p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene

Abstract

The p53 tumor suppressor gene product is a transcription factor involved in cell-cycle regulation, apoptosis, and DNA repair. We and others have shown that p53 is required for efficient nucleotide excision repair (NER) of UV-induced DNA lesions. p53-deficient cells are defective in the repair of UV photoproducts in genomic DNA but proficient for transcription-coupled repair. Therefore, we examined whether p53 regulates the expression of genes required for global genomic repair. In this study, we demonstrate that the mRNA and protein products of the xeroderma pigmentosum group C (XPC) gene are UV-inducible in a time-and dose-dependent manner in human WI38 fibroblasts and HCT116 colorectal cancer cells wild type for p53. However, no significant induction of XPC was observed in p53-deficient counterparts to these cells. Furthermore, regulated expression of wild-type p53 in p53 null Li-Fraumeni syndrome human fibroblasts significantly augmented the expression of XPC protein. Analysis of the human XPC gene sequence revealed a putative p53 response element in the XPC promoter that was capable of mediating sequence-specific DNA binding to p53 in vitro. These results provide strong evidence that the NER gene XPC is a DNA damage-inducible and p53-regulated gene and likely plays a role in the p53-dependent NER pathway.

Base excision DNA repair defect in Gadd45a-deficient cells

“…As a mechanism of p53 role for BER, most reports have implicated a direct role of p53 protein via protein-protein interactions with BER proteins including DNA polymerase b and AP endonuclease (Gaiddon et al, 1999;Offer et al, 2001;Zhou et al, 2001;Lee and Chung, 2003). In contrast, p53 controls NER by transcriptional regulation of NER proteins including p48XPE and XPC (Adimoolam and Ford, 2002). In this study, we describe an alternative pathway of p53-mediated BER involving the p53-regulated protein Gadd45a.…”

E2F regulates DDB2: consequences for DNA repair in Rb-deficient cells

“…We (Prost et al, 1998a, b) and many other groups (reviewed in Adimoolam and Ford, 2003) have shown that p53 is involved in NER in both human and mouse cells and that loss of p53 function affects GGR, but not TCR Hanawalt, 1995, 1997;Prost et al, 1998b;Zhu et al, 2000). This effect is more specific to the removal of CPDs than another UV-induced damage (6-4 photoproducts).…”

Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63

“…One mechanism by which p53 regulates GGR in non-keratinocyte cells appears to involve direct transcriptional activation of certain genes, including DDB2 and XPC that encode key DNA damage recognition proteins (1,2,48). While both TAp63 and ΔNp63 have been reported to directly transactivate various target genes, the lack of decreased DDB2, XPC and XPA mRNA levels upon p63 knockdown in a p53-deficient cell suggests that neither p63 nor p53 directly regulates these genes in keratinocytes.…”

“…The importance of NER in the response to solar ultraviolet radiation (UVR) is illustrated by the disease xeroderma pigmentosum in which mutations in certain NER proteins dramatically increase the risk of non-melanoma skin cancer due to impairment of the global genomic repair (GGR) subpathway of NER in which repair in non-transcribed DNA is defective. In many cell types, p53 has been shown to regulate GGR by transcriptionally activating certain genes, including XPC and DDB2 that encode key DNA damage recognition proteins (1)(2)(3). In several cell types, a p53 deficiency impairs GGR of certain DNA lesions, including the most common UVR-induced lesions, cyclobutane pyrimidine dimers (CPDs) (4).…”