Skp2-Cyclin A Interaction Is Necessary for Mitotic Entry and Maintenance of Diploidy.

[Display omitted] • Skp2 functions with the mitotic Cyclin A-Cdk1 complex to promote entry into mitosis. • Skp2 and cyclin A physically interact in Drosophila and Skp2 is required to maintain cyclin A levels. • By-pass of mitosis in Skp2 mutants results in polyploidy. • Polyploid Skp2 mutant cells that enter mitosis trigger checkpoints that arrest or delay mitosis or promote apoptosis. Skp2, the substrate recognition component of the SCFSkp2 ubiquitin ligase, has been implicated in the targeted destruction of a number of key cell cycle regulators and the promotion of S-phase. One of its critical targets is the Cyclin dependent kinase (Cdk) inhibitor p27, and indeed the overexpression of Skp2 in a number of cancers is directly correlated with the premature degradation of p27. Skp2 was first identified as a protein that interacts with Cyclin A in transformed cells, but its role in this complex has remained unclear. In this paper, we demonstrate that Skp2 interacts with Cyclin A in Drosophila and is required to maintain Cyclin A levels and permit mitotic entry. Failure of mitotic entry in Skp2 mutant cells results in polyploidy. If these cells enter mitosis again they are unable to properly segregate their chromosomes, leading to checkpoint dependent cell cycle arrest or apoptosis. Thus, Skp2 is required for mitosis and for maintaining diploidy and genome stability. [ABSTRACT FROM AUTHOR]