A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage
A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage
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DOI：
10.1038/35003506
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发表时间：
2000-03-02
期刊：
影响因子：
64.8
通讯作者：
Nakamura, Y
中科院分区：
文献类型：
--
作者：
Tanaka, H;Arakawa, H;Nakamura, Y
p53基因在人类癌症中经常失活。在这里，我们已经分离出一个p53诱导基因，p53 R2，通过使用差异显示检查信使RNA在癌症衍生的人类细胞系携带一个高度调节的野生型p53表达系统。p53 R2在内含子1中含有p53结合序列，并编码一个351个氨基酸的肽，与核糖核苷酸还原酶小亚基（R2）具有惊人的相似性，这在细胞分裂期间的DNA合成中很重要。p53 R2的表达，而不是R2，诱导紫外线和γ-照射和阿霉素治疗的野生型p53依赖性的方式。在p53缺陷细胞中诱导p53 R2引起G2/M期阻滞并防止细胞响应阿霉素而死亡。在具有完整的p53依赖性DNA损伤检查点的细胞中抑制内源性p53 R2表达降低了暴露于各种遗传毒素后的核糖核苷酸还原酶活性、DNA修复和细胞存活。我们的研究结果表明，p53 R2编码的核糖核苷酸还原酶直接参与p53检查点修复受损的DNA，p53 R2的发现澄清了核糖核苷酸还原酶活性参与修复受损的DNA和肿瘤抑制p53之间的关系。
The p53 gene is frequently inactivated in human cancers. Here we have isolated a p53-inducible gene, p53R2,by using differential display to examine messenger RNAs in a cancer-derived human cell line carrying a highly regulated wild-type p53 expression system. p53R2 contains a p53-binding sequence in intron 1 and encodes a 351-amino-acid peptide with striking similarity to the ribonucleotide reductase small subunit(R2), which is important in DNA synthesis during cell division. Expression of p53R2, but not R2, was induced by ultraviolet and gamma-irradiation and adriamycin treatment in a wild-type p53-dependent manner. Induction of p53R2 in p53-deficient cells caused G2/M arrest and prevented cells from death in response to adriamycin, Inhibition of endogenous p53R2 expression in cells that have an intact p53-dependent DNA damage checkpoint reduced ribonucleotide reductase activity, DNA repair and cell survival after exposure to various genotoxins. Our results indicate that p53R2 encodes a ribonucleotide reductase that is directly involved in the p53 checkpoint for repair of damaged DNA, The discovery of p53R2 clarifies a relationship between a ribonucleotide reductase activity involved in repair of damaged DNA and tumour suppression by p53.