Whi5 phosphorylation embedded in the G1/S network dynamically controls critical cell size and cell fate.
In budding yeast, overcoming of a critical size to enter S phase and the mitosis/mating switch--two central cell fate events--take place in the G1 phase of the cell cycle. Here we present a mathematical model of the basic molecular mechanism controlling the G1/S transition, whose major regulatory feature is multisite phosphorylation of nuclear Whi5. Cln3-Cdk1, whose nuclear amount is proportional to cell size, and then Cln1,2-Cdk1, randomly phosphorylate both decoy and functional Whi5 sites. Full phosphorylation of functional sites releases Whi5 inhibitory activity, activating G1/S transcription. Simulation analysis shows that this mechanism ensures coherent release of Whi5 inhibitory action and accounts for many experimentally observed properties of mitotically growing or conjugating G1 cells. Cell cycle progression and transcriptional analyses of a Whi5 phosphomimetic mutant verify the model prediction that coherent transcription of the G1/S regulon and ensuing G1/S transition requires full phosphorylation of Whi5 functional sites.
SYSBIO.IT Center for Systems Biology, Italy.|CNR-IASI, Italian National Research Council - Institute for Systems Analysis and Computer Science, Via dei Taurini 19, 00185 Rome, Italy.
Pasquale
P
Palumbo
SYSBIO.IT Center for Systems Biology, Italy.|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
Marco
M
Vanoni
SYSBIO.IT Center for Systems Biology, Italy.|CNR-IASI, Italian National Research Council - Institute for Systems Analysis and Computer Science, Via dei Taurini 19, 00185 Rome, Italy.
Valerio
V
Cusimano
SYSBIO.IT Center for Systems Biology, Italy.|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
Stefano
S
Busti
SYSBIO.IT Center for Systems Biology, Italy.|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
Francesca
F
Marano
CNR-IASI, Italian National Research Council - Institute for Systems Analysis and Computer Science, Via dei Taurini 19, 00185 Rome, Italy.|Department of Information Engineering, Computer Science and Mathematics, University of L'Aquila, Via Vetoio, 67100 Coppito (L'Aquila), Italy.
Costanzo
http://orcid.org/0000-0002-0771-7413
C
Manes
SYSBIO.IT Center for Systems Biology, Italy.|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
Lilia
http://orcid.org/0000-0003-1694-931X
L
Alberghina
D016203:CDC2 Protein Kinase / Q000235:genetics* / Q000378:metabolism; D048429:Cell Size; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal; D009154:Mutation; D010766:Phosphorylation; D018085:Regulon; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
C082719:CLN1 protein, S cerevisiae; C082721:CLN2 protein, S cerevisiae; C079895:CLN3 protein, S cerevisiae; D016213:Cyclins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C508130:Whi5 protein, S cerevisiae; D016203:CDC2 Protein Kinase