To segregate chromosomes in mitosis, cells assemble a mitotic spindle, a molecular machine with centrosomes at two opposing cell poles and chromosomes at the equator. Microtubules and molecular motors connect the poles to kinetochores, specialized protein assemblies on the centromere regions of the chromosomes. Bipolarity of the spindle is crucial for the proper cell division, and two centrosomes in animal cells naturally become two spindle poles. Cancer cells are often multicentrosomal, yet they are able to assemble bipolar spindles by clustering centrosomes into two spindle poles. Mechanisms of this clustering are debated. In this study, we computationally screen effective forces between 1) centrosomes, 2) centrosomes and kinetochores, 3) centrosomes and chromosome arms, and 4) centrosomes and cell cortex to understand mechanics that determines three-dimensional spindle architecture. To do this, we use the stochastic Monte Carlo search for stable mechanical equilibria in the effective energy landscape of the spindle. We find that the following conditions have to be met to robustly assemble the bipolar spindle in a multicentrosomal cell: 1) the strengths of centrosomes' attraction to each other and to the cell cortex have to be proportional to each other and 2) the strengths of centrosomes' attraction to kinetochores and repulsion from the chromosome arms have to be proportional to each other. We also find that three other spindle configurations emerge if these conditions are not met: 1) collapsed, 2) monopolar, and 3) multipolar spindles, and the computational screen reveals mechanical conditions for these abnormal spindles.

中文翻译：

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双极有丝分裂纺锤体中多中心体聚类的机制

为了在有丝分裂中分离染色体，细胞组装有丝分裂纺锤体，这是一种分子机器，中心体位于两个相对的细胞极，染色体位于赤道。微管和分子马达将两极连接到着丝粒，即染色体着丝粒区域上的特殊蛋白质组装体。纺锤体的双极性对于正常的细胞分裂至关重要，动物细胞中的两个中心体自然成为两个纺锤体极。癌细胞通常是多中心体，但它们能够通过将中心体聚集成两个纺锤体极来组装双极纺锤体。这种聚类的机制存在争议。在这项研究中，我们通过计算筛选了 1) 中心体，2) 中心体和动粒，3) 中心体和染色体臂之间的有效力，和 4) 中心体和细胞皮层，以了解决定三维纺锤体结构的力学。为此，我们使用随机蒙特卡罗搜索在主轴的有效能量景观中寻找稳定的机械平衡。我们发现必须满足以下条件才能在多中心体细胞中牢固地组装双极纺锤体：1）中心体相互吸引和对细胞皮层的吸引力必须相互成正比，2）中心体对动粒的吸引力和来自染色体臂的排斥必须相互成比例。我们还发现，如果不满足这些条件，则会出现其他三种纺锤体配置：1) 折叠，2) 单极，和 3) 多极纺锤体，