Methylation of PLK1 by SET7/9 ensures accurate kinetochore-microtubule dynamics
Methylation of PLK1 by SET7/9 ensures accurate kinetochore-microtubule dynamics
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SET7/9 对 PLK1 的甲基化确保了准确的动粒微管动力学
DOI：
10.1093/jmcb/mjz107
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发表时间：
2019
影响因子：
5.5
通讯作者：
Xuebiao Yao
中科院分区：
文献类型：
--
作者：
Ruoying Yu;Huihui Wu;Hazrat Ismail;Shihao Du;Jun Cao;Jianyu Wang;Tarsha Ward;Fengrui Yang;Ping Gui;Mahboob Ali;Lingluo Chu;Fei Mo;Qi Wang;Youjun Chu;Yun Zhao;Mingliang Ye;Guowei Fang;Peng R. Chen;Zhen Dou;Xinjiao Gao;Wenwen Wang;Xing Liu;Xuebiao Yao
有丝分裂染色体的忠实分离需要姐妹染色单体的双向取向，这依赖于纺锤体微管和动粒之间正确附着的传感。虽然PLK 1激活的潜在机制已被广泛研究，但将PLK 1活性与准确的染色体分离结合的调控机制尚未得到很好的理解。特别是，PLK 1涉及稳定的动粒微管附件，但如何动粒PLK 1活性的调节，以避免超稳定的有丝分裂中的动粒微管仍然难以捉摸。在这里，我们表明，着丝粒PLK 1激酶活性调节SET 7/9通过赖氨酸甲基化在早期有丝分裂。SET 7/9引起的二甲基化发生在PLK 1的Lys 191，这通过限制ATP利用来调节其活性。过表达的非甲基化PLK 1突变体或化学抑制SET 7/9甲基转移酶活性导致有丝分裂停滞由于不稳定的激动剂微管附件。这些数据表明，动粒PLK 1是必不可少的稳定的动粒微管附件和甲基化SET 7/9促进动态动粒微管附件准确的纠错。我们的研究结果定义了一种新的动粒稳态调节，它将蛋白质磷酸化和甲基化与精确的染色体分离结合起来，以维持基因组的稳定性。
Faithful segregation of mitotic chromosomes requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms underlying PLK1 activation have been extensively studied, the regulatory mechanisms that couple PLK1 activity to accurate chromosome segregation are not well understood. In particular, PLK1 is implicated in stabilizing kinetochore–microtubule attachments, but how kinetochore PLK1 activity is regulated to avoid hyperstabilized kinetochore–microtubules in mitosis remains elusive. Here, we show that kinetochore PLK1 kinase activity is modulated by SET7/9 via lysine methylation during early mitosis. The SET7/9-elicited dimethylation occurs at the Lys191 of PLK1, which tunes down its activity by limiting ATP utilization. Overexpression of the non-methylatable PLK1 mutant or chemical inhibition of SET7/9 methyltransferase activity resulted in mitotic arrest due to destabilized kinetochore–microtubule attachments. These data suggest that kinetochore PLK1 is essential for stable kinetochore–microtubule attachments and methylation by SET7/9 promotes dynamic kinetochore–microtubule attachments for accurate error correction. Our findings define a novel homeostatic regulation at the kinetochore that integrates protein phosphorylation and methylation with accurate chromosome segregation for maintenance of genomic stability.