Control analysis of the eukaryotic cell cycle using gene copy-number series in yeast tetraploids.

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TitleControl analysis of the eukaryotic cell cycle using gene copy-number series in yeast tetraploids.
Publication TypeJournal Article
Year of Publication2013
AuthorsAlcasabas, AA, de Clare, M, Pir, P, Oliver, SG
JournalBMC Genomics
Volume14
Pagination744
Date Published2013 Oct 31
ISSN1471-2164
KeywordsAntigens, CD28, Cell Cycle Proteins, Cell Division, Cyclin B, DNA Copy Number Variations, G2 Phase, Mitogen-Activated Protein Kinases, Models, Theoretical, Phenotype, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Tetraploidy
Abstract

<p><b>BACKGROUND: </b>In 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.</p><p><b>RESULTS: </b>We 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.</p><p><b>CONCLUSIONS: </b>For 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.</p>

DOI10.1186/1471-2164-14-744
Alternate JournalBMC Genomics
PubMed ID24176122
PubMed Central IDPMC3826841
Grant List089703 / / Wellcome Trust / United Kingdom
BB/C505140/2 / / Biotechnology and Biological Sciences Research Council / United Kingdom
BB/C505140/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom