Bub1 autophosphorylation feeds back to regulate kinetochore docking and promote localized substrate phosphorylation.
Bub1 autophosphorylation feeds back to regulate kinetochore docking and promote localized substrate phosphorylation.
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DOI：
10.1038/ncomms9364
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发表时间：
2015-09-24
影响因子：
16.6
通讯作者：
Elowe S
中科院分区：
文献类型：
--
作者：
Asghar A;Lajeunesse A;Dulla K;Combes G;Thebault P;Nigg EA;Elowe S
在有丝分裂过程中，Bub 1激酶磷酸化组蛋白H2 A-T120，通过募集shugoshin（Sgo）蛋白来促进着丝粒姐妹染色单体的凝聚。H2 A-T120磷酸化的调节和动力学知之甚少。使用定量磷酸化蛋白质组学，我们表明，Bub 1是自磷酸化在许多网站。我们确认有丝分裂特异性的几个残基的自磷酸化，并表明，Bub 1激活引发的间期，但完全实现只有在有丝分裂。单个自磷酸化位点T589的突变改变了Bub 1的动粒周转，并导致均匀的H2 A-T120磷酸化和Sgo募集沿着染色体臂。因此，观察到不适当的姐妹染色单体分辨率和染色体分离错误。Bub 1-T589 A的动粒束缚使H2 A-T120磷酸化和Sgo 1重新聚焦于着丝粒。最近，Bub 1-Bub 3-BubR 1轴向动粒的募集被广泛研究。我们的数据提供了新的见解的调节和动粒驻留的Bub 1，并表明其本地化是动态的，通过反馈自磷酸化严格控制。 Bub 1激酶在着丝粒磷酸化组蛋白H2 A-T120，以募集shugoshin蛋白并促进有丝分裂期间姐妹染色单体的凝聚。在这里，作者表明T589上的Bub 1自磷酸化影响了动粒上的Bub 1动力学，并将H2 A-T120磷酸化限制在着丝粒上。
During mitosis, Bub1 kinase phosphorylates histone H2A-T120 to promote centromere sister chromatid cohesion through recruitment of shugoshin (Sgo) proteins. The regulation and dynamics of H2A-T120 phosphorylation are poorly understood. Using quantitative phosphoproteomics we show that Bub1 is autophosphorylated at numerous sites. We confirm mitosis-specific autophosphorylation of a several residues and show that Bub1 activation is primed in interphase but fully achieved only in mitosis. Mutation of a single autophosphorylation site T589 alters kinetochore turnover of Bub1 and results in uniform H2A-T120 phosphorylation and Sgo recruitment along chromosome arms. Consequently, improper sister chromatid resolution and chromosome segregation errors are observed. Kinetochore tethering of Bub1-T589A refocuses H2A-T120 phosphorylation and Sgo1 to centromeres. Recruitment of the Bub1-Bub3-BubR1 axis to kinetochores has recently been extensively studied. Our data provide novel insight into the regulation and kinetochore residency of Bub1 and indicate that its localization is dynamic and tightly controlled through feedback autophosphorylation. Bub1 kinase phosphorylates histone H2A-T120 at the centromere to recruit shugoshin proteins and promote sister chromatid cohesion during mitosis. Here the authors show that Bub1 autophosphorylation on T589 influences Bub1 dynamics at the kinetochore and restricts H2A-T120 phosphorylation to centromeres.