Network topology creates independent control of G2-M from G1-S checkpoints in the fission yeast cell cycle system

Physiological functions of cells arise from the dynamics of chemical reaction networks. The cell cycle of fission yeast is controlled by dynamical changes in two cyclin-dependent kinase (CDK)-cyclin complexes based on a complicated reaction network consisting of protein synthesis, complex formation, and degradation1,2. Each of the two checkpoints, G1-S and G2-M, is driven by an increase in the concentration of CDK-Cig2 and CDK-Cdc13, respectively. However, it is not understood how these complexes in the single connected network are controlled independently in a stage-specific manner. Here we theoretically predict that independent control of CDK-Cdc13 from CDK-Cig2 is achieved by the topology of the cell cycle network, and experimentally validate this prediction, while updating the network information by comparing predictions and experiments. We analyzed a known cell cycle network using a topology-based theory3-6 and revealed that the two CDK-cyclin complexes are included in different "regulatory modules", suggesting that the concentration of each CDK-cyclin complex is controlled independently from the other. Experimental validation confirmed that the concentration of CDK-Cdc13 is controlled by the Cdc13 synthesis rate, independently from CDK-Cig2, as predicted. Conversely, the Cig2 synthesis rate affected not only CDK-Cig2 but also CDK-Cdc13. The fact, however, indicates the necessity of updating the network. We theoretically predicted the existence of an unknown necessary reaction, a Cdc13 degradation pathway, and experimentally confirmed it. The prediction and validation approach using the topology-based theory proposes a new systems biology, which progresses by comparing network structures with manipulation experiments and updating network information.