bioRxiv2025
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.