Kinetochore stretching-mediated rapid silencing of the spindle-assembly checkpoint required for failsafe chromosome segregation
Kinetochore stretching-mediated rapid silencing of the spindle-assembly checkpoint required for failsafe chromosome segregation
复制标题
DOI：
10.1016/j.cub.2021.01.062
复制
发表时间：
2021-04-26
期刊：
影响因子：
9.2
通讯作者：
Hirota, Toru
中科院分区：
文献类型：
--
作者：
Uchida, Kazuhiko S. K.;Jo, Minji;Hirota, Toru
纺锤体组装检查点通过延迟后期开始响应于着丝粒处的微管空位而促进有丝分裂保真度。微管附着后，动粒接受微管衍生的力，这导致动粒经历重复的变形循环;这种现象被称为动粒拉伸。力的性质和与这种变形有关的相关性还没有很好地理解。在这里，我们表明，着丝粒拉伸发生在一个框架内的单端上连接的着丝粒，不管微管极向拉力。有条件地干扰拉伸的实验方法使我们能够确定动粒拉伸包括一个重要的检查点沉默的过程，通过促进PP 1磷酸酶招聘后，建立端对附件和删除大多数的检查点激活激酶Mps 1从动粒。值得注意的是，我们发现较低频率的动粒伸展在很大程度上与染色体不稳定的癌细胞系中延长的中期相关联。在染色体稳定的细胞中，动粒拉伸和检查点沉默的扰动产生了后期桥，这可以通过减少染色体负载的粘附素来缓解。这些观察结果表明，动粒拉伸介导的检查点沉默提供了一个意想不到的病因基础染色体不稳定性，并强调了快速中期到后期的过渡在维持有丝分裂保真度的重要性。
The spindle-assembly checkpoint facilitates mitotic fidelity by delaying anaphase onset in response to micro tubule vacancy at kinetochores. Following microtubule attachment, kinetochores receive microtubulederived force, which causes kinetochores to undergo repetitive cycles of deformation; this phenomenon is referred to as kinetochore stretching. The nature of the forces and the relevance relating this deformation are not well understood. Here, we show that kinetochore stretching occurs within a framework of single end-on attached kinetochores, irrespective of microtubule poleward pulling force. An experimental method to conditionally interfere with the stretching allowed us to determine that kinetochore stretching comprises an essential process of checkpoint silencing by promoting PP1 phosphatase recruitment after the establishment of end-on attachments and removal of the majority of checkpoint-activating kinase Mps1 from kinetochores. Remarkably, we found that a lower frequency of kinetochore stretching largely correlates with a prolonged metaphase in cancer cell lines with chromosomal instability. Perturbation of kinetochore stretching and checkpoint silencing in chromosomally stable cells produced anaphase bridges, which can be alleviated by reducing chromosome-loaded cohesin. These observations indicate that kinetochore stretching-mediated checkpoint silencing provides an unanticipated etiology underlying chromosomal instability and underscores the importance of a rapid metaphase-to-anaphase transition in sustaining mitotic fidelity.