Cyclin proteolysis and CDK inhibitors - Two redundant pathways to maintain genome stability in mammalian cells

Cyclin-dependent kinases (CDKs) are regulated by cyclin proteolysis and CDK inhibitors (CKIs) during mitotic exit and G(1) phase in yeast and Drosophila, and disruption of both regulatory pathways leads to genomic instability. Our study using mouse cell lines that constitutively express a stabilized mutant of cyclin A revealed that three CKIs, p21, p27, and Rb-related p107, are responsible for cyclin proteolysis-independent inactivation of CDK during mitotic exit and G1. Enforced expression of cyclin A in the cells lacking all three CKIs induced rapid tetraploidization. Thus, the redundant pathways consisting of cyclin proteolysis and CKIs control CDK activity during mitotic exit and contribute to maintenance of genome stability in mammalian cells.