title: Control analysis of the eukaryotic cell cycle using gene copy-number series in yeast tetraploids.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Annette A
authors.initials: AA
authors.lastname: Alcasabas
authors.forename: Michaela
authors.initials: M
authors.lastname: de Clare
authors.forename: Pınar
authors.initials: P
authors.lastname: Pir
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK. sgo24@cam.ac.uk.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Oliver
mesh_terms: D018106:CD28 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D019926:Cyclin B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics*; D016195:G2 Phase; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008962:Models, Theoretical; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D057891:Tetraploidy
chemical_list: D018106:CD28 Antigens; D018797:Cell Cycle Proteins; D019926:Cyclin B; D029701:Saccharomyces cerevisiae Proteins; C099685:SWE1 protein, S cerevisiae; D011505:Protein-Tyrosine Kinases; C106494:HSL1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C088589:HOG1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases