Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway
Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway
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DOI：
10.1038/sj.onc.1202925
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发表时间：
1999-07-15
期刊：
影响因子：
8
通讯作者：
Zhou, BBS
中科院分区：
文献类型：
--
作者：
Chaturvedi, P;Eng, WK;Zhou, BBS
作为对DNA损伤和复制阻断的反应，细胞激活阻止细胞周期并诱导促进修复的基因转录的途径。在哺乳动物中，ATM（共济失调毛细血管扩张突变）激酶与其他检查点激酶一起是这种反应的重要组成部分。我们已经克隆了酿酒酵母Rad 53和粟酒裂殖酵母Cds 1的大鼠和人类同源物，称为检查点激酶2（chk 2）。互补研究表明，Chk 2可以部分取代缺陷的检查点激酶在CDS 1缺陷的酵母菌株的功能。Chk 2以ATM依赖的方式被磷酸化并激活以响应DNA损伤。利用质谱技术，我们发现Chk 2与Chk 1一样，可以磷酸化Cdc 25 C上的丝氨酸216，这是一个已知参与Cdc 25 C负调控的位点。这些结果表明，Chk 2是ATM依赖的DNA损伤检查点通路的下游效应子。Chk 2的激活可能不仅延迟有丝分裂进入，而且增加培养细胞在γ-辐射或拓扑异构酶-I抑制剂拓扑替康处理后的存活能力。
In response to DNA damage and replication blocks, cells activate pathways that arrest the cell cycle and induce the transcription of genes that facilitate repair. In mammals, ATM (ataxia telangiectasia mutated) kinase together with other checkpoint kinases are important components in this response. We have cloned the rat and human homologs of Saccharomyces cerevisiae Rad 53 and Schizosaccharomyces pombe Cds1, called checkpoint kinase 2 (chk2). Complementation studies suggest that Chk2 can partially replace the function of the defective checkpoint kinase in the Cds1 deficient yeast strain. Chk2 was phosphorylated and activated in response to DNA damage in an ATM dependent manner. Its activation in response to replication blocks by hydroxyurea (HU) treatment, however, was independent of ATM, Using mass spectrometry, me found that, similar to Chk1, Chk2 can phosphorylate serine 216 in Cdc25C, a site known to be involved in negative regulation of Cdc25C, These results suggest that Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Activation of Chk2 might not only delay mitotic entry, but also increase the capacity of cultured cells to survive after treatment with gamma-radiation or with the topoisomerase-I inhibitor topotecan.