Chromosomes function as a barrier to mitotic spindle bipolarity in polyploid cells
Chromosomes function as a barrier to mitotic spindle bipolarity in polyploid cells
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DOI：
10.1083/jcb.201908006
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发表时间：
2020-04-06
影响因子：
7.8
通讯作者：
Basto, Renata
中科院分区：
文献类型：
--
作者：
Goupil, Alix;Nano, Maddalena;Basto, Renata
倍性变异如基因组加倍在人类肿瘤中是常见的，并且与有利于肿瘤进展的遗传不稳定性相关。多倍体细胞如何处理增加的中心体数量和DNA含量仍然未知。利用果蝇神经母细胞和人类癌细胞研究多倍体细胞中的有丝分裂纺锤体组装，我们发现大多数多倍体细胞以多极方式分裂。我们表明，即使最初的中心体聚类步骤可以发生在有丝分裂进入，建立的kinetochore-microtubule附件导致空间染色体配置，从而抑制了最终合并成一个双极阵列的额外的极点。使用在硅片上的方法和各种纺锤体和DNA扰动，我们表明，染色体作为一个物理屏障，阻止纺锤体极聚结和双极性。重要的是，微管稳定抑制多极化，提高中心体聚类和极聚结。这项工作确定了多倍体细胞中双极分裂的抑制剂，并为了解多倍体癌细胞典型的染色体不稳定性提供了理论基础。
Ploidy variations such as genome doubling are frequent in human tumors and have been associated with genetic instability favoring tumor progression. How polyploid cells deal with increased centrosome numbers and DNA content remains unknown. Using Drosophila neuroblasts and human cancer cells to study mitotic spindle assembly in polyploid cells, we found that most polyploid cells divide in a multipolar manner. We show that even if an initial centrosome clustering step can occur at mitotic entry, the establishment of kinetochore-microtubule attachments leads to spatial chromosome configurations, whereby the final coalescence of supernumerary poles into a bipolar array is inhibited. Using in silico approaches and various spindle and DNA perturbations, we show that chromosomes act as a physical barrier blocking spindle pole coalescence and bipolarity. Importantly, microtubule stabilization suppressed multipolarity by improving both centrosome clustering and pole coalescence. This work identifies inhibitors of bipolar division in polyploid cells and provides a rationale to understand chromosome instability typical of polyploid cancer cells.