Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A
Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A
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DOI：
10.1038/ncomms5397
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发表时间：
2014-07-01
影响因子：
16.6
通讯作者：
Mayer, Thomas U.
中科院分区：
文献类型：
--
作者：
Haefner, Julia;Mayr, Monika I.;Mayer, Thomas U.
在纺锤体赤道聚集时，脊椎动物染色体显示振荡运动，这种振荡运动通常随着细胞向后期发展而下降。Kinesin-8 Kif18A已被确定为染色体运动的抑制因子，但其活性如何在后期开始前暂时调节以抑制染色体振荡仍然是一个谜。在这里，我们发现了一个由细胞周期蛋白依赖性激酶-1 （Cdk1）和蛋白磷酸酶-1 （PP1）组成的调控网络，可以拮抗调节Kif18A。cdk1介导的Kif18A抑制磷酸化促进早期中期染色体振荡。PP1通过直接去磷酸化Kif18A诱导中期板变薄。染色体附着诱导Cdk1失活和PP1 α / γ的着丝点募集。因此，我们提出染色体双向性通过打破平衡来调节中期板上染色体的排列，这种平衡有利于去磷酸化的Kif18A，能够抑制染色体的振荡运动。值得注意的是，干扰染色体振荡严重损害姐妹染色单体分离的保真度，这表明及时控制染色体动力学对于维持基因组完整性的重要性。
Upon congression at the spindle equator, vertebrate chromosomes display oscillatory movements which typically decline as cells progress towards anaphase. Kinesin-8 Kif18A has been identified as a suppressor of chromosome movements, but how its activity is temporally regulated to dampen chromosome oscillations before anaphase onset remained mysterious. Here, we identify a regulatory network composed of cyclin-dependent kinase-1 (Cdk1) and protein phosphatase-1 (PP1) that antagonistically regulate Kif18A. Cdk1-mediated inhibitory phosphorylation of Kif18A promotes chromosome oscillations in early metaphase. PP1 induces metaphase plate thinning by directly dephosphorylating Kif18A. Chromosome attachment induces Cdk1 inactivation and kinetochore recruitment of PP1 alpha/gamma. Thus, we propose that chromosome biorientation mediates the alignment of chromosomes at the metaphase plate by tipping the balance in favour of dephosphorylated Kif18A capable of suppressing the oscillatory movements of chromosomes. Notably, interfering with chromosome oscillations severely impairs the fidelity of sister chromatid segregation demonstrating the importance of timely controlled chromosome dynamics for the maintenance of genome integrity.