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.

p53肿瘤抑制基因产物是一种参与细胞周期调控、细胞凋亡及DNA修复的转录因子。我们与其他研究团队均已证实，p53对于高效完成紫外线诱导DNA损伤的核苷酸切除修复（nucleotide excision repair, NER）是必需的。p53缺陷细胞在修复基因组DNA中的紫外线光产物时存在功能缺陷，但却可正常进行转录偶联修复。为此，我们探究了p53是否可调控全局基因组修复所需基因的表达。在本研究中，我们证实：在p53野生型的人WI38成纤维细胞与HCT116结直肠癌细胞内，着色性干皮病C组（xeroderma pigmentosum group C, XPC）基因的信使RNA与蛋白产物会以时间及剂量依赖性方式被紫外线诱导表达。然而，在对应p53缺陷的细胞系中，并未观察到XPC的显著诱导表达。进一步研究发现，在p53缺失的李-弗劳梅尼综合征人成纤维细胞中，过表达野生型p53可显著增强XPC蛋白的表达。对人类XPC基因序列的分析显示，其启动子区域存在一个推定的p53应答元件，该元件可在体外介导序列特异性的p53 DNA结合。上述研究结果为NER基因XPC属于DNA损伤诱导且受p53调控的基因提供了强有力的证据，提示XPC可能在p53依赖的NER通路中发挥作用。