Growth Rate and Cell Size Modulate the Synthesis of, and Requirement for, G₁-Phase Cyclins at Start

Abstract

In Saccharomyces cerevisiae, commitment to cell cycle progression occurs at Start. Progression past Start requires cell growth and protein synthesis, a minimum cell size, and G 1 -phase cyclins. We examined the relationships among these factors. Rapidly growing cells expressed, and required, dramatically more Cln protein than did slowly growing cells. To clarify the role of cell size, we expressed defined amounts of CLN mRNA in cells of different sizes. When Cln was expressed at nearly physiological levels, a critical threshold of Cln expression was required for cell cycle progression, and this critical threshold varied with both cell size and growth rate: as cells grew larger, they needed less CLN mRNA, but as cells grew faster, they needed more Cln protein. At least in part, large cells had a reduced requirement for CLN mRNA because large cells generated more Cln protein per unit of mRNA than did small cells. When Cln was overexpressed, it was capable of promoting Start rapidly, regardless of cell size or growth rate. In summary, the amount of Cln required for Start depends dramatically on both cell size and growth rate. Large cells generate more Cln1 or Cln2 protein for a given amount of CLN mRNA, suggesting the existence of a novel posttranscriptional size control mechanism.

Ccr4 Alters Cell Size in Yeast by Modulating the Timing of CLN1 and CLN2 Expression

“…Cell cycle synchronizations and cell size analyses: Centrifugal elutriation was used for cell cycle synchronizations as previously described (Day et al 2004;Schneider et al 2004). Fractions containing the smallest unbudded cells were collected, pelleted, and resuspended in fresh medium.…”

Revisiting the role of yeast Sfp1 in ribosome biogenesis and cell size control: a chemostat study

“…In the budding yeast Saccharomyces cerevisiae, as in higher eukaryotes, homeostatic mechanisms are active to coordinate growth, metabolism and cell cycle progression (Polymenis & Schmidt, 1999;Schneider et al, 2004;Sudbery, 2002). In S. cerevisiae, external and intracellular signals are integrated at Start during the G1-to S-phase transition, when cells become committed to a new division cycle (Futcher, 1996;Li & Johnston, 1997;Mendenhall & Hodge, 1998).…”

Dynamic variability in apoptotic threshold as a strategy for combating fractional killing

“…On the one hand, 2 some important cellular processes depend on precision in the timing of key intracellular 3 events, e.g., cell fate decision presumably requires a precise control of gene expression 4 timing [2][3][4][5][6][7][8][9][10][11][12][13][14][15], and the controls of cell cycle and circadian clocks require timing precision 5 that can be crucial for the correct physiology [16][17][18][19][20][21][22][23][24]. Most of these processes are based 6 on gene expression, e.g., an activated gene may be required to reach in a precise time threshold level of p53 to execute apoptosis and this threshold increases with time [26].…”

“…Characterization of control strategies that 17 reduces variability in the event timing or/and shortens arrival time is critically needed 18 to understand both reliable functioning of diverse intracellular pathways that relies on 19 precision in the timing and drug efficacy that depends on the time that drug-dependent 20 regulatory proteins reach threshold levels. 21 In general, internal signals and environmental cues can induce the expression of one 22 or several regulators, which in turn can trigger an appropriate cellular response when 23 their concentrations reach critical threshold levels . However, a gene may reach 24 a critical threshold of expression with substantial cell-to-cell variability even among 25 isogenic cells exposed to the same constant stimulus.…”

“…Our model also 489 ignored feedback regulation, which however exists widely in biological regulatory systems. 490 Ghusinga, Dennehy and Singh [23] studied the influence of feedback regulation on the 491 timing of events in the case of fixed threshold. They found that there is an optimal 492 feedback strategy to regulate the synthesis of a protein to ensure that an event will 493 occur at a precise time, while minimizing deviations or noise about the mean.…”