Abstract
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.
Highlights
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
Our simulations show that the G1/S transition kinetics are quite insensitive to the specific pattern of Cln[3] accumulation (Supplementary Figs 1–2), while they are dependent on average Cln[3] level during G1
Coherent transcriptional activation of the G1/S regulon[36] leads to synchronous expression of hundreds of gene products, orderly driving the G1/S transition that starts the pathway towards mitosis
Summary
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. In the presence of nutrients—and in the absence of the complementary mating factors—haploid G1 cells of the budding yeast Saccharomyces cerevisiae—a widely used model for the study of the eukaryotic cell cycle—grow to the critical cell size required to enter S phase[2,3] and are committed to proliferation. A well-accepted critical cell size control theory assumes two distinct, but interconnected, functions: sensing of actual cell size and setting of the critical cell size according to growth conditions[2,26]. Single-cell analysis suggested a sizer plus timer model, in which Cln[3] is involved in a noisy sizer control (whose complementary molecular component is unspecified), which sets a period within G1 (called T1) of considerable length in small daughter cells, but much shorter in parent cells[13]. A recently proposed model substantially departs from this common background to hold that the critical cell size is robustly set by the rate of linear growth during G1 and that the chaperone Ydj[1] has an important role in regulating critical cell size[29]
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