Cell cycle progression is driven by cyclin-dependent kinase (CDK) activity, with CDK levels rising ∼50-fold over the cell cycle and peaking in mitosis. However, it is still unknown whether these high activity levels are actually required for mitosis. In their Short Report, Souradeep Basu, Paul Nurse and co-workers (Basu et al., 2022) now ask whether fission yeast cells are able to tolerate lower CDK activity levels and still be capable of undergoing mitosis. To that end, they progressively reduce the in vivo CDK activity levels in a strain in which Cdc2, the only cell cycle CDK in Schizosaccharomyces pombe, has been engineered to be sensitive to an ATP analogue. Using this approach, they find that sublethal levels of CDK activity increase the time cells spend in mitosis but do not result in mitotic defects per se. This suggests that maximum levels of cellular CDK activity are actually higher than needed to progress during the different mitotic stages, pointing to a buffering of this activity that will ensure mitosis completion when CDK activity is compromised. To test this idea, the authors reasoned that increasing the overall CDK activity by removing its counteracting phosphatases might increase the CDK activity buffer capacity and thus make cells more resistant to acute CDK inhibition. Indeed, removal of Clp1, a major CDK phosphatase, increases the tolerance of cells to CDK inhibition, but the exact mechanisms underlying the buffer of CDK activity, and thus the robustness of cells to its loss, remain to be determined.
