Uncoordinated loss of chromatid cohesion is a common outcome of extended metaphase arrest.
Uncoordinated loss of chromatid cohesion is a common outcome of extended metaphase arrest.
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DOI：
10.1371/journal.pone.0022969
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Desai A
中科院分区：
文献类型：
--
作者：
Stevens D;Gassmann R;Oegema K;Desai A
染色体分离要求姐妹染色单体在有丝分裂纺锤体上的所有染色体双向定位后协调分离。中期到后期的染色单体分离是通过裂解将染色单体结合在一起的粘附素复合体来完成的。在这里，我们使用活细胞成像显示，使用五个独立的扰动(不可降解的Cyclin B的表达，防止纺锤体检查点沉默的纺锤点突变体的表达，耗尽后期诱导子Cdc20，用蛋白酶体抑制剂处理，或用CENP-E中有丝分裂运动的抑制剂处理)延长中期生物定向状态，导致染色体最终分散在纺锤体上。这种散射表型的特征是一些但不是所有姐妹染色单体之间的凝聚力不协调丧失，以及随后的纺锤体缺陷，包括中心粒分离。染色体分散的细胞长期处于有丝分裂状态，最终死亡或退出。在转化细胞和核型正常细胞中都观察到了部分凝聚力丢失相关的散射，尽管外显率较低。抑制微管动力学减少了散射，这表明着丝粒的凝聚力无法抵抗动态微管依赖的动心拉力。与这一观点一致，通过抑制负责去除它的两条途径来加强凝聚力，可显著抑制散射。这些结果表明，由于染色单体凝聚力的不协调部分丧失而导致的染色体散射是人类细胞中双向染色体长期停滞后的常见结果。这些发现对分析人类细胞的有丝分裂表型和开发抗有丝分裂的化疗方法治疗癌症具有重要意义。
Chromosome segregation requires coordinated separation of sister chromatids following biorientation of all chromosomes on the mitotic spindle. Chromatid separation at the metaphase-to-anaphase transition is accomplished by cleavage of the cohesin complex that holds chromatids together. Here we show using live-cell imaging that extending the metaphase bioriented state using five independent perturbations (expression of non-degradable Cyclin B, expression of a Spindly point mutant that prevents spindle checkpoint silencing, depletion of the anaphase inducer Cdc20, treatment with a proteasome inhibitor, or treatment with an inhibitor of the mitotic kinesin CENP-E) leads to eventual scattering of chromosomes on the spindle. This scattering phenotype is characterized by uncoordinated loss of cohesion between some, but not all sister chromatids and subsequent spindle defects that include centriole separation. Cells with scattered chromosomes persist long-term in a mitotic state and eventually die or exit. Partial cohesion loss-associated scattering is observed in both transformed cells and in karyotypically normal human cells, albeit at lower penetrance. Suppressing microtubule dynamics reduces scattering, suggesting that cohesion at centromeres is unable to resist dynamic microtubule-dependent pulling forces on the kinetochores. Consistent with this view, strengthening cohesion by inhibiting the two pathways responsible for its removal significantly inhibits scattering. These results establish that chromosome scattering due to uncoordinated partial loss of chromatid cohesion is a common outcome following extended arrest with bioriented chromosomes in human cells. These findings have important implications for analysis of mitotic phenotypes in human cells and for development of anti-mitotic chemotherapeutic approaches in the treatment of cancer.
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影响因子：
9.8
作者：
McGuinness BE;Hirota T;Kudo NR;Peters JM;Nasmyth K
通讯作者：
Nasmyth K
影响因子：
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作者：
Matos, Irina;Pereira, Antonio J.;Maiato, Helder
通讯作者：
Maiato, Helder
影响因子：
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作者：
Hauf S;Roitinger E;Koch B;Dittrich CM;Mechtler K;Peters JM
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Peters JM
影响因子：
10.5
作者：
Gassmann, Reto;Holland, Andrew J.;Desai, Arshad
通讯作者：
Desai, Arshad
影响因子：
64.5
作者：
Jallepalli, PV;Waizenegger, IC;Lengauer, C
通讯作者：
Lengauer, C