Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211, Geneva 4, Switzerland.
Centre for Mechanochemical Cell Biology & Division of Biomedical Sciences, Warwick Medical School, University of Warwick, CV4 7AL, Coventry, UK.
Nat Commun. 2018 May 23;9(1):2042. doi: 10.1038/s41467-018-04427-x.
Kinetochores are multi-protein complexes that power chromosome movements by tracking microtubules plus-ends in the mitotic spindle. Human kinetochores bind up to 20 microtubules, even though single microtubules can generate sufficient force to move chromosomes. Here, we show that high microtubule occupancy at kinetochores ensures robust chromosome segregation by providing a strong mechanical force that favours segregation of merotelic attachments during anaphase. Using low doses of the microtubules-targeting agent BAL27862 we reduce microtubule occupancy and observe that spindle morphology is unaffected and bi-oriented kinetochores can still oscillate with normal intra-kinetochore distances. Inter-kinetochore stretching is, however, dramatically reduced. The reduction in microtubule occupancy and inter-kinetochore stretching does not delay satisfaction of the spindle assembly checkpoint or induce microtubule detachment via Aurora-B kinase, which was so far thought to release microtubules from kinetochores under low stretching. Rather, partial microtubule occupancy slows down anaphase A and increases incidences of lagging chromosomes due to merotelically attached kinetochores.
着丝粒是一种多蛋白复合物，通过在有丝分裂纺锤体中追踪微管的正极来驱动染色体运动。人类着丝粒可结合多达 20 根微管，尽管单个微管就能产生足以移动染色体的力。在这里，我们表明，高微管占据率可通过提供强大的机械力来确保染色体的稳健分离，从而有利于后期有丝分裂中桥联连接的分离。使用低剂量的微管靶向药物 BAL27862，我们降低了微管占有率，观察到纺锤体形态不受影响，双定向着丝粒仍能以正常的着丝粒内距离进行振荡。然而，着丝粒间的拉伸显著减少。微管占有率和着丝粒间拉伸的减少不会延迟纺锤体组装检查点的满足，也不会通过 Aurora-B 激酶诱导微管脱离，迄今为止，人们认为 Aurora-B 激酶在低拉伸下将微管从着丝粒上释放出来。相反，部分微管占有率会减缓后期 A 的进程，并因桥联连接的着丝粒而增加滞后染色体的发生率。
