The N-Terminal Non-Kinase-Domain-Mediated Binding of Haspin to Pds5B Protects Centromeric Cohesion in Mitosis
The N-Terminal Non-Kinase-Domain-Mediated Binding of Haspin to Pds5B Protects Centromeric Cohesion in Mitosis
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Haspin 与 Pds5B 的 N 端非激酶结构域介导的结合可保护有丝分裂中的着丝粒凝聚
DOI：
10.1016/j.cub.2017.02.019
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发表时间：
2017
期刊：
影响因子：
9.2
通讯作者：
Wang Fangwei
中科院分区：
文献类型：
--
作者：
Zhou Linli;Liang Cai;Chen Qinfu;Zhang Zhenlei;Zhang Bo;Yan Haiyan;Qi Feifei;Zhang Miao;Yi Qi;Guan Youchen;Xiang Xingfeng;Zhang Xiaoqing;Ye Sheng;Wang Fangwei
姐妹染色单体的凝聚，由多亚基凝聚素复合体介导，必须精确调节，以防止染色体的错误分离。在前期和前中期，染色体臂上的大部分粘着蛋白被其拮抗剂Wapl去除，而着丝粒上的粘着蛋白被保留以确保染色体双取向，直到后期开始。它仍然不完全了解如何保护着丝粒粘连蛋白对Wapl在有丝分裂。在这里，我们表明，有丝分裂组蛋白激酶Haspin结合的粘附调节亚基Pds 5 B通过保守的YGA/R基序在其非催化N末端，这是类似于最近报道的YSR基序依赖性结合Wapl Pds 5 B。Haspin的敲除或Haspin-Pds 5 B相互作用的破坏导致减弱的着丝粒凝聚力和过早的染色单体分离，这可以通过着丝粒靶向含有Pds 5 B结合基序的Haspin的N-末端短片段或通过防止Wapl依赖性凝聚素去除来逆转。相反，能够结合Pds 5 B的过量Haspin从Pds 5 B置换Wapl并抑制Wapl活性，并且其在很大程度上绕过Wapl拮抗剂Sgo 1用于内聚保护。总之，这些数据表明，Haspin-Pds 5 B相互作用是确保正确的姐妹染色单体凝聚力所必需的，最有可能是通过拮抗Wapl介导的凝聚素从有丝分裂着丝粒释放。
Sister-chromatid cohesion, mediated by the multi-subunit cohesin complex, must be precisely regulated to prevent chromosome mis-segregation. In prophase and prometaphase, whereas the bulk of cohesin on chromosome arms is removed by its antagonist Wapl, cohesin at centromeres is retained to ensure chromosome biorientation until anaphase onset. It remains incompletely understood how centromeric cohesin is protected against Wapl in mitosis. Here we show that the mitotic histone kinase Haspin binds to the cohesin regulatory subunit Pds5B through a conserved YGA/R motif in its non-catalytic N terminus, which is similar to the recently reported YSR-motif-dependent binding of Wapl to Pds5B. Knockout of Haspin or disruption of Haspin-Pds5B interaction causes weakened centromeric cohesion and premature chromatid separation, which can be reverted by centromeric targeting of a N-terminal short fragment of Haspin containing the Pds5B-binding motif or by prevention of Wapl-dependent cohesin removal. Conversely, excessive Haspin capable of binding Pds5B displaces Wapl from Pds5B and suppresses Wapl activity, and it largely bypasses the Wapl antagonist Sgo1 for cohesion protection. Taken together, these data indicate that the Haspin-Pds5B interaction is required to ensure proper sister-chromatid cohesion, most likely through antagonizing Wapl-mediated cohesin release from mitotic centromeres.