Scaling of G1 Duration with Population Doubling Time by a Cyclin in Saccharomyces cerevisiae

Abstract

Abstract The longer cells stay in particular phases of the cell cycle, the longer it will take these cell populations to increase. However, the above qualitative description has very little predictive value, unless it can be codified mathematically. A quantitative relation that defines the population doubling time (Td) as a function of the time eukaryotic cells spend in specific cell cycle phases would be instrumental for estimating rates of cell proliferation and for evaluating introduced perturbations. Here, we show that in human cells, the length of the G1 phase (TG1) regressed on Td with a slope of ≈0.75, while in the yeast Saccharomyces cerevisiae, the slope was slightly smaller, at ≈0.60. On the other hand, cell size was not strongly associated with Td or TG1 in cell cultures that were proliferating at different rates. Furthermore, we show that levels of the yeast G1 cyclin Cln3p were positively associated with rates of cell proliferation over a broad range, at least in part through translational control mediated by a short upstream ORF (uORF) in the CLN3 transcript. Cln3p was also necessary for the proper scaling between TG1 and Td. In contrast, yeast lacking the Whi5p transcriptional repressor maintained the scaling between TG1 and Td. These data reveal fundamental scaling relationships between the duration of eukaryotic cell cycle phases and rates of cell proliferation, point to the necessary role of Cln3p in these relationships in yeast, and provide a mechanistic basis linking Cln3p levels to proliferation rates and the scaling of G1 with doubling time.