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Bistability of the Cdk1-Wee1-Cdc25 mitotic control network underlies the switch-like transitions between interphase and mitosis. Here, we show by mathematical modeling and experiments in Xenopus egg extracts that protein phosphatase 2A (PP2A), which can dephosphorylate Cdk1 substrates, is essential for this bistability. PP2A inhibition in early interphase abolishes the switch-like response of the system to Cdk1 activity, promoting mitotic onset even with very low levels of Cyclin, Cdk1, and Cdc25, while simultaneously inhibiting DNA replication. Furthermore, even if replication has already initiated, it cannot continue in mitosis. Exclusivity of S and M phases does not depend on bistability only, since partial PP2A inhibition prevents replication without inducing mitotic onset. In these conditions, interphase-level mitotic kinases inhibit Cyclin E-Cdk2 chromatin loading, blocking initiation complex formation. Therefore, by counteracting both Cdk1 activation and activity of mitotic kinases, PP2A ensures robust separation of S phase and mitosis and dynamic transitions between the two states.

Original publication




Journal article


Mol Cell

Publication Date





437 - 450


Animals, CDC2 Protein Kinase, Cell Cycle Proteins, Chromatin Assembly and Disassembly, Computer Simulation, Cyclin E, Cyclin-Dependent Kinase 2, DNA Replication, Enzyme Inhibitors, M Phase Cell Cycle Checkpoints, Models, Biological, Numerical Analysis, Computer-Assisted, Phosphorylation, Protein Phosphatase 2, Protein-Tyrosine Kinases, S Phase Cell Cycle Checkpoints, Time Factors, Xenopus, Xenopus Proteins, cdc25 Phosphatases