Mechanics of Multicentrosomal Clustering in Bipolar Mitotic Spindles
Mechanics of Multicentrosomal Clustering in Bipolar Mitotic Spindles
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DOI：
10.1016/j.bpj.2020.06.004
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发表时间：
2020-07-21
影响因子：
3.4
通讯作者：
Paul, Raja
中科院分区：
文献类型：
--
作者：
Chatterjee, Saptarshi;Sarkar, Apurba;Paul, Raja
为了在有丝分裂中分离染色体，细胞组装一个有丝分裂纺锤体，这是一个分子机器，在两个相对的细胞极有中心体，在赤道有染色体。微管和分子马达将极点连接到着丝点，动点是染色体着丝粒区域上的特殊蛋白质集合。纺锤体的两极对细胞的正常分裂至关重要，动物细胞中的两个中心体自然成为两个纺锤体极。癌细胞通常是多体的，但它们能够通过将中心体聚集成两个纺锤体极来组装两极纺锤体。对这种聚集的机制进行了讨论。在这项研究中，我们通过计算筛选1)中心体、2)中心体和动粒、3)中心体和染色体臂以及4)中心体和细胞皮质之间的有效作用力，以了解决定三维纺锤体结构的机制。为了做到这一点，我们使用随机蒙特卡罗搜索，在纺锤的有效能量景观中寻找稳定的力学平衡。我们发现，要在多体细胞中强健地组装两极纺锤体，必须满足以下条件：1)中心体相互吸引的强度必须与细胞皮质的吸引力成正比，2)中心体对着丝点的吸引和对染色体臂的排斥的强度必须成比例。我们还发现，如果不满足这些条件，还会出现另外三种纺锤形：1)坍塌，2)单极，和3)多极纺锤，计算屏幕显示了这些异常纺锤的力学条件。
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.