title: 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. 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.
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kabeche
authors.forename: Duane A
authors.initials: DA
authors.lastname: Compton
mesh_terms: D002460:Cell Line; D020090:Chromosome Segregation / Q000187:drug effects / Q000502:physiology*; D019925:Cyclin A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D055550:Protein Stability; D011743:Pyrimidines / Q000494:pharmacology; D013871:Thiones / Q000494:pharmacology
chemical_list: D019925:Cyclin A; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D013871:Thiones; C400223:monastrol