PDF(Pubmed)
Abstract：
The ring-shaped Cohesin complex, consisting of core subunits Smc1, Smc3, Scc1, and SA2 (or its paralog SA1), topologically entraps two duplicated sister DNA molecules to establish sister chromatid cohesion in S-phase. It remains largely elusive how the Cohesin release factor Wapl binds the Cohesin complex, thereby inducing Cohesin disassociation from mitotic chromosomes to allow proper resolution and separation of sister chromatids. Here, we show that Wapl uses two structural modules containing the FGF motif and the YNARHWN motif, respectively, to simultaneously bind distinct pockets in the extensive composite interface between Scc1 and SA2. Strikingly, only when both docking modules are mutated, Wapl completely loses the ability to bind the Scc1-SA2 interface and release Cohesin, leading to erroneous chromosome segregation in mitosis. Surprisingly, Sororin, which contains a conserved FGF motif and functions as a master antagonist of Wapl in S-phase and G2-phase, does not bind the Scc1-SA2 interface. Moreover, Sgo1, the major protector of Cohesin at mitotic centromeres, can only compete with the FGF motif but not the YNARHWN motif of Wapl for binding Scc1-SA2 interface. Our data uncover the molecular mechanism by which Wapl binds Cohesin to ensure precise chromosome segregation.
摘要：
环状的Cohesin复合体,由核心亚基Smc1，Smc3，Scc1和SA2（或其模拟SA1）组成，拓扑地捕获两个重复的姐妹DNA分子，以在S期建立姐妹染色单体内聚力。Cohesin释放因子Wapl如何结合Cohesin复合物仍然很难理解，从而诱导Cohesin从有丝分裂染色体上解离，以允许姐妹染色单体的适当解析和分离。这里,我们证明Wapl使用两个包含FGF基序和YNARHWN基序的结构模块，分别,在Scc1和SA2之间的广泛复合界面中同时结合不同的口袋。引人注目的是，只有当两个对接模块都变异时，Wapl完全失去了绑定Scc1-SA2接口和释放Cohesin的能力，导致有丝分裂中错误的染色体分离。令人惊讶的是,索罗林,它包含一个保守的FGF基序，在S期和G2期作为Wapl的主要拮抗剂，不绑定Scc1-SA2接口。此外，SGo1，在有丝分裂着丝粒上的主要保护者，只能与FGF基序竞争，而不能与Wapl的YNARHWN基序竞争结合Scc1-SA2接口。我们的数据揭示了Wapl结合Cohesin以确保精确染色体分离的分子机制。
