Letter | Published:

Dilution of the cell cycle inhibitor Whi5 controls budding-yeast cell size

Nature volume 526, pages 268272 (08 October 2015) | Download Citation

Abstract

Cell size fundamentally affects all biosynthetic processes by determining the scale of organelles and influencing surface transport1,2. Although extensive studies have identified many mutations affecting cell size, the molecular mechanisms underlying size control have remained elusive3. In the budding yeast Saccharomyces cerevisiae, size control occurs in G1 phase before Start, the point of irreversible commitment to cell division4,5. It was previously thought that activity of the G1 cyclin Cln3 increased with cell size to trigger Start by initiating the inhibition of the transcriptional inhibitor Whi5 (refs 6, 7, 8). Here we show that although Cln3 concentration does modulate the rate at which cells pass Start, its synthesis increases in proportion to cell size so that its total concentration is nearly constant during pre-Start G1. Rather than increasing Cln3 activity, we identify decreasing Whi5 activity—due to the dilution of Whi5 by cell growth—as a molecular mechanism through which cell size controls proliferation. Whi5 is synthesized in S/G2/M phases of the cell cycle in a largely size-independent manner. This results in smaller daughter cells being born with higher Whi5 concentrations that extend their pre-Start G1 phase. Thus, at its most fundamental level, size control in budding yeast results from the differential scaling of Cln3 and Whi5 synthesis rates with cell size. More generally, our work shows that differential size-dependency of protein synthesis can provide an elegant mechanism to coordinate cellular functions with growth.

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Acknowledgements

We thank O. Atay and J. Feldman for reagents, R. de Bruin, A. Gladfelter, M. Cyert, and M. Loog for comments on the manuscript, the Burroughs Wellcome Fund (CASI), the National Science Foundation (CAREER), National Institutes of Health training grant GM007276 (to J.J.T.), and Human Frontier Science Program (postdoctoral fellowships to K.M.S. and M.K.) for funding.

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Affiliations

  1. Department of Biology, Stanford University, Stanford, California 94305, USA

    • Kurt M. Schmoller
    • , J. J. Turner
    • , M. Kõivomägi
    •  & Jan M. Skotheim

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Contributions

All authors designed experiments and wrote the manuscript; K.M.S., J.T. and M.K. performed experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jan M. Skotheim.

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https://doi.org/10.1038/nature14908

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