Kinetochore Stretching-Mediated Rapid Silencing of Mitotic Checkpoint Required for Failsafe Chromosome Segregation
50 Pages Posted: 24 Oct 2019 Sneak Peek Status: Review CompleteMore...
The spindle-assembly checkpoint facilitates mitotic fidelity by delaying anaphase onset in response to microtubule vacancy at kinetochores. Following microtubule attachment, kinetochores receive microtubule-derived forces, which causes kinetochores to undergo repetitive cycles of deformations, the motion referred to as kinetochore stretching. The nature of forces and the relevance relating this motion are not well understood. Here we show that kinetochore stretching occurs within a framework of single end-on attached kinetochores, irrespectively of microtubule poleward pulling-force. An experimental setup to conditionally interfere with the stretching allowed us to define that kinetochore stretching comprises an essential process of checkpoint silencing by promoting PP1 phosphatase recruitment, after establishing of end-on attachments and removing the majority of checkpoint-activating kinase Mps1 from kinetochores. Remarkably, we found that the lower frequency of kinetochore stretching correlates with prolonged metaphase and also with the degree of chromosomal instability in cancer cell lines. 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 underscore the significance of a rapid metaphase-to-anaphase transition in sustaining mitotic fidelity.
Keywords: Cell division, Chromosomal instability, Kinetochore, Mitosis, Metaphase-to-Anaphase transition, Spindle-assembly checkpoint
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