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Cyclin A regulates kinetochore microtubules to promote faithful chromosome segregation

机译:细胞周期蛋白A调节线粒体微管以促进忠实的染色体分离

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摘要

The most conspicuous event in the cell cycle is the alignment of chromosomes in metaphase. Chromosome alignment fosters faithful segregation through the formation of bi-oriented attachments of kine-tochores to spindle microtubules. Notably, numerous kinetochore-microtubule (k-MT) attachment errors are present in early mitosis (prometaphase) and the persistence of those errors is the leading cause of chromosome mis-segregation in aneuploid human tumour cells that continually mis-segregate whole chromosomes and display chromosomal instability. How robust error correction is achieved in prometaphase to ensure error-free mitosis remains unknown. Here we show that k-MT attachments in prometaphase cells are considerably less stable than in metaphase cells. The switch to more stable k-MT attachments in metaphase requires the proteasome-dependent destruction of cyclin A in prometaphase. Persistent cyclin A expression prevents k-MT stabilization even in cells with aligned chromosomes. By contrast, k-MTs are prematurely stabilized in cyclin-A-deficient cells. Consequently, cells lacking cyclin A display higher rates of chromosome mis-segregation. Thus, the stability of k-MT attachments increases decisively in a coordinated fashion among all chromosomes as cells transit from prometaphase to metaphase. Cyclin A creates a cellular environment that promotes microtubule detachment from kinetochores in prometaphase to ensure efficient error correction and faithful chromosome segregation.
机译:细胞周期中最明显的事件是中期染色体的排列。染色体排列通过形成动子束到纺锤体微管的双向定向,促进了忠实的分离。值得注意的是,早期有丝分裂(前中期)存在大量的动粒-微管(k-MT)附着错误,并且这些错误的持续存在是非整倍体人类肿瘤细胞中染色体错误分离的主要原因,这种错误不断地将整个染色体错误地分离并显示。染色体不稳定。在前中期如何实现强大的错误校正以确保无错误的有丝分裂仍然未知。在这里,我们显示前中期细胞中的k-MT附着远不如中期细胞中的稳定。在中期过渡到更稳定的k-MT附件需要在中期进行蛋白酶体依赖性细胞周期蛋白A破坏。持久性细胞周期蛋白A的表达即使在具有对齐染色体的细胞中也可阻止k-MT稳定。相比之下,k-MT在细胞周期蛋白A缺陷型细胞中过早稳定。因此,缺乏细胞周期蛋白A的细胞显示出较高的染色体错误分离率。因此,随着细胞从前中期过渡到中期,k-MT附着的稳定性以协调的方式决定性地增加。细胞周期蛋白A创造了一个细胞环境,该细胞环境促进了前中期的动植物微管脱离,以确保有效的纠错和忠实的染色体分离。

著录项

  • 来源
    《Nature》 |2013年第7469期|110-113|共4页
  • 作者单位

    Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA,Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA;

    Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA,Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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