Exit from mitosis is regulated by drosophila fizzy and the sequential destruction of cyclins A, B and B3

Abstract

While entry into mitosis is triggered by activation of cdc2 kinase, exit from mitosis requires inactivation of this kinase. Inactivation results from proteolytic degradation of the regulatory cyclin subunits during mitosis. At least three different cyclin types, cyclins A, B and B3, associate with cdc2 kinase in higher eukaryotes and are sequentially degraded in mitosis. We show here that mutations in the Drosophila gene fizzy (fzy) block the mitotic degradation of these cyclins. Moreover, expression of mutant cyclins (Δcyclins) lacking the destruction box motif required for mitotic degradation affects mitotic progression at distinct stages. Δcyclin A results in a delay in metaphase, Δcyclin B in an early anaphase arrest and Δcyclin B3 in a late anaphase arrest, suggesting that mitotic progression beyond metaphase is ordered by the sequential degradation of these different cyclins. Co-expression of Δcyclins A, B and B3 allows a delayed separation of sister chromosomes, but interferes with chromosome segregation to the poles. Mutations in fzy block both sister chromosome separation and segregation, indicating that fzy plays a crucial role in the metaphase/anaphase transition.