The CDK1 inhibitory kinase MYT1 in DNA damage checkpoint recovery
The CDK1 inhibitory kinase MYT1 in DNA damage checkpoint recovery
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DOI：
10.1038/onc.2012.504
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发表时间：
2013-10-03
期刊：
影响因子：
8
通讯作者：
Poon, R. Y. C.
中科院分区：
文献类型：
--
作者：
Chow, J. P. H.;Poon, R. Y. C.
细胞周期蛋白依赖性激酶1（CDK1）的磷酸化抑制是一个关键的调节机制，为未受干扰的细胞周期和DNA损伤检查点。虽然WEE1和MYT1都可以磷酸化CDK1，但对MYT1的贡献知之甚少。我们发现，与WEE 1相反，MYT 1对正常细胞周期或检查点激活并不重要。然而，延时显微镜显示MYT1在检查点恢复过程中确实具有速率决定作用。当检查点被CHK 1或WEE 1的抑制剂废除时，MYT 1的耗尽诱导早熟的有丝分裂进入，表明MYT 1独立于WEE 1而有助于检查点恢复。MYT1耗竭细胞中检查点恢复的加速是由于CDK1活化阈值的降低。MYT1的激酶活性在检查点激活期间较高，在检查点恢复期间降低。重要的是，虽然单独消耗MYT1不影响长期细胞生长，但它增强了DNA损伤，抑制了克隆存活和肿瘤异种移植模型中的细胞生长。这些结果揭示了MYT1在检查点恢复中的功能，并突出了MYT1作为抗癌治疗靶点的潜力。
Inhibition of cyclin-dependent kinase 1 (CDK1) by phosphorylation is a key regulatory mechanism for both the unperturbed cell cycle and the DNA damage checkpoint. Although both WEE1 and MYT1 can phosphorylate CDK1, little is known about the contribution of MYT1. We found that in contrast to WEE1, MYT1 was not important for the normal cell cycle or checkpoint activation. Time-lapse microscopy indicated that MYT1 did, however, have a rate-determining role during checkpoint recovery. Depletion of MYT1 induced precocious mitotic entry when the checkpoint was abrogated with inhibitors of either CHK1 or WEE1, indicating that MYT1 contributes to checkpoint recovery independently of WEE1. The acceleration of checkpoint recovery in MYT1-depleted cells was due to a lowering of threshold for CDK1 activation. The kinase activity of MYT1 was high during checkpoint activation and reduced during checkpoint recovery. Importantly, although depletion of MYT1 alone did not affect long-term cell growth, it potentiated with DNA damage to inhibit cell growth in clonogenic survival and tumor xenograft models. These results reveal the functions of MYT1 in checkpoint recovery and highlight the potential of MYT1 as a target for anti-cancer therapies.