The long-term goal of this competing continuation of grant (CA84199) is to understand the functions of tumor suppressor BRCA1 protein. We previously purified and identified a BRCA1 protein complex, BASC. The composition of this complex has led us to propose that BASC functions as genome surveillance complex in which the DNA repair proteins function in the upstream of the DNA damage response pathway to detect DNA lesions of different types. We will further test the genome surveillance complex hypothesis. Despite the mounting evidence that BRCA1 functions in DNA damage response, the precise roles of BRCA1 and its associated partners in the conceptual framework of DNA damage response need to be addressed. We hypothesize that TopBP1 functions as an adaptor and forms a checkpoint module with BRCA1 in response to DNA damage that parallels that of scRad9 and scRad53 in S. cerevisiae. This hypothesis thus expands the effector enzymatic activity to include an E3 ligase in the DNA damage response, adding to the effector enzymes of kinases so far (Chkl and Chk2). Furthermore, we propose that BRCA1 exerts its functions through its substrates. The many implicated functions of BRCA1 that are often seemingly unrelated and confusing may now be rationalized as the effects of different substrates. The identification of BRCA1 substrates through which the checkpoint activation is executed is another goal of this proposal.
The specific aims are (1) To test the hypothesis that RFC and/or BLM within the BASC function upstream in the response to DNA replication stress, (2) To purify BRCA1 complexes after DNA damage, (3) To test the hypothesis that TopBP1 and BRCA1 form a checkpoint module that parallels that of scRad9 and scRad53, and (4) To identify and characterize substrates of the BRCA1 ubiquitin ligase activity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA084199-04
Application #
6680632
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Mietz, Judy
Project Start
1999-12-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$282,940
Indirect Cost
Name
Baylor College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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