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

BMC Genomics

Research Article

Michaela de Clare¹  Stephen G Oliver¹  Pınar Pir²  Annette A Alcasabas³ 

[1] Department of Biochemistry, University of Cambridge, Tennis Court Road, CB2 1GA, Cambridge, UK;Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, CB2 1GA, Cambridge, UK;Department of Biochemistry, University of Cambridge, Tennis Court Road, CB2 1GA, Cambridge, UK;Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, CB2 1GA, Cambridge, UK;Babraham Institute, Babraham Campus, CB22 3AT, Cambridge, UK;Department of Biochemistry, University of Cambridge, Tennis Court Road, CB2 1GA, Cambridge, UK;Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, CB2 1GA, Cambridge, UK;BioSyntha Technology, BioPark Hertfordshire, Broadwater Road, AL7 3AX, Welwyn Garden City, UK;

关键词: Cell cycle;    Control analysis;    Copy number variation;    Logical model;    Tetraploid;    Yeast;   

DOI  :  10.1186/1471-2164-14-744

 received in 2013-07-09, accepted in 2013-10-18,  发布年份 2013

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Alcasabas et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.