Release of Mps1 from kinetochores is crucial for timely anaphase onset.

Mps1 regulates its own turnover at kinetochores to ensure mitotic checkpoint silencing in metaphase. Mps1 kinase activity is required for proper chromosome segregation during mitosis through its involvements in microtubule–chromosome attachment error correction and the mitotic checkpoint. Mps1 dynamically exchanges on unattached kinetochores but is largely removed from kinetochores in metaphase. Here we show that Mps1 promotes its own turnover at kinetochores and that removal of Mps1 upon chromosome biorientation is a prerequisite for mitotic checkpoint silencing. Inhibition of Mps1 activity increases its half-time of recovery at unattached kinetochores and causes accumulation of Mps1 protein at these sites. Strikingly, preventing dissociation of active Mps1 from kinetochores delays anaphase onset despite normal chromosome attachment and alignment, and high interkinetochore tension. This delay is marked by continued recruitment of Mad1 and Mad2 to bioriented chromosomes and is attenuated by Mad2 depletion, indicating chronic engagement of the mitotic checkpoint in metaphase. We propose that release of Mps1 from kinetochores is essential for mitotic checkpoint silencing and a fast metaphase-to-anaphase transition.

Mps1调节其自身在动粒上的周转，以确保中期有丝分裂检查点的沉默。 Mps1激酶活性通过参与微管 - 染色体附着错误校正和有丝分裂检查点，在有丝分裂期间染色体的正确分离中是必需的。Mps1在未附着的动粒上动态交换，但在中期很大程度上从动粒上移除。在此我们表明，Mps1促进其自身在动粒上的周转，并且在染色体双向定向时Mps1的移除是有丝分裂检查点沉默的先决条件。抑制Mps1活性会增加其在未附着动粒上恢复的半衰期，并导致Mps1蛋白在这些位点的积累。引人注目的是，尽管染色体附着和排列正常，且动粒间张力较高，但阻止活性Mps1从动粒上解离会延迟后期的开始。这种延迟的特征是Mad1和Mad2持续募集到双向定向的染色体上，并且通过Mad2的缺失而减弱，这表明中期有丝分裂检查点的持续启动。我们提出，Mps1从动粒上的释放对于有丝分裂检查点沉默以及从中期到后期的快速转变是必不可少的。