Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability
Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability
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DOI：
10.1242/jcs.03031
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发表时间：
2006-08-01
影响因子：
4
通讯作者：
Fujita, Masatoshi
中科院分区：
文献类型：
--
作者：
Tatsumi, Yasutoshi;Sugimoto, Nozomi;Fujita, Masatoshi
人类Cdt1的活性受到多种机制的负调控。这表明去监管Cdt1可能会产生有害的影响。事实上，有研究表明，过表达Cdt1可以在癌细胞中诱导rereplication，并且rereplication激活共济失调毛细血管扩张突变（ATM）激酶和/或ATM和rad3相关（ATR）激酶依赖的checkpoint通路。在本报告中，我们强调了Cdt1失调的一个新的和有趣的方面：来自几个不同系统的数据都强烈表明，在病理生理水平上不受调节的Cdt1过表达可以诱导非转化细胞的染色体损伤，而不是rereplication。这些研究中最重要的发现是，即使在静止细胞中，失调的Cdt1也会诱导染色体损伤和ATM-Chk2 DNA损伤检查点通路的激活。这些Cdt1活性受到细胞周期蛋白A/Cdks的负调控，可能是通过磷酸化修饰。此外，我们发现失调的Cdt1诱导正常人类细胞的染色体不稳定。由于Cdt1在癌细胞中过表达，这可能是导致癌变的一种新的分子机制。
The activity of human Cdt1 is negatively regulated by multiple mechanisms. This suggests that Cdt1 deregulation may have a deleterious effect. Indeed, it has been suggested that overexpression of Cdt1 can induce rereplication in cancer cells and that rereplication activates Ataxia-telangiectasia-mutated (ATM) kinase and/or ATM- and Rad3-related (ATR) kinase-dependent checkpoint pathways. In this report, we highlight a new and interesting aspect of Cdt1 deregulation: data from several different systems all strongly indicate that unregulated Cdt1 overexpression at pathophysiological levels can induce chromosomal damage other than rereplication in nontransformed cells. The most important finding in these studies is that deregulated Cdt1 induces chromosomal damage and activation of the ATM-Chk2 DNA damage checkpoint pathway even in quiescent cells. These Cdt1 activities are negatively regulated by cyclin A/Cdks, probably through modification by phosphorylation. Furthermore, we found that deregulated Cdt1 induces chromosomal instability in normal human cells. Since Cdt1 is overexpressed in cancer cells, this would be a new molecular mechanism leading to carcinogenesis.