title: From START to FINISH: the influence of osmotic stress on the cell cycle.
abstract: The cell cycle is a sequence of biochemical events that are controlled by complex but robust molecular machinery. This enables cells to achieve accurate self-reproduction under a broad range of different conditions. Environmental changes are transmitted by molecular signalling networks, which coordinate their action with the cell cycle. The cell cycle process and its responses to environmental stresses arise from intertwined nonlinear interactions among large numbers of simpler components. Yet, understanding of how these pieces fit together into a coherent whole requires a systems biology approach. Here, we present a novel mathematical model that describes the influence of osmotic stress on the entire cell cycle of S. cerevisiae for the first time. Our model incorporates all recently known and several proposed interactions between the osmotic stress response pathway and the cell cycle. This model unveils the mechanisms that emerge as a consequence of the interaction between the cell cycle and stress response networks. Furthermore, it characterises the role of individual components. Moreover, it predicts different phenotypical responses for cells depending on the phase of cells at the onset of the stress. The key predictions of the model are: (i) exposure of cells to osmotic stress during the late S and the early G2/M phase can induce DNA re-replication before cell division occurs, (ii) cells stressed at the late G2/M phase display accelerated exit from mitosis and arrest in the next cell cycle, (iii) osmotic stress delays the G1-to-S and G2-to-M transitions in a dose dependent manner, whereas it accelerates the M-to-G1 transition independently of the stress dose and (iv) the Hog MAPK network compensates the role of the MEN network during cell division of MEN mutant cells. These model predictions are supported by independent experiments in S. cerevisiae and, moreover, have recently been observed in other eukaryotes.
authors.affiliation: Institute for Complex Systems and Mathematical Biology, SUPA, University of Aberdeen, Aberdeen, United Kingdom. radmaneshfar@gmail.com
authors.forename: Elahe
authors.initials: E
authors.lastname: Radmaneshfar
authors.forename: Despoina
authors.initials: D
authors.lastname: Kaloriti
authors.forename: Michael C
authors.initials: MC
authors.lastname: Gustin
authors.forename: Neil A R
authors.initials: NA
authors.lastname: Gow
authors.forename: Alistair J P
authors.initials: AJ
authors.lastname: Brown
authors.forename: Celso
authors.initials: C
authors.lastname: Grebogi
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Romano
authors.forename: Marco
authors.initials: M
authors.lastname: Thiel
mesh_terms: D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D008962:Models, Theoretical; D009997:Osmotic Pressure / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012965:Sodium Chloride / Q000494:pharmacology
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D012965:Sodium Chloride; C088589:HOG1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases