Transient endoreplication down-regulates the kinesin-14 HSET and contributes to genomic instability.
Transient endoreplication down-regulates the kinesin-14 HSET and contributes to genomic instability.
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DOI：
10.1091/mbc.e16-03-0159
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发表时间：
2016-10-01
影响因子：
3.3
通讯作者：
Walczak CE
中科院分区：
文献类型：
--
作者：
Chen S;Stout JR;Dharmaiah S;Yde S;Calvi BR;Walczak CE
通过核内复制产生高度多倍体细胞的模型显示，iEC具有较低水平的HSET，其过表达挽救了纺锤体多极性。这些结果提供了对交替细胞周期导致多倍体细胞分裂和基因组不稳定性的机制的深入了解。多倍体癌细胞表现出染色体不稳定性（CIN），其与肿瘤发生和治疗抗性相关。诱导多倍体的机制以及这些机制如何导致CIN尚不完全清楚。在这里，我们评估CIN在人类细胞，成为多倍体通过实验诱导的内复制周期。当这些诱导的内复制细胞（iECs）返回到有丝分裂，它导致在子细胞的非整倍体。这种非整倍体是由多极分裂、染色体错误分离和胞质分裂失败引起的。iECs经过几轮分裂，最终产生倍性降低的增殖细胞。iEC具有降低的驱动蛋白-14HSET水平，这可能是多极分裂的原因，并且HSET的过表达降低了纺锤体多极性。然而，HSET过表达对CIN只有轻微的影响，这表明额外的缺陷必须有助于分裂iEC的基因组不稳定性。总体而言，我们的结果表明，短暂的胞内复制周期产生了多样化的增殖非整倍体细胞群体，这些细胞有可能导致肿瘤异质性。
A model for generating highly polyploid cells through endoreplication shows that iECs have lower levels of HSET, overexpression of which rescues spindle multipolarity. The results provide insight into the mechanisms by which alternative cell cycles lead to polyploid cell division and genomic instability. Polyploid cancer cells exhibit chromosomal instability (CIN), which is associated with tumorigenesis and therapy resistance. The mechanisms that induce polyploidy and how these mechanisms contribute to CIN are not fully understood. Here we evaluate CIN in human cells that become polyploid through an experimentally induced endoreplication cycle. When these induced endoreplicating cells (iECs) returned to mitosis, it resulted in aneuploidy in daughter cells. This aneuploidy resulted from multipolar divisions, chromosome missegregation, and failure in cytokinesis. The iECs went through several rounds of division, ultimately spawning proliferative cells of reduced ploidy. iECs have reduced levels of the kinesin-14 HSET, which likely accounts for the multipolar divisions, and overexpression of HSET reduced spindle multipolarity. However, HSET overexpression had only mild effects on CIN, suggesting that additional defects must contribute to genomic instability in dividing iECs. Overall our results suggest that transient endoreplication cycles generate a diverse population of proliferative aneuploid cells that have the potential to contribute to tumor heterogeneity.