PP2A-B56 par1 Opposes CDK Phosphorylation of Rum1 and Promotes Ste9 Activation During Pre-Start G1 Phase

Exit from the cell cycle during the establishment of the quiescent state and upon cell differentiation requires the sustained inactivation of CDK complexes. In human cells, CDK inhibitors (CKIs) belonging to CIP/KIP family (p21, p27 and p57) are key elements in this regulation and are essential for the cell cycle arrest that precedes differentiation and during quiescence. Similarly, fission yeast cells exposed to the absence of nitrogen halt their cell cycle progression in pre-Start G1 before becoming quiescent or, if a mating partner is available, undergoing sexual differentiation. The CKI Rum1 and the APC/C activator Ste9 are fundamental elements of this arrest, but they are subject to negative regulation by CDK complexes. Here, we show that the phosphatase PP2A-B56Par1 is required to counteract CDK-phosphorylation of Rum1 during the establishment of a pre-Start G1 arrest. In the absence of PP2A-B56Par1, cells fail to stabilize Rum1 and this results in persistent CDK activity, Ste9 inactivation and retention of the mitotic cyclin Cdc13. This, in turn, leads to impaired withdrawal from the cell cycle. Importantly, mutation of a putative B56 interacting motif present in Rum1 recapitulates these defects. Altogether, these results underscore the importance of phosphatase activity during cell cycle exit and differentiation. Moreover, they highlight the relevance of CDK-counteracting phosphatases when investigating the quiescent state, and escape from it in tumour cells, in humans.