It has been proposed that the BRCA1 gene suppresses tumor formation by facilitating the cellular response to DNA damage. The major polypeptide encoded by BRCA1 has two tandem copies of the BRCT protein motif, and studies of tumor-associated mutations indicate that these sequences are required for BRCA1-mediated tumor suppression. In addition, recent work has shown that BRCA1 is a potent regulator of RNA transcription, and that the BRCT domains are also essential for this activity. Therefore, the Sos-recruitment system (SRS), a novel form of yeast two-hybrid analysis, was used to screen for proteins that bind this critical region of BRCA1. The preliminary data show that the BRCT domains interact in vivo with CtIP, a protein originally identified on the basis of its association with the CtBP transcriptional co-repressor. This finding suggests that BRCA1 regulates gene expression, at least in part, by modulating CtBP-mediated transcriptional repression. Moreover, the in vivo interaction between BRCA1 and CtIP is completely ablated by each of three independent tumor-associated mutations affecting the BRCT motifs, indicating that the BRCA/1/CtIP interaction may also be required for tumor suppression by BRCA1. In order to test these hypotheses, three Specific Aims will be pursued. First, the expression and in vivo association of BRCA1 and CtIP will be defined with respect to cell cycle progression and the cellular response to DNA damage. Second, CtIP-deficient mice will be used to investigate the role of CtIP in tumor suppression at the organismal level and in the DNA damage response at the cellular level. Third, the effects of CtIP on CtBP-dependent transcriptional repression and BRCA1-modulated transcriptional activation will be explored. These studies should yield new insights into the function of the BRCT domains with respect to BRCA1-mediated tumor suppression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA088545-01
Application #
2884838
Study Section
Pathology B Study Section (PTHB)
Program Officer
Gallahan, Daniel L
Project Start
2000-02-15
Project End
2005-01-31
Budget Start
2000-02-15
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$299,074
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Kleiman, Frida E; Wu-Baer, Foon; Fonseca, Danae et al. (2005) BRCA1/BARD1 inhibition of mRNA 3' processing involves targeted degradation of RNA polymerase II. Genes Dev 19:1227-37