Binding of CtlP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage
Authors: Shang Li,*, Phang-Lang Chen, Dave Sharp, and Wen-Hwa Lee
Departments of Molecular Medicine/institute of Biotechnology, UTHSCSA
Presenter: Mr.Shang Li, Ph.D. Candidate
Departments of molecular Medicine/Institute of Biotechnology, UTHSCSA
摘要：
Mutations in BRCA1are responsible for nearly all of the hereditary ovarian and breast cancers, and about half of those in breast cancer-only kindreds. The ability of BRCA1 to transactivate the p21 promoter can be inactivated by mutation of the C-terminal conserved BRCT domains. To explore the mechanisms of this BRCA1 function, the BRCT domains were used as bait in a yeast tow-hybrid screen. A known protein, CtlP, a co-repressor with CtBP, was found. CtlP interacts specifically with the BRCT domains of BRCA1, both in vitro and in vivo, and tumor-derived mutations abolished these interactions. The association of BRCA1 with CtlP was also abrogated in cells treated with DNA-damaging agents including UV, g-irradiation and adrimaycin, a response correlated with BRCA1 phosphorylation. The transactivation of the p21 promoter by BRCA1 was diminished by expression of exogenous CtlP and CtBP. These results suggest that the binding of the BRCT domains of BRCA1 to CtlP/CtBP is critical in mediating transcriptional regulation of p21 in response to DNA damage.