Ku70 and Poly(ADP-Ribose) Polymerase-1 Competitively Regulate β-Catenin and T-Cell Factor-4–Mediated Gene Transactivation: Possible Linkage of DNA Damage Recognition and Wnt Signaling

Open Access
Publisher Website
Google Scholar
Abstract
Formation of the T-cell factor-4 (TCF-4) and β-catenin nuclear complex is considered crucial to embryonic development and colorectal carcinogenesis. We previously reported that poly(ADP-ribose) polymerase-1 (PARP-1) interacts with the TCF-4 and β-catenin complex and enhances its transcriptional activity. However, its biological significance remains unexplained. Using immunoprecipitation and mass spectrometry, we found that two Ku proteins, Ku70 and Ku80, were also associated with the complex. Knockdown of Ku70 by RNA interference increased the amount of β-catenin associated with TCF-4 and enhanced the transcriptional activity. PARP-1 competed with Ku70 for binding to TCF-4. Treatment with bleomycin, a DNA-damaging alkylating agent, induced polyADP-ribosylation of PARP-1 protein and inhibited its interaction with TCF-4. Bleomycin conversely increased the amounts of Ku70 coimmunoprecipitated with TCF-4 and removed β-catenin from TCF-4. We propose a working model in which the transcriptional activity of TCF-4 is regulated by the relative amount of Ku70, PARP-1, and β-catenin proteins binding to TCF-4. Identification of the functional interaction of Ku70 as well as PARP-1 with the TCF-4 and β-catenin transcriptional complex may provide insights into a novel linkage between DNA damage recognition/repair and Wnt signaling. [Cancer Res 2007;67(3):911–8]