Nonequilibrium and nonlinear kinetics as key determinants for bistability in fission yeast G2-M transition

A living cell is an open, nonequilibrium biochemical system where ATP hydrolysis serves as the energy source for a wide range of intracellular processes, possibly including the assurance for decision-making. In the fission yeast cell cycle, the transition from G2 to M phase is driven by the activation of Cdc13/Cdc2 and Cdc25 and the deactivation of Wee1 through phosphorylation-dephosphorylation cycles with feedback loops. Here, we present a kinetic description of the G2-M circuit which reveals that both cellular ATP level and ATP hydrolysis free energy critically control Cdc2 activation. Using fission yeast nucleoplasmic extract (YNPE), we experimentally verify that increased ATP level drives the activation of Cdc2 which exhibits bistability and hysteresis in response to changes in cellular ATP level and ATP hydrolysis energy. These findings suggest that cellular ATP level and ATP hydrolysis energy are determinants of the bistability and robustness of Cdc2 activation during G2-M transition.