p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene
p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene
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DOI：
10.1073/pnas.202485699
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发表时间：
2002-10-01
影响因子：
11.1
通讯作者：
Ford, JM
中科院分区：
文献类型：
--
作者：
Adimoolam, S;Ford, JM
p53 肿瘤抑制基因产物是一种参与细胞周期调节、细胞凋亡和 DNA 修复的转录因子。我们和其他人已经证明，p53 是紫外线诱导的 DNA 损伤的有效核苷酸切除修复 (NER) 所必需的。 p53 缺陷细胞在基因组 DNA 中的紫外线光产物修复方面存在缺陷，但在转录偶联修复方面却很擅长。因此，我们检查了 p53 是否调节全局基因组修复所需基因的表达。在这项研究中，我们证明色素性干皮病 C 组 (XPC) 基因的 mRNA 和蛋白质产物在人 W138 成纤维细胞和野生型 p53 结直肠癌细胞中以时间和剂量依赖性方式受到紫外线诱导。然而，在这些细胞的 p53 缺陷对应细胞中没有观察到 XPC 的显着诱导。此外，p53缺失的Li-Fraumeni综合征人成纤维细胞中野生型p53的表达受到调节，显着增强了XPC蛋白的表达。对人类 XPC 基因序列的分析揭示了 XPC 启动子中推定的 p53 反应元件，能够在体外介导序列特异性 DNA 与 p53 的结合。这些结果提供了强有力的证据，证明 NER 基因 XPC 是 DNA 损伤诱导型和 p53 调节基因，并且可能在 p53 依赖性 NER 途径中发挥作用。
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 W138 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.