Léveillard T, Andera L, Bissonnette N, Schaeffer L, Bracco L, Egly J M, Wasylyk B
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
EMBO J. 1996 Apr 1;15(7):1615-24.
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.
p53肿瘤抑制因子在大多数人类肿瘤中发生突变。p53作为基因组守护者的假定作用体现在其对转录、基因组稳定性、细胞生长和存活的多种影响上。我们发现p53在物理和功能上均与TFIIH复合物相互作用。存在多个蛋白质 - 蛋白质接触点，涉及p53的两个区域以及TFIIH的三个亚基，即ERCC2（XPD）、ERCC3（XPB）和p62。在没有TFIIH的情况下，p53及其C末端（氨基酸320 - 393）会抑制TFIIH的两种解旋酶以及体外转录。TFIIH可克服转录抑制。缺乏C末端的p53 N末端区域（1 - 320）自身无活性，但显然会影响天然蛋白质中C末端的活性。有趣的是，在肿瘤中经常发现的突变型p53对解旋酶和转录的抑制作用较弱。我们推测，这些相互作用为p53与TFIIH在转录、DNA修复以及可能的细胞周期中的多种功能提供了直接且即时的联系。
