Countervailing effects of cyclin isoforms A and B during mitosis

Abstract

Faithful chromosome segregation requires the spatial and temporal remodeling of cell structures driven largely by cyclin-dependent kinase (Cdk) activity. In some experimental systems the timely elevation of one cyclin isoform is sufficient to support mitotic entry and progression. In human somatic cells, however, three cyclins - Cyclin A2, Cyclin B1, and Cyclin B2 - are present at mitotic entry, and their distinct contributions during mitosis remain largely unclear. We demonstrate that Cyclin A2 promotes the kinetochore localization of Cyclin B1, Cyclin B2 and the fibrous corona component CENPF, while suppressing recruitment of the kinetochore-microtubule (k-MT) stabilizer Astrin. Extending Cyclin A2 into metaphase by expressing a non-degradable mutant causes persistent kinetochore localization of Cyclin B1, Cyclin B2, and CENPF. Conversely, Cyclin B1 limits kinetochore localization of Cyclin B2 and CENPF, promotes Astrin recruitment, and stabilizes k-MT attachments and Cyclin B1 overexpression further reduces kinetochore localization of CENPF during prometaphase. These findings reveal an interdependence among mitotic cyclins in early mitosis and the countervailing activities of Cyclin A2 versus Cyclin B1/B2 in regulating key mitotic events. We propose that this circuitry enforces a switch-like transition from prometaphase - marked by corona assembly and high k-MT turnover - to metaphase - marked by corona disassembly, stabilization of end-on k-MT attachments, and eventual spindle assembly checkpoint satisfaction - to choreograph the structural changes required to ensure faithful chromosome segregation.