Phosphorylation-enabled binding of SGO1–PP2A to cohesin protects sororin and centromeric cohesion during mitosis
Phosphorylation-enabled binding of SGO1–PP2A to cohesin protects sororin and centromeric cohesion during mitosis
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DOI：
10.1038/ncb2688
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发表时间：
2013-02
影响因子：
21.3
通讯作者：
Hong Liu;Susannah Rankin;Hongtao Yu
中科院分区：
文献类型：
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作者：
Hong Liu;Susannah Rankin;Hongtao Yu
有丝分裂中姐妹染色单体内聚的及时溶解保证了染色体的准确分离，以防止非整倍体和肿瘤的发生。shugoshin和蛋白磷酸酶2A的复合体（SGO1-PP2A）保护着丝粒上的黏结蛋白免受前期有丝分裂激酶和WAPL的过早移除。本文研究了人类SGO1在着丝粒内聚保护中的调控和机制，并表明细胞周期蛋白依赖激酶（cyclin-dependent kinase， CDK）介导的SGO1有丝分裂特异性磷酸化激活了SGO1的内聚保护功能，使其能够直接与内聚蛋白结合。磷酸化- sgo1结合的内聚复合物含有PP2A、PDS5和低磷酸化的sororin，但缺乏WAPL。非磷酸化sororin的表达绕过了SGO1-PP2A在着丝性内聚中的要求。因此，SGO1的有丝分裂磷酸化使SGO1 - pp2a靶向内聚蛋白，促进pds5结合的sororin的去磷酸化，并保护着丝粒内聚蛋白免受WAPL的影响。pp2a介导的内聚蛋白的位点选择性去磷酸化及其调节因子是着丝性内聚保护的基础。
Timely dissolution of sister-chromatid cohesion in mitosis ensures accurate chromosome segregation to guard against aneuploidy and tumorigenesis. The complex of shugoshin and protein phosphatase 2A (SGO1–PP2A) protects cohesin at centromeres from premature removal by mitotic kinases and WAPL in prophase. Here we address the regulation and mechanism of human SGO1 in centromeric cohesion protection, and show that cyclin-dependent kinase (CDK)-mediated, mitosis-specific phosphorylation of SGO1 activates its cohesion-protection function and enables its direct binding to cohesin. The phospho-SGO1-bound cohesin complex contains PP2A, PDS5 and hypophosphorylated sororin, but lacks WAPL. Expression of non-phosphorylatable sororin bypasses the requirement for SGO1–PP2A in centromeric cohesion. Thus, mitotic phosphorylation of SGO1 targets SGO1–PP2A to cohesin, promotes dephosphorylation of PDS5-bound sororin and protects centromeric cohesin from WAPL. PP2A-orchestrated, site-selective dephosphorylation of cohesin and its regulators underlies centromeric cohesion protection.