Chromosomes function as a barrier to mitotic spindle bipolarity in polyploid cells

被引:19
作者
Goupil, Alix [1 ]
Nano, Maddalena [1 ,4 ]
Letort, Gaelle [2 ]
Gemble, Simon [1 ]
Edwards, Frances [1 ]
Goundiam, Oumou [1 ,3 ]
Gogendeau, Delphine [1 ]
Pennetier, Carole [1 ]
Basto, Renata [1 ]
机构
[1] Paris Sci & Lettres Res Univ, Inst Curie, Unite Mixte Rech UMR144, Biol Centrosomes & Genet Instabil Lab,CNRS, Paris, France
[2] Coll France, Ctr Interdisciplinary Res Biol, UMR7241 U1050, Paris, France
[3] PSL Univ, Inst Curie, Dept Translat Res, Paris, France
[4] Univ Calif Santa Barbara, Mol Cellular & Dev Biol Dept, Santa Barbara, CA 93106 USA
基金
欧洲研究理事会;
关键词
SMALL-MOLECULE INHIBITOR; CENTROSOME; PROTEIN; MICROTUBULES; INSTABILITY; CHECKPOINT; KINESIN; TUMORIGENESIS; CYTOKINESIS; MECHANISMS;
D O I
10.1083/jcb.201908006
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页数:27
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