Abstract
BackgroundIn the model eukaryote, Saccharomyces cerevisiae, previous experiments have identified those genes that exert the most significant control over cell growth rate. These genes are termed HFC for high flux control. Such genes are overrepresented within pathways controlling the mitotic cell cycle.ResultsWe postulated that the increase/decrease in growth rate is due to a change in the rate of progression through specific cell cycle steps. We extended and further developed an existing logical model of the yeast cell cycle in order elucidate how the HFC genes modulated progress through the cycle. This model can simulate gene dosage-variation and calculate the cycle time, determine the order and relative speed at which events occur, and predict arrests and failures to correctly execute a step. To experimentally test our model’s predictions, we constructed a tetraploid series of deletion mutants for a set of eight genes that control the G2/M transition. This system allowed us to vary gene copy number through more intermediate levels than previous studies and examine the impact of copy-number variation on growth, cell-cycle phenotype, and response to different cellular stresses.ConclusionsFor the majority of strains, the predictions agreed with experimental observations, validating our model and its use for further predictions. Where simulation and experiment diverged, we uncovered both novel tetraploid-specific phenotypes and a switch in the determinative execution point of a key cell-cycle regulator, the Cdc28 kinase, from the G1/S to the S/G2 boundaries.
Highlights
In the model eukaryote, Saccharomyces cerevisiae, previous experiments have identified those genes that exert the most significant control over cell growth rate
Copy number variation affects growth rate, viability, and cell cycle progression, and in silico simulations are predictive of in vivo behaviour In an attempt to predict the trends in phenotypic variation that we might observe in the tetraploid mutant series, we constructed a logical model of the S.cerevisiae cell cycle and simulated the effects of deleting the high flux-control coefficient’ (HFC) G2/M checkpoint genes
S and G2 phases are characterised by the degradation of the B-type cyclin inhibitors and the consequent accumulation of Clb1p and Clb2p, the emergence of a bud, and the subsequent activation of the morphogenesis checkpoint genes
Summary
Saccharomyces cerevisiae, previous experiments have identified those genes that exert the most significant control over cell growth rate. These genes are termed HFC for high flux control. As we seek to here, the relative importance of given genes within the genome of the model eukaryote Saccharomyces cerevisiae, and constrain the value of a given protein’s (i.e. effector’s) control coefficient, complementary experiments must be performed: 1. Changing the flux through the pathway and measuring the impact upon protein concentration (described in [4,5]); 2. As we seek to here, the relative importance of given genes within the genome of the model eukaryote Saccharomyces cerevisiae, and constrain the value of a given protein’s (i.e. effector’s) control coefficient, complementary experiments must be performed: 1. changing the flux through the pathway and measuring the impact upon protein concentration (described in [4,5]); 2. changing the protein concentration and measuring the impact upon the pathway flux
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