Functional interactions between p53 and the TFIIH complex are affected by tumour-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, involving two regions of p53 and three subunits of TFIIH, ERCC2 (XPD), ERCC3 (XPB) and p62. p53 and its C-terminus (amino acids 320-393) inhibit both of the TFIIH helicases and in vitro transcription in the absence of TFIIH. Transcription inhibition is overcome by TFIIH. The N-terminal region of p53 (1-320), lacking the C-terminus, is inactive on its own, yet apparently affects the activity of the C-terminus in the native protein. Interestingly, mutant p53s that are frequently found in tumours are less efficient inhibitors of the helicases and transcription. We hypothesize that the interactions provide an immediate and direct link for p53 to the multiple functions of TFIIH in transcription, DNA repair and possibly the cell cycle.
Léveillard
T
T
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Andera
L
L
Bissonnette
N
N
Schaeffer
L
L
Bracco
L
L
Egly
J M
JM
Wasylyk
B
B
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002453:Cell Cycle; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019473:Transcription Factors, TFII; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D051759:Xeroderma Pigmentosum Group D Protein
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011506:Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D016159:Tumor Suppressor Protein p53; D051758:Transcription Factor TFIIH; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human