Cyclin A regulates kinetochore microtubules to promote faithful chromosome segregation

Abstract

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. Strikingly, numerous kinetochore-microtubule (k-MT) attachment errors are present in early mitosis (prometaphase)1, and the persistence of those errors is the leading cause of chromosome mis-segregation in aneuploid human tumor cells that continually mis-segregate whole chromosomes (e.g. chromosomal instability)2–7. 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 significantly 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. In 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.