A checkpoints capturing timing-robust Boolean model of the budding yeast cell cycle regulatory network

Abstract

Background: Cell cycle process of budding yeast (Saccharomyces cerevisiae) consists of four phases: G1, S, G2 and M. Initiated by stimulation of the G1 phase, cell cycle returns to the G1 stationary phase through a sequence of the S, G2 and M phases. During the cell cycle, a cell verifies whether necessary conditions are satisfied at the end of each phase (i.e., checkpoint) since damages of any phase can cause severe cell cycle defect. The cell cycle can proceed to the next phase properly only if checkpoint conditions are met. Over the last decade, there have been several studies to construct Boolean models that capture checkpoint conditions. However, they mostly focused on robustness to network perturbations, and the timing robustness has not been much addressed. Only recently, some studies suggested extension of such models towards timing-robust models, but they have not considered checkpoint conditions. Results: To construct a timing-robust Boolean model that preserves checkpoint conditions of the budding yeast cell cycle, we used a model verification technique, 'model checking'. By utilizing automatic and exhaustive verification of model checking, we found that previous models cannot properly capture essential checkpoint conditions in the presence of timing variations. In particular, such models violate the M phase checkpoint condition so that it allows a division of a budding yeast cell into two before the completion of its full DNA replication and synthesis. In this paper, we present a timing-robust model that preserves all the essential checkpoint conditions properly against timing variations. Our simulation results show that the proposed timing-robust model is more robust even against network perturbations and can better represent the nature of cell cycle than previous models. Conclusions: To our knowledge this is the first work that rigorously examined the timing robustness of the cell cycle process of budding yeast with respect to checkpoint conditions using Boolean models. The proposed timing-robust model is the complete state-of-the-art model that guarantees no violation in terms of checkpoints known to date.