathways of DSB repair, while BRCA2, which is located downstream of BRCA1, only promotes the process of error-free HR. Thus, it is predicted that the error-prone repair phenotype observed in BRCAl-deficient cells is different, and perhaps more severe, than in cells without BRCA2. We will study the outcome of error-prone repair on both the DNA sequence and the chromosomal level using novel plasmid-based assay systems. (2) BRCA1 interacts with (i) the cell-cycle checkpoint regulator Chk2, which is connected to the replication-fork-associated hMus81 protein, and with (ii) the DNA damage processing and signaling complex comprised of the Mrel 1, Rad50, and NBS1 (MRN) proteins. We will test a dual model ofBRCA1, in which BRCA1 in conjunction with Chk2 promotes homologymediated repair and replication restart, while at the same time inhibits the error-prone repair activity that is inherent to the MRN complex. These experiments may support the recent epidemiological evidence that places Chk2 and the BRCA proteins in a common breast cancer-preventing pathway. The primary goal of this study is to define the roles of BRCA1 and BRCA2 in homology-mediated DSB repair. Ultimately, the defects in HR that promote carcinogenesis by causing genetic instability may also offer a novel therapeutic target against the cancers that arise in this setting.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107640-04
Application #
7046685
Study Section
Special Emphasis Panel (ZRG1-CDF-2 (90))
Program Officer
Pelroy, Richard
Project Start
2004-04-14
Project End
2009-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
4
Fiscal Year
2006
Total Cost
$286,215
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Fridlich, Ram; Annamalai, Devi; Roy, Rohini et al. (2015) BRCA1 and BRCA2 protect against oxidative DNA damage converted into double-strand breaks during DNA replication. DNA Repair (Amst) 30:11-20
Lok, B H; Carley, A C; Tchang, B et al. (2013) RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination. Oncogene 32:3552-8
Chun, Jarin; Buechelmaier, Erika S; Powell, Simon N (2013) Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway. Mol Cell Biol 33:387-95
Guo, Gong-She; Zhang, Feng-Mei; Gao, Rui-Jie et al. (2011) DNA repair and synthetic lethality. Int J Oral Sci 3:176-9
Feng, Zhihui; Scott, Shaun P; Bussen, Wendy et al. (2011) Rad52 inactivation is synthetically lethal with BRCA2 deficiency. Proc Natl Acad Sci U S A 108:686-91
Roy, Rohini; Chun, Jarin; Powell, Simon N (2011) BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer 12:68-78
Barker, Christopher A; Powell, Simon N (2010) Enhancing radiotherapy through a greater understanding of homologous recombination. Semin Radiat Oncol 20:267-273.e3
Willers, Henning; Taghian, Alphonse G; Luo, Chen-Mei et al. (2009) Utility of DNA repair protein foci for the detection of putative BRCA1 pathway defects in breast cancer biopsies. Mol Cancer Res 7:1304-9
Evans, James W; Chernikova, Sophia B; Kachnic, Lisa A et al. (2008) Homologous recombination is the principal pathway for the repair of DNA damage induced by tirapazamine in mammalian cells. Cancer Res 68:257-65
Zhang, Junran; Powell, Simon N (2005) The role of the BRCA1 tumor suppressor in DNA double-strand break repair. Mol Cancer Res 3:531-9

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