Abstract
Cyclin A prevents premature stabilization of kinetochore–microtubule (k–MT) attachments.
Major finding: Cyclin A prevents premature stabilization of kinetochore–microtubule (k–MT) attachments.
Concept: Stabilization of k–MT attachments after prometaphase is dependent on cyclin A degradation.
Impact: Cyclin A deficiency leads to an increase in lagging chromosomes and chromosome segregation errors.
During metaphase, chromosomes align and attachments necessary for chromosome segregation form between kinetochores and spindle microtubules. Kinetochore–microtubule (k–MT) attachment errors frequently occur early in metaphase (prometaphase), but it is unknown how these errors are corrected. Using dissipation of photoactivated GFP-tagged tubulin as a measure of k–MT attachment stability, Kabeche and Compton found that k–MT attachments stabilized in a coordinated manner during the progression from prometaphase to metaphase, suggesting that an increased probability of k–MT detachment during prometaphase could facilitate correction of k–MT attachment errors. The switch in k–MT attachment stability was dependent on protein turnover, as k–MT attachments did not stabilize in metaphase in the presence of proteasome inhibitors. Consistent with these findings, expression of a nondegradable mutant version of cyclin A, which is normally degraded in prometaphase, prevented the stabilization of k–MT attachments in metaphase. Cyclin A levels and k–MT attachment stability were not linearly related, indicating that the persistent presence of cyclin A above a particular threshold is sufficient to maintain k–MT attachment instability. In the converse experiment, cyclin A knockdown prematurely stabilized k–MT attachments in prometaphase. Subsequently, the frequency of lagging chromosomes, which are a direct result of incorrect k–MT attachments, significantly increased. Overexpression of wild-type cyclin A in cancer cell lines destabilized k–MT attachments in metaphase similar to the nondegradable mutant but increased chromosome segregation fidelity. The identification of a link between cyclin A and regulation of k–MT attachment stability suggests that cyclin A has an unappreciated role in maintaining chromosomal integrity during mitosis.
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