A kinase-dependent role for Haspin in antagonizing Wapl and protecting mitotic centromere cohesion
A kinase-dependent role for Haspin in antagonizing Wapl and protecting mitotic centromere cohesion
复制标题
Haspin 在拮抗 Wapl 和保护有丝分裂着丝粒凝聚方面具有激酶依赖性作用。
DOI：
10.15252/embr.201744737
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发表时间：
2018-01-01
期刊：
影响因子：
7.7
通讯作者：
Wang, Fangwei
中科院分区：
文献类型：
--
作者：
Liang, Cai;Chen, Qinfu;Wang, Fangwei
在有丝分裂过程中，姐妹染色单体间的紧密结合是染色体精确分离的基础。Wapl通过与Pds 5亚基结合，在前期从染色体臂上释放大量的粘附素，而着丝粒粘附素在后期开始之前被保护不受Wapl影响。强的着丝粒凝聚力需要有丝分裂组蛋白激酶Haspin的着丝粒定位，这依赖于其非催化N-末端与Pds 5 B的相互作用。目前尚不清楚Haspin如何完全阻断着丝粒处的Wapl-Pds 5 B相互作用。在这里，我们表明Haspin的C-末端激酶结构域（Haspin-KD）结合并磷酸化Wapl的YSR基序（Wapl-YSR），从而直接抑制Wapl与Pds 5 B的YSR基序依赖性相互作用。表达Haspin的Wapl结合缺陷突变体或用Haspin抑制剂处理的细胞显示着丝粒内聚缺陷。Wapl YSR中的磷酸模拟突变阻止Wapl结合Pds 5 B并释放粘附素。将Haspin-KD强制靶向至着丝粒部分地绕过了在内聚保护中对Haspin-Pds 5 B相互作用的需要。两者合计，这些结果表明，激酶依赖性的作用Haspin拮抗Wapl和保护着丝粒凝聚力在有丝分裂。
Sister-chromatid cohesion mediated by the cohesin complex is fundamental for precise chromosome segregation in mitosis. Through binding the cohesin subunit Pds5, Wapl releases the bulk of cohesin from chromosome arms in prophase, whereas centromeric cohesin is protected from Wapl until anaphase onset. Strong centromere cohesion requires centromeric localization of the mitotic histone kinase Haspin, which is dependent on the interaction of its non-catalytic N-terminus with Pds5B. It remains unclear how Haspin fully blocks the Wapl-Pds5B interaction at centromeres. Here, we show that the C-terminal kinase domain of Haspin (Haspin-KD) binds and phosphorylates the YSR motif of Wapl (Wapl-YSR), thereby directly inhibiting the YSR motif-dependent interaction of Wapl with Pds5B. Cells expressing a Wapl-binding-deficient mutant of Haspin or treated with Haspin inhibitors show centromeric cohesion defects. Phospho-mimetic mutation in WaplYSR prevents Wapl from binding Pds5B and releasing cohesin. Forced targeting Haspin-KD to centromeres partly bypasses the need for Haspin-Pds5B interaction in cohesion protection. Taken together, these results indicate a kinase-dependent role for Haspin in antagonizing Wapl and protecting centromeric cohesion in mitosis.