FUNCTIONAL INTERACTIONS BETWEEN P53 AND THE TFIIH COMPLEX ARE AFFECTED BY TUMOR-ASSOCIATED MUTATIONS

The p53 tumour suppressor is mutated in the majority of human tumours. p53's proposed role as the guardian of the genome is reflected in its multiple effects on transcription, genome stability, cell growth and survival. We show that p53 interacts both physically and functionally with the TFIIH complex. There are multiple protein-protein contacts, i nvolving two regions of p53 and three subunits of TFIIH, ERCC2 (XPD), ERCC3 (XPB) and p62, p53 and its C-terminus (amino acids 320-393) inhi bit both of the TFIIH helicases and in vitro transcription in the abse nce of TFIIH. Transcription inhibition is overcome by TFIIH. The N-ter minal region of p53 (1-320), lacking the C-terminus, ia inactive on it s own, yet apparently affects the activity of the C-terminus in the na tive protein. Interestingly, mutant p53s that are frequently found in tumours are less efficient inhibitors of the helicases and transcripti on. We hypothesize that the interactions provide an immediate and dire ct link for p53 to the multiple functions of TFIIH in transcription, D NA repair and possibly the cell cycle.