Interlinked bistable mechanisms generate robust mitotic transitions

The transitions between phases of the cell cycle have evolved to be robust and switch-like, which ensures temporal separation of DNA replication, sister chromatid separation, and cell division. Mathematical models describing the biochemical interaction networks of cell cycle regulators attribute these properties to underlying bistable switches, which inherently generate robust, switch-like, and irreversible transitions between states. We have recently presented new mathematical models for two control systems that regulate crucial transitions in the cell cycle: mitotic entry and exit,¹ Mochida S, Rata S, Hino H, Nagai T, Novák B. Two Bistable Switches Govern M Phase Entry. Curr Biol. 2016;26:3361-3367. doi:10.1016/j.cub.2016.10.022. PMID:27889260Crossref], PubMed], Web of Science ®] Google Scholar] and the mitotic checkpoint.² Mirkovic M, Hutter LH, Novák B, Oliveira RA. Premature sister chromatid separation is poorly detected by the spindle assembly checkpoint as a result of system-level feedback. Cell Rep. 2015;13:469-478. doi:10.1016/j.celrep.2015.09.020Crossref], PubMed], Web of Science ®] Google Scholar] Each of the two control systems is characterized by two interlinked bistable switches. In the case of mitotic checkpoint control, these switches are mutually activating, whereas in the case of the mitotic entry/exit network, the switches are mutually inhibiting. In this Perspective we describe the qualitative features of these regulatory motifs and show that having two interlinked bistable mechanisms further enhances robustness and irreversibility. We speculate that these network motifs also underlie other cell cycle transitions and cellular transitions between distinct biochemical states.