Cancer cells often display errors in chromosome segregation, some of which result from improper chromosome alignment at the spindle midplane. Chromosome alignment is facilitated by different rates of microtubule poleward flux between sister kinetochore fibers. However, the role of the poleward flux in supporting mitotic fidelity remains unknown. Here, we introduce the hypothesis that the finely tuned poleward flux safeguards against lagging chromosomes and micronuclei at mitotic exit by promoting chromosome alignment in metaphase. We used human untransformed RPE-1 cells depleted of KIF18A/kinesin-8 as a system with reduced mitotic fidelity, which we rescued by three mechanistically independent treatments, comprising low-dose taxol or codepletion of the spindle proteins HAUS8 or NuMA. The rescue of mitotic errors was due to shortening of the excessively long overlaps of antiparallel microtubules, serving as a platform for motor proteins that drive the flux, which in turn slowed down the overly fast flux and improved chromosome alignment. In contrast to the prevailing view, the rescue was not accompanied by reduction of overall microtubule growth rates. Instead, speckle microscopy revealed that the improved chromosome alignment in the rescue treatments was associated with slower growth and flux of kinetochore microtubules. In a similar manner, a low-dose taxol treatment rescued mitotic errors in a high-grade serous ovarian carcinoma cell line OVKATE. Collectively, our results highlight the potential of targeting microtubule poleward flux to modify chromosome instability and provide insight into the mechanism through which low doses of taxol rescue certain mitotic errors in cancer cells.

中文翻译：

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微管极向通量作为修饰染色体分离错误的靶标


癌细胞经常表现出染色体分离错误，其中一些是由于纺锤体中平面的染色体排列不当造成的。姐妹着丝粒纤维之间不同速率的微管极向通量促进了染色体排列。然而，极向通量在支持有丝分裂保真度中的作用仍然未知。在这里，我们介绍了一个假设，即微调的极向通量通过促进中期染色体对齐来防止有丝分裂出口处的滞后染色体和微核。我们使用耗尽 KIF18A/驱动蛋白-8 的人类未转化的 RPE-1 细胞作为有丝分裂保真度降低的系统，我们通过三种机制独立的处理来挽救它，包括低剂量紫杉醇或纺锤体蛋白 HAUS8 或 NuMA 的编码耗竭。有丝分裂错误的拯救是由于缩短了反平行微管的过长重叠，作为驱动通量的运动蛋白的平台，这反过来又减慢了过快的通量并改善了染色体排列。与普遍观点相反，救援并没有伴随着整体微管生长速率的降低。相反，斑点显微镜显示，挽救治疗中染色体排列的改善与着丝粒微管的生长和通量减慢有关。以类似的方式，低剂量紫杉醇治疗挽救了高级别浆液性卵巢癌细胞系 OVKATE 中的有丝分裂错误。总的来说，我们的结果强调了靶向微管极向通量以改变染色体不稳定性的潜力，并提供了对低剂量紫杉醇拯救癌细胞中某些有丝分裂错误的机制的见解。