Genome stability is ensured by temporal control of kinetochore-microtubule dynamics.
Genome stability is ensured by temporal control of kinetochore-microtubule dynamics.
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DOI：
10.1038/ncb1809
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发表时间：
2009-01
影响因子：
21.3
通讯作者：
Compton, Duane A.
中科院分区：
文献类型：
--
作者：
Bakhoum, Samuel F.;Thompson, Sarah L.;Manning, Amity L.;Compton, Duane A.
大多数实体肿瘤为非整倍体，并且许多肿瘤经常发生染色体错误分离。这种染色体不稳定性通常是由染色体与纺锤体微管持续错误定向连接所导致。染色体分离需要在动粒处有稳定的微管连接，但这些连接必须具有足够的动态性以允许对错误定向进行纠正。这种平衡是如何实现的尚不清楚，而且对于基因组稳定性至关重要的连接稳定性与动态性的允许界限仍知之甚少。在此我们表明，两种微管解聚驱动蛋白Kif2b和MCAK在有丝分裂的不同阶段刺激动粒 - 微管的动态变化以纠正错误定向。动粒 - 微管转换率降低几倍，尤其是在有丝分裂早期，会引发严重的染色体分离缺陷。此外，我们表明刺激动粒处的微管动态可恢复染色体不稳定的肿瘤细胞系的染色体稳定性，从而确立了动粒 - 微管动态失调与染色体不稳定性之间的因果关系。因此，在有丝分裂期间对微管与染色体连接的时间控制对于人类细胞的基因组稳定性至关重要。
Most solid tumors are aneuploid and many frequently mis-segregate chromosomes. This chromosomal instability is commonly caused by persistent maloriented attachment of chromosomes to spindle microtubules. Chromosome segregation requires stable microtubule attachment at kinetochores, yet those attachments must be sufficiently dynamic to permit correction of malorientations. How this balance is achieved is unknown, and the permissible boundaries of attachment stability versus dynamics essential for genome stability remain poorly understood. Here we show that two microtubule-depolymerizing kinesins, Kif2b and MCAK, stimulate kinetochore-microtubule dynamics during distinct phases of mitosis to correct malorientations. Few-fold reductions in kinetochore-microtubule turnover, particularly in early mitosis, induce severe chromosome segregation defects. In addition, we show that stimulation of microtubule dynamics at kinetochores restores chromosome stability to chromosomally unstable tumor cell lines, establishing a causal relationship between deregulation of kinetochore-microtubule dynamics and chromosomal instability. Thus, temporal control of microtubule attachment to chromosomes during mitosis is central to genome stability in human cells.
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Salmon, ED
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