Human homologue of yeast rad23 protein A interacts with p300/cyclic AMP-responsive element binding (CREB)-binding protein to down-regulate transcriptional activity of p53

The tumor suppressor protein p53 regulates various cellular responses to DN A damage and plays a significant role in DNA repair. The nuclear p300/cycli c AMP-responsive element binding (CREB)-binding protein (CBP) proteins act as coactivators in supporting the transcription function of p53. We examine d the role of the human homologue of yeast Rad23 protein A (hHR23A), one of the two human homologues of the Saccharomyces cerevisiae nucleotide excisi on repair gene product Rad23, in the p300/CBP-associated regulation of p53 activity. Overexpression of wildtype hHR23A inhibits the p53 transcriptiona l activity and results in a decreased steady-state protein level of cellula r p53. The inhibitory effect of hHR23A can be overcome by the concomitant e xpression of p300, CBP, and p300 segments harboring C/H1 domain and neutral ized by the coexpression of HIV accessory protein Vpr, which binds COOH ter minus of hHR23A/B. Additionally, hHR23A was shown to interact in vitro and in vivo with p300 segments harboring C/H1 domain. These studies provide evi dence for the involvement of hHR23A in the regulation of p53 activity throu gh p300/CBP. Although the precise direct role of hHR23 proteins in regulati on of p53 and DNA repair remains to be elucidated, our data suggest that th e interaction between hHR23A and p300/CBP has important implications in cro ss-talk between the p53 pathway and DNA repair.