Kliuchnikov Evgenii, Marx Kenneth A, Barsegov Valeri, Mogilner Alex
Department of Chemistry, University of Massachusetts, Lowell, MA 01854.
Courant Institute for Mathematical Sciences and Department of Biology, New York University, New York, NY 10012.
Proc Natl Acad Sci U S A. 2025 Feb 4;122(5):e2416459122. doi: 10.1073/pnas.2416459122. Epub 2025 Jan 30.
Accurate chromosome segregation in mitosis depends on proper connections of sister chromatids, through microtubules, to the opposite poles of the early mitotic spindle. Transiently, many inaccurate connections are formed and rapidly corrected throughout the mitotic stages, but a small number of merotelic connections, in which a chromatid is connected to both spindle poles, remain lagging at the spindle's equator in anaphase. Most of the lagging chromatids are eventually moved to one or the other pole, likely by a combination of microtubules' turnover and the brute force of pulling by the microtubules' majority from the one pole against the microtubules' minority from the other pole. We use computer simulations from two stochastic models (1D and full 3D CellDynaMo model) combining force balances and microtubules' dynamics for the lagging chromatids to investigate what maximizes the percentage of segregated laggards. We find that a) brute force tug-of-war with slow (< 0.0001 s) microtubules' detachment rate can move asymmetric laggards to the poles in limited time, b) rapid (> 0.01 s) microtubules' detachment rate leads to a significant loss of the laggards, and c) intermediate (~ 0.001 s) microtubules' detachment rate ensures higher than 90% accuracy of segregation. The simulations also shed light on the waiting time required to correct the merotelic errors in anaphase and on the roles of chromatid-attached microtubule number and Aurora B-mediated, spatially graded regulation of microtubule kinetics in anaphase.
有丝分裂过程中准确的染色体分离取决于姐妹染色单体通过微管与早有丝分裂纺锤体的相对两极正确连接。在整个有丝分裂阶段，会短暂形成许多不准确的连接并迅速得到纠正，但少数着丝粒连接（即一条染色单体与纺锤体两极都相连）在后期仍滞留在纺锤体赤道处。大多数滞后的染色单体最终会移动到其中一极，这可能是微管周转以及来自一极的微管多数派相对于来自另一极的微管少数派的强力牵拉共同作用的结果。我们使用两个随机模型（一维和全三维CellDynaMo模型）进行计算机模拟，结合滞后染色单体的力平衡和微管动力学，以研究如何使分离的滞后染色单体的百分比最大化。我们发现：a）微管脱离速率缓慢（<0.0001秒）的强力拔河可以在有限时间内将不对称的滞后染色单体移动到两极；b）微管脱离速率较快（>0.01秒）会导致大量滞后染色单体丢失；c）中等（约0.001秒）的微管脱离速率可确保高于90%的分离准确率。这些模拟还揭示了后期纠正着丝粒错误所需的等待时间，以及后期染色单体附着微管数量和极光B介导的微管动力学空间分级调节的作用。
