Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions

Abstract Bistability is a common mechanism to ensure robust and irreversible cell cycle transitions. Whenever biological parameters or external conditions change such that a threshold is crossed, the system abruptly switches between different cell cycle states. Experimental studies indicate that the shape of the bistable response curve changes dynamically in time. Here, we show how such a dynamically changing bistable switch can provide a cell with better control over the timing of cell cycle transitions. Moreover, cell cycle oscillations built on bistable switches are more robust when the bistability is modulated in time. Our results are not specific to cell cycle models and may apply to other bistable systems in which the bistable response curve is time-dependent. Author summary Many systems in nature show bistability, which means they can evolve to one of two stable steady states under exactly the same conditions. Which state they evolve to depends on where the system comes from. Such bistability underlies the switching behavior that is essential for cells to progress in the cell division cycle. A quick switch happens when the cell jumps from one steady state to another steady state. Typical of this switching behavior is its robustness and irreversibility. In this paper, we expand this viewpoint of the dynamics of the cell cycle by considering bistable switches which themselves are changing in time. This gives the cell an extra layer of control over transitions both in time and in space, and can make those transitions more robust. Such dynamically changing bistability can appear very naturally. We show this in a model of mitotic entry, in which we include a nuclear and cytoplasmic compartment. The activity of a crucial cell cycle protein follows a bistable switch in each compartment, but the shape of its response is changing in time as proteins are imported and exported from the nucleus.