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Fen1 由 p53 依赖性诱导,并参与紫外线诱导的复制抑制的恢复过程。

Fen1 is induced p53 dependently and involved in the recovery from UV-light-induced replication inhibition.

作者信息

Christmann Markus, Tomicic Maja T, Origer Judith, Kaina Bernd

机构信息

Department of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany.

出版信息

Oncogene. 2005 Dec 15;24(56):8304-13. doi: 10.1038/sj.onc.1208994.

Abstract

Mouse embryonic fibroblasts (MEFs) that lack p53 are hypersensitive to the cytotoxic and genotoxic effect of ultraviolet (UV-C) light. They also display a defect in the recovery from UV-C-induced DNA replication inhibition. An enzyme involved in processing stalled DNA replication forks is flap endonuclease 1 (Fen1). Gene expression profiling of UV-C-irradiated MEFs revealed fen1 to be upregulated, which was confirmed by RT-PCR and Western blot experiments. Increased Fen1 levels upon UV-C exposure are due to transcriptional activation, as revealed by inhibitor studies. Fen1 induction was dose- and time-dependent; it occurred on protein level already 3 h after irradiation. Induction of Fen1 by UV-C requires p53 since it was observed in p53 wild-type (wt) but not in p53 null (p53-/-) fibroblasts. Fen1 upregulation paralleled the increase in p53 protein level in replicating wt cells, whereas in nonreplicating cells both Fen1 and p53 were not induced by UV-C. The mouse fen1 promoter was cloned and shown to harbor a p53 consensus sequence to which p53 binds. In cotransfection experiments, p53 stimulated the expression of a fen1 promoter-reporter construct. Transgenic expression of Fen1 in p53 null cells attenuated UV-C light-induced DNA replication inhibition, supporting the hypothesis that Fen1 induction is involved in the recovery of cells from DNA damage.

摘要

缺乏p53的小鼠胚胎成纤维细胞(MEF)对紫外线(UV-C)的细胞毒性和遗传毒性作用高度敏感。它们在从UV-C诱导的DNA复制抑制中恢复方面也表现出缺陷。一种参与处理停滞的DNA复制叉的酶是瓣状核酸内切酶1(Fen1)。对UV-C照射的MEF进行基因表达谱分析显示fen1上调,这通过RT-PCR和蛋白质印迹实验得到证实。抑制剂研究表明,UV-C照射后Fen1水平升高是由于转录激活。Fen1的诱导具有剂量和时间依赖性;在照射后3小时就已在蛋白质水平上出现。UV-C对Fen1的诱导需要p53,因为在p53野生型(wt)成纤维细胞中观察到了这种现象,而在p53缺失(p53-/-)的成纤维细胞中则未观察到。在复制的wt细胞中,Fen1的上调与p53蛋白水平的增加平行,而在非复制细胞中,UV-C不会诱导Fen1和p53。克隆了小鼠fen1启动子,并显示其含有p53结合的共有序列。在共转染实验中,p53刺激了fen1启动子-报告基因构建体的表达。在p53缺失细胞中Fen1的转基因表达减弱了UV-C光诱导的DNA复制抑制,支持了Fen1诱导参与细胞从DNA损伤中恢复的假说。

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