Cell cycle commitment in budding yeast emerges from the cooperation of multiple bistable switches.
The start-transition (START) in the G1 phase marks the point in the cell cycle at which a yeast cell initiates a new round of cell division. Once made, this decision is irreversible and the cell is committed to progressing through the entire cell cycle, irrespective of arrest signals such as pheromone. How commitment emerges from the underlying molecular interaction network is poorly understood. Here, we perform a dynamical systems analysis of an established cell cycle model, which has never been analysed from a commitment perspective. We show that the irreversibility of the START transition and subsequent commitment can be consistently explained in terms of the interplay of multiple bistable molecular switches. By applying an existing mathematical model to a novel problem and by expanding the model in a self-consistent manner, we achieve several goals: we bring together a large number of experimental findings into a coherent theoretical framework; we increase the scope and the applicability of the original model; we give a systems level explanation of how the START transition and the cell cycle commitment arise from the dynamical features of the underlying molecular interaction network; and we make clear, experimentally testable predictions.
Oxford Centre for Integrative Systems Biology (OCISB), Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Tongli
T
Zhang
Bernhard
B
Schmierer
Béla
B
Novák
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D016193:G1 Phase / Q000235:genetics / Q000502:physiology; D005800:Genes, Fungal; D008954:Models, Biological; D009154:Mutation; D010675:Pheromones / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins; C081353:FAR1 protein, S cerevisiae; D010675:Pheromones; C080321:STE5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D016203:CDC2 Protein Kinase