Mutation of the Breast Cancer 1 gene product (BRCA1) accounts for approximately 20,000 cases of inherited breast and ovarian cancers annually. An established function for BRCA1 is maintaining genomic integrity through the repair of DNA double strand breaks (DSBs). Inappropriate repair of DSBs can result in genomic instability -- including chromosomal rearrangements and deletions -- both of which are implicated in oncogenesis. BRCA1 is phosphorylated in response to DNA damage by the breast cancer suppressor checkpoint kinases ATM and CHK2, bolstering the concept that a BRCA1 dependent pathway of DNA repair is required to suppress malignancy. Preliminary data presented in this proposal supports a new model for BRCA1 function in DNA repair. DNA damage induced phosphorylation of BRCA1 by ATM and CHK2 kinases enables new, DNA damage specific associations for BRCA1. The resultant damage induced BRCA1 supercomplexes are biochemically and functionally distinct. Thus, BRCA1 and associated proteins do not function as a single entity to survey the genome as is widely accepted, but rather as an inducible network of modular units with distinct repair activities. This view may be relevant for a deeper understanding of DNA repair and tumor suppression phenotypes that occur in individuals harboring inactivating mutations in BRCA1 interacting proteins. The future directions described in this proposal will investigate a relationship between BRCA1 DNA damage checkpoint function and chromatin. Relationships between BRCA1 and chromatin structure are proposed to contribute to novel checkpoint and repair mechanisms. Through a series of mentored research and structured learning activities, this proposal seeks (1) to gain novel insights into the BRCA1 pathway of genome integrity maintenance and (2) to develop the requisite skills to become a successful, independent investigator in the field of cancer biology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA106597-05
Application #
7840396
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2006-05-19
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$135,677
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Coleman, Kara A; Greenberg, Roger A (2011) The BRCA1-RAP80 complex regulates DNA repair mechanism utilization by restricting end resection. J Biol Chem 286:13669-80
Tang, Jiang-Bo; Greenberg, Roger A (2010) Connecting the Dots: Interplay between Ubiquitylation and SUMOylation at DNA Double-Strand Breaks. Genes Cancer 1:787-96
Shanbhag, Niraj M; Greenberg, Roger A (2010) Neighborly DISCourse: DNA double strand breaks silence transcription. Cell Cycle 9:3635-6
Solyom, Szilvia; Patterson-Fortin, Jeffery; Pylkäs, Katri et al. (2010) Mutation screening of the MERIT40 gene encoding a novel BRCA1 and RAP80 interacting protein in breast cancer families. Breast Cancer Res Treat 120:165-8
Shanbhag, Niraj M; Rafalska-Metcalf, Ilona U; Balane-Bolivar, Carlo et al. (2010) ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. Cell 141:970-81
Patterson-Fortin, Jeffrey; Shao, Genze; Bretscher, Heidi et al. (2010) Differential regulation of JAMM domain deubiquitinating enzyme activity within the RAP80 complex. J Biol Chem 285:30971-81
Shao, Genze; Patterson-Fortin, Jeffrey; Messick, Troy E et al. (2009) MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes Dev 23:740-54
Domchek, Susan M; Greenberg, Roger A (2009) Breast cancer gene variants: separating the harmful from the harmless. J Clin Invest 119:2895-7
Shao, Genze; Lilli, Dana R; Patterson-Fortin, Jeffrey et al. (2009) The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proc Natl Acad Sci U S A 106:3166-71

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