Fragilities Caused by Dosage Imbalance in Regulation of the Budding Yeast Cell Cycle 英文参考文献.docVIP

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Fragilities Caused by Dosage Imbalance in Regulation of the Budding Yeast Cell Cycle 英文参考文献.doc

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Fragilities Caused by Dosage Imbalance in Regulation of the Budding Yeast Cell Cycle 英文参考文献

FragilitiesCausedbyDosageImbalanceinRegulationof theBuddingYeastCellCycle KazunariKaizu1,2,3,HisaoMoriya4,5*,HiroakiKitano2,3,6 1DepartmentofScienceandTechnology,KeioUniversity,Yokohama-shi,Kanagawa,Japan,2SonyComputerScienceLaboratories,Shinagawa-ku,Tokyo,Japan,3The SystemsBiologyInstitute,Minato-ku,Tokyo,Japan,4ResearchCoreforInterdisciplinarySciences,OkayamaUniversity,Okayama-shi,Okayama,Japan,5PRESTO,Japan ScienceandTechnologyAgency,Chiyoda-ku,Tokyo,Japan,6OpenBiologyUnit,OkinawaInstituteofScienceandTechnology,Kunigami,Okinawa,Japan Abstract Cells can maintain their functions despite fluctuations in intracellular parameters, such as protein activities and gene expression levels. This commonly observed biological property of cells is called robustness. On the other hand, these parametershavedifferentlimitations,eachreflectingthepropertyofthesubsystemcontainingtheparameter.Thebudding yeastcellcycleisquitefragileuponoverexpressionofCDC14,butisrobustuponoverexpressionofESP1.Thegeneproducts of both CDC14 and ESP1 are regulated by 1:1 binding with their inhibitors (Net1 and Pds1), and a mathematical model predicts the extreme fragility of the cell cycle upon overexpression of CDC14 and ESP1 caused by dosage imbalance betweenthesegenes.However,ithasnotbeenexperimentallyshownthatdosageimbalancecausesfragilityofthecell cycle.Inthisstudy,wemeasuredthequantitativegeneticinteractionsofthesegenesbyperformingcombinatorial‘‘genetic tug-of-war’’experiments.WefirstshowedexperimentalevidencethatdosageimbalancebetweenCDC14andNET1causes fragility.WealsoshowedthatfragilityarisingfromdosageimbalancebetweenESP1andPDS1ismaskedbyCDH1andCLB2. ThemaskingfunctionofCLB2wasstabilizationofPds1byitsphosphorylation.WefinallymodifiedChen’smodelaccording toourfindings.Wethusproposethatdosageimbalancecausesfragilityinbiologicalsystems. Citation:KaizuK,MoriyaH,KitanoH(2010)FragilitiesCausedbyDosageImbalanceinRegulationoftheBuddingYeastCellCycle.PLoSGenet6(4):e1000919. doi:10.1371/journal.pgen.100