Research Institute of Molecular Pathology, A-1030 Vienna, Austria.
Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13404-9. doi: 10.1073/pnas.1305020110. Epub 2013 Jul 30.
Sister chromatid cohesion depends on Sororin, a protein that stabilizes acetylated cohesin complexes on DNA by antagonizing the cohesin release factor Wings-apart like protein (Wapl). Cohesion is essential for chromosome biorientation but has to be dissolved to enable sister chromatid separation. To achieve this, the majority of cohesin is removed from chromosome arms in prophase and prometaphase in a manner that depends on Wapl and phosphorylation of cohesin's subunit stromal antigen 2 (SA2), whereas centromeric cohesin is cleaved in metaphase by the protease separase. Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. At centromeres, the cohesin protector shugoshin (Sgo1)-protein phosphatase 2A (PP2A) antagonizes Aurora B and Cdk1 partly by dephosphorylating Sororin and thus maintains cohesion until metaphase. We propose that the stepwise loss of cohesion between chromosome arms and centromeres is caused by local regulation of Wapl activity, which is controlled by the phosphorylation state of Sororin.
姐妹染色单体黏合依赖于 Sororin，这是一种通过拮抗黏合释放因子 Wings-apart 样蛋白（Wapl）来稳定乙酰化黏合复合物在 DNA 上的蛋白质。黏合对于染色体的双定向是必不可少的，但为了实现姐妹染色单体的分离，它必须被溶解。为了实现这一点，大多数黏合蛋白在前中期和前中期以依赖于 Wapl 和黏合蛋白亚基基质抗原 2（SA2）磷酸化的方式从染色体臂上去除，而着丝粒的黏合蛋白在中期被蛋白酶 separase 切割。在这里，我们表明有丝分裂激酶 Aurora B 和细胞周期蛋白依赖性激酶 1（Cdk1）通过磷酸化 Sororin 来破坏 Sororin 与黏合亚基提前分离姐妹蛋白 5（Pds5）之间的相互作用，导致乙酰化黏合蛋白从染色体臂上释放，并失去黏合。在着丝粒处，黏合蛋白保护蛋白 shugoshin（Sgo1）-蛋白磷酸酶 2A（PP2A）通过去磷酸化 Sororin 来部分拮抗 Aurora B 和 Cdk1，从而维持黏合直到中期。我们提出，染色体臂和着丝粒之间黏合的逐步丧失是由 Wapl 活性的局部调节引起的，这种调节受 Sororin 的磷酸化状态控制。
