Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
Howard Hughes Medical Institute, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Cell Syst. 2017 Jun 28;4(6):645-650.e5. doi: 10.1016/j.cels.2017.05.003. Epub 2017 Jun 7.
Proper segregation of the replicated genome requires that kinetochores form and maintain bioriented, amphitelic attachments to microtubules from opposite spindle poles and eliminate erroneous, syntelic attachments to microtubules from the same spindle pole. Phosphorylation of kinetochore proteins destabilizes low-tension kinetochore-microtubule attachments, yet tension stabilizes bioriented attachments. This conundrum for forming high-tension amphitelic attachments is recognized as the "initiation problem of biorientation (IPBO)." A delay before kinetochore-microtubule detachment solves the IPBO, but it lacks a mechanistic framework. We developed a stochastic mathematical model for kinetochore-microtubule error correction in yeast that reveals: (1) under low chromatin tension, requiring a large number of phosphorylation events at multiple sites to achieve detachment provides the necessary delay; and (2) kinetochore-induced microtubule depolymerization generates tension in amphitelic, but not syntelic, attachments. With these requirements, the model provides a mechanistic framework for the delay before detachment to solve the IPBO and demonstrates the high degree of amphitely observed experimentally for wild-type spindles under optimal conditions.
正确分离复制的基因组需要动粒形成并维持与来自纺锤体相反两极的微管的双取向、两性联附着，并消除与来自同一纺锤体极的微管的错误、同型联附着。动粒蛋白的磷酸化会使低张力动粒-微管附着不稳定，但张力会稳定双取向附着。这种形成高张力两性联附着的难题被认为是“双取向起始问题（IPBO）”。在动粒-微管脱离之前的延迟解决了 IPBO，但它缺乏机械框架。我们开发了一种用于酵母动粒-微管错误校正的随机数学模型，揭示了：（1）在低染色质张力下，需要在多个位点进行大量磷酸化事件才能实现脱离，从而提供了必要的延迟；（2）动粒诱导的微管解聚在两性联附着中产生张力，但不在同型联附着中产生张力。有了这些要求，该模型为脱离前的延迟提供了一个机械框架，以解决 IPBO，并证明了在最佳条件下，野生型纺锤体观察到的高度两性联。
