Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA.
Nature. 2013 Oct 3;502(7469):110-3. doi: 10.1038/nature12507. Epub 2013 Sep 8.
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 kinetochores 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.
细胞周期中最显著的事件是染色体在中期的排列。染色体的排列通过动粒与纺锤体微管的双取向附着促进忠实的分离。值得注意的是，在早期有丝分裂（前期）中存在大量的动粒-微管（k-MT）附着错误，并且这些错误的持续存在是导致非整倍体人类肿瘤细胞中染色体错误分离的主要原因，这些细胞不断错误地分离整条染色体并表现出染色体不稳定。在前期中如何实现稳健的错误校正以确保无错误的有丝分裂仍然未知。在这里，我们表明前期细胞中的 k-MT 附着明显不如中期细胞稳定。中期更稳定的 k-MT 附着的转变需要在前期通过蛋白酶体依赖性破坏细胞周期蛋白 A。在染色体排列的细胞中，持续的细胞周期蛋白 A 表达甚至会阻止 k-MT 稳定。相比之下，细胞周期蛋白 A 缺失的细胞中 k-MTs 会过早稳定。因此，缺乏细胞周期蛋白 A 的细胞显示出更高的染色体错误分离率。因此，随着细胞从前期过渡到中期，所有染色体都以协调的方式决定性地增加 k-MT 附着的稳定性。细胞周期蛋白 A 创造了一种细胞环境，促进微管在前期从动粒上脱离，以确保有效的错误校正和忠实的染色体分离。
