p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene.
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.
Adimoolam
Shanthi
S
Departments of Medicine (Oncology) and Genetics, Stanford University School of Medicine, 1115 CCSR Building, 269 Campus Drive, Stanford, CA 94305, USA.
Ford
James M
JM
D000595:Amino Acid Sequence; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D016158:Genes, p53; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C086984:XPC protein, human