p53 modulation of TFIIH–associated nucleotide excision repair activity

Abstract

p53 has pleiotropic functions including control of genomic plasticity and integrity. Here we report that p53 can bind to several transcription factor IIH-associated factors, including transcription-repair factors, XPD (Rad3) and XPB, as well as CSB involved in strand-specific DNA repair, via its C-terminal domain. We also found that wild-type, but not Arg273His mutant p53 inhibits XPD (Rad3) and XPB DNA helicase activities. Moreover, repair of UV-induced dimers is slower in Li-Fraumeni syndrome cells (heterozygote p53 mutant) than in normal human cells. Our findings indicate that p53 may play a direct role in modulating nucleotide excision repair pathways.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…This conclusion was substantiated when it was reported that cotransfection of a p53 expression vector with a plasmid containing a wild-type p53-binding site placed upstream of a reporter gene results in a high level of reporter gene expression in mammalian cells. The consensus sequence is present either in the regulatory region or in intron of a variety of target genes and is thought to activate transcription via an interaction between its N-terminal acidic domain (®rst 42 amino acids) and the basal transcription apparatus (possibly TATA box binding protein associated factors such as human TAF II 40 and TAF II 60 (Thut et al, 1995), and the p62 subunit of the dual transcription/repair factor TFIIH (Wang et al, 1995a).…”

“…Recent research suggests that p53 may participate in the repair machinery (Smith et al, 1994;Wang et al, 1995a;Ford and Hanawalt, 1995;. For example (Wang et al, , 1995a, it was shown that p53 binds to and modulates the repair activity of the nucleotide excision repair factors XPB and XPD.…”

“…For example (Wang et al, , 1995a, it was shown that p53 binds to and modulates the repair activity of the nucleotide excision repair factors XPB and XPD. More recently (Buchlop et al, 1997) it has been demonstrated that p53 interacts with human Rad51 protein, a proposed member of the mammalian recombination machinery.…”

“…These modi®cations are thought to activate p53 by causing a conformational change of the protein, regulated by an allosteric e ect. A number of viral and cellular proteins have been shown to bind to C-terminal region of p53, including the hepatitis B virus X protein, the TFIIH subunits XPD and XPB which are two helicases in vitro, and TBP (Wang et al, , 1995bHorikoshi et al, 1995). A third helicase, designated CSB, involved in a DNA repair pathway, binds also to the C-terminal region of p53 Levine, 1997).…”

Persistence of p53 mutations and resistance of keratinocytes to apoptosis are associated with the increased susceptibility of mice lacking the XPC gene to UV carcinogenesis

“…The p53 tumor suppressor gene codes for a DNAbinding protein that plays a key role in gene transcription, control of the cell cycle, DNA repair and apoptosis (Levine et al, 1991;Vogelstein and Kinzler, 1992;Harris, 1996;Smith et al, 1995;Wang et al, 1995;Li et al, 1996Li et al, , 1997. Mutations in p53 play an essential role in the pathogenesis of human and mouse UV-induced skin cancers (reviewed in Brash et al, 1996;Nataraj et al, 1995), and p53 knockout mice are more susceptible to UV carcinogenesis than wildtype mice (Jiang et al, 1999).…”