Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase.
Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase.
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DOI：
10.1083/jcb.200905059
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发表时间：
2010-03-08
期刊：
影响因子：
--
通讯作者：
Sørensen CS
中科院分区：
文献类型：
--
作者：
Beck H;Nähse V;Larsen MS;Groth P;Clancy T;Lees M;Jørgensen M;Helleday T;Syljuåsen RG;Sørensen CS
WEE1和CHK1共同调节Cdk活性，防止复制过程中的DNA损伤。维持基因组的完整性对细胞至关重要。为了确定基因组完整性的关键调控因子，我们用kinome小干扰RNA文库筛选了一株人类细胞系。WEE1是有丝分裂进入的主要调节因子，CHK1也在鉴定的基因之列。这两种激酶都是CDK1和-2的重要负调节因子。引人注目的是，WEE1缺失迅速诱导新复制DNA的S期DNA损伤，并伴随着单链DNA的显著增加。这种DNA损伤依赖于CDK1和-2以及复制蛋白MCM2和CDT1，但不依赖于CDC25A。相反，CHK1抑制后的DNA损伤高度依赖于CDC25A。此外，CDC25A的共耗尽显著改善了chk1缺失细胞的低增殖。我们得出结论，在正常DNA复制过程中，有丝分裂激酶WEE1和CHK1共同维持Cdk活性的平衡细胞控制，这对于防止复制过程中有害DNA损伤的产生至关重要。
WEE1 and CHK1 jointly regulate Cdk activity to prevent DNA damage during replication. Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication.
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
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作者：
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3.8
作者：
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通讯作者：
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影响因子：
9.2
作者：
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