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.
Highlights
The cell cycle is the most fundamental biological clock underlying all forms of life
By considering the whole picture, rather than focusing on a special cell cycle phase, we are able to unveil mechanisms that emerge as a consequence of the multiple interactions between different parts of the cell cycle and osmotic stress response
The two main predictions of our model are: (i) upon osmotic stress in late S or early G2/M phase, cells undergo a second incidence of DNA replication before mitosis, (ii) cells stressed at late G2/M phase have an accelerated exit from mitosis and get arrested in the cell cycle
Summary
The cell cycle is the most fundamental biological clock underlying all forms of life. The cell cycle can be considered as a sequence of biochemical events governed by a complex but robust molecular network. This network has evolved in a sophisticated way, allowing cells to achieve accurate self reproduction in various conditions. Cell cycle and stress response networks have generally been studied in separation. It has recently become clear, that to understand cellular responses to stresses, cell cycle and signalling networks have to be considered simultaneously. In the case of osmotic stress [1,2,3,4,5], have revealed some key links between stress response and cell cycle networks
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