Chair of Genetics, University of Bayreuth, 95440, Bayreuth, Germany.
EMBO J. 2024 Nov;43(21):5237-5259. doi: 10.1038/s44318-024-00228-9. Epub 2024 Sep 13.
Sister chromatid cohesion is mediated by the cohesin complex. In mitotic prophase cohesin is removed from chromosome arms in a Wapl- and phosphorylation-dependent manner. Sgo1-PP2A protects pericentromeric cohesion by dephosphorylation of cohesin and its associated Wapl antagonist sororin. However, Sgo1-PP2A relocates to inner kinetochores well before sister chromatids are separated by separase, leaving pericentromeric regions unprotected. Why deprotected cohesin is not removed by Wapl remains enigmatic. By reconstituting Wapl-dependent cohesin removal from chromatin in vitro, we discovered a requirement for Nek2a and Cdk1/2-cyclin A2. These kinases phosphorylate cohesin-bound Pds5b, thereby converting it from a sororin- to a Wapl-interactor. Replacement of endogenous Pds5b by a phosphorylation mimetic variant causes premature sister chromatid separation (PCS). Conversely, phosphorylation-resistant Pds5b impairs chromosome arm separation in prometaphase-arrested cells and suppresses PCS in the absence of Sgo1. Early mitotic degradation of Nek2a and cyclin A2 may therefore explain why only separase, but not Wapl, can trigger anaphase.
姐妹染色单体黏合由黏合蛋白复合物介导。在有丝分裂前期，Wapl 和磷酸化依赖性方式从染色体臂上去除黏合蛋白。Sgo1-PP2A 通过去磷酸化黏合蛋白及其相关的 Wapl 拮抗剂 Sororin 来保护着丝粒周围的黏合。然而，Sgo1-PP2A 在分离酶将姐妹染色单体分离之前就迁移到了动粒的内部，使着丝粒周围区域没有得到保护。为什么去保护的黏合蛋白没有被 Wapl 去除仍然是个谜。通过在体外重新构建依赖 Wapl 的黏合蛋白从染色质上的去除，我们发现需要 Nek2a 和 Cdk1/2-cyclin A2。这些激酶磷酸化黏合蛋白结合的 Pds5b，从而将其从 Sororin 转化为 Wapl 相互作用蛋白。用磷酸化模拟变体替换内源性 Pds5b 会导致姐妹染色单体过早分离 (PCS)。相反，磷酸化抗性的 Pds5b 会在有丝分裂前期阻滞的细胞中阻碍染色体臂的分离，并在没有 Sgo1 的情况下抑制 PCS。因此，Nek2a 和 cyclin A2 的早期有丝分裂降解可能解释了为什么只有分离酶，而不是 Wapl，能够引发后期。
