Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The effects of molecular noise and size control on variability in the budding yeast cell cycle

An Erratum to this article was published on 20 December 2007

Abstract

Molecular noise in gene expression can generate substantial variability in protein concentration1. However, its effect on the precision of a natural eukaryotic circuit such as the control of cell cycle remains unclear. We use single-cell imaging of fluorescently labelled budding yeast to measure times from division to budding (G1) and from budding to the next division. The variability in G1 decreases with the square root of the ploidy through a 1N/2N/4N ploidy series, consistent with simple stochastic models for molecular noise. Also, increasing the gene dosage of G1 cyclins decreases the variability in G1. A new single-cell reporter for cell protein content allows us to determine the contribution to temporal G1 variability of deterministic size control (that is, smaller cells extending G1). Cell size control contributes significantly to G1 variability in daughter cells but not in mother cells. However, even in daughters, size-independent noise is the largest quantitative contributor to G1 variability. Exit of the transcriptional repressor Whi5 from the nucleus partitions G1 into two temporally uncorrelated and functionally distinct steps. The first step, which depends on the G1 cyclin gene CLN3, corresponds to noisy size control that extends G1 in small daughters, but is of negligible duration in mothers. The second step, whose variability decreases with increasing CLN2 gene dosage, is similar in mothers and daughters. This analysis decomposes the regulatory dynamics of the Start transition into two independent modules, a size sensing module and a timing module, each of which is predominantly controlled by a different G1 cyclin.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Noise in G1 duration is reduced by increased ploidy or increased G1 cyclin gene dosage.
Figure 2: The correlation between cell size and G1 duration shows that a noisy size control operates in daughters.
Figure 3: The correlation between cell size and the regulation of Whi5 nuclear residence supports decomposition of Start into a size-control module and an independent timing module.

References

  1. Samoilov, M. S., Price, G. & Arkin, A. P. From fluctuations to phenotypes: the physiology of noise. Sci. STKE 366, re17 (2006)

    Google Scholar 

  2. Hartwell, L. H., Culotti, J., Pringle, J. R. & Reid, B. J. Genetic control of the cell division cycle in yeast. Science 183, 46–51 (1974)

    ADS  CAS  Article  Google Scholar 

  3. Hartwell, L. H. & Unger, M. W. Unequal division in Saccharomyces cerevisiae and its implications for the control of cell division. J. Cell Biol. 75, 422–435 (1977)

    CAS  Article  Google Scholar 

  4. Johnston, G. C., Pringle, J. R. & Hartwell, L. H. Coordination of growth with cell division in the yeast Saccharomyces cerevisiae. Exp. Cell Res. 105, 79–98 (1977)

    CAS  Article  Google Scholar 

  5. Moore, S. A. Kinetic evidence for a critical rate of protein synthesis in the Saccharomyces cerevisiae yeast cell cycle. J. Biol. Chem. 263, 9674–9681 (1988)

    CAS  PubMed  Google Scholar 

  6. Lord, P. G. & Wheals, A. E. Variability in individual cell cycles of Saccharomyces cerevisiae. J. Cell Sci. 50, 361–376 (1981)

    CAS  PubMed  Google Scholar 

  7. Wheals, A. E. Size control-models of Saccharomyces cerevisiae cell proliferation. Mol. Cell. Biol. 2, 361–368 (1982)

    CAS  Article  Google Scholar 

  8. Lord, P. G. & Wheals, A. E. Rate of cell cycle initiation of yeast cells when cell size is not a rate-determining factor. J. Cell Sci. 59, 183–201 (1983)

    CAS  PubMed  Google Scholar 

  9. Nurse, P. Cell cycle control—both deterministic and probabilistic. Nature 286, 9–10 (1980)

    ADS  CAS  Article  Google Scholar 

  10. Spudich, J. L. & Koshland, D. E. Non-genetic individuality: chance in the single cell. Nature 262, 467–471 (1976)

    ADS  CAS  Article  Google Scholar 

  11. Jorgensen, P. & Tyers, M. How cells coordinate growth and division. Curr. Biol. 14, R1014–R1027 (2004)

    CAS  Article  Google Scholar 

  12. Schroedinger, E. What is Life? (Cambridge Univ. Press, Cambridge, 1944)

    Google Scholar 

  13. Bi, E. et al. Involvement of an actomyosin contractile ring in Saccharomyces cerevisiae cytokinesis. J. Cell Biol. 142, 1301–1312 (1998)

    CAS  Article  Google Scholar 

  14. Cross, F. R. DAF1, a mutant gene affecting size control, pheromone arrest, and cell cycle kinetics of Saccharomyces cerevisiae.. Mol. Cell. Biol. 8, 4675–4684 (1988)

    CAS  Article  Google Scholar 

  15. Nash, R., Tokiwa, G., Anand, S., Erickson, K. & Futcher, A. B. The WHI1+ gene of Saccharomyces cerevisiae tethers cell division to cell size and is a cyclin homolog. EMBO J. 7, 4335–4346 (1988)

    CAS  Article  Google Scholar 

  16. Tyers, M., Tokiwa, G. & Futcher, B. Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. EMBO J. 12, 1955–1968 (1993)

    CAS  Article  Google Scholar 

  17. Dirick, L., Bohm, T. & Nasmyth, K. Roles and regulation of Cln-Cdc28 kinases at the start of the cell cycle of Saccharomyces cerevisiae. EMBO J. 14, 4803–4813 (1995)

    CAS  Article  Google Scholar 

  18. Stuart, D. & Wittenberg, C. CLN3, not positive feedback, determines the timing of CLN2 transcription in cycling cells. Genes Dev. 9, 2780–2794 (1995)

    CAS  Article  Google Scholar 

  19. Cross, F. R. Starting the cell cycle: what's the point? Curr. Opin. Cell Biol. 7, 790–797 (1995)

    CAS  Article  Google Scholar 

  20. McInerny, C. J., Partridge, J. F., Mikesell, G. E., Creemer, D. P. & Breeden, L. L. A novel Mcm1-dependent element in the SWI4, CLN3, CDC6, and CDC47 promoters activates M/G1-specific transcription. Genes Dev. 11, 1277–1288 (1997)

    CAS  Article  Google Scholar 

  21. Koch, C., Schleiffer, A., Ammerer, G. & Nasmyth, K. Switching transcription on and off during the yeast cell cycle: Cln/Cdc28 kinases activate bound transcription factor SBF (Swi4/Swi6) at start, whereas Clb/Cdc28 kinases displace it from the promoter in G2. Genes Dev. 10, 129–141 (1996)

    CAS  Article  Google Scholar 

  22. Wijnen, H., Landman, A. & Futcher, B. The G(1) cyclin Cln3 promotes cell cycle entry via the transcription factor Swi6. Mol. Cell. Biol. 22, 4402–4418 (2002)

    CAS  Article  Google Scholar 

  23. Holstege, F. C. P. et al. Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95, 717–728 (1998)

    CAS  Article  Google Scholar 

  24. Bean, J. M., Siggia, E. D. & Cross, F. R. Coherence and timing of cell cycle start examined at single-cell resolution. Mol. Cell 21, 3–14 (2006)

    CAS  Article  Google Scholar 

  25. Elliott, S. G. & McLaughlin, C. S. Rate of macromolecular synthesis through the cell cycle of the yeast Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 75, 4384–4388 (1978)

    ADS  CAS  Article  Google Scholar 

  26. Donnan, L. & John, P. C. Cell cycle control by timer and sizer in Chlamydomonas. Nature 304, 630–633 (1983)

    ADS  CAS  Article  Google Scholar 

  27. Sveiczer, A., Novak, B. & Mitchinson, J. M. The size control of fission yeast revisited. J. Cell Sci. 109, 2947–2957 (1996)

    CAS  PubMed  Google Scholar 

  28. Costanzo, M. et al. CDK activity antagonizes Whi5, an inhibitor of G1/S transcription in yeast. Cell 117, 899–913 (2004)

    CAS  Article  Google Scholar 

  29. de Bruin, R. A. M., McDonald, W. H., Kalashnikova, T. I., Yates, J. & Wittenberg, C. Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5. Cell 117, 887–898 (2004)

    CAS  Article  Google Scholar 

  30. Wittenberg, C. & Reed, S. I. Cell cycle-dependent transcription in yeast: promoters, transcription factors, and transcriptomes. Oncogene 24, 2746–2755 (2005)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank J. Haber, E. Bi and the NCRR Yeast Resource Center, University of Washington, for plasmids and strains; P. Nurse and T. Ryan for discussions; and N. Buchler, B. Drapkin, J. Robbins, J. Roberts and J. Widom for comments on the manuscript. This work was supported by the National Institute of Health (J.M.S., E.D.S., F.R.C.), the Howard Hughes Medical Institute (J.M.B.), and the National Science Foundation (E.D.S.).

Author Contributions Experimental work by S.D. and J.M.S.; project planning, data analysis and manuscript preparation by all authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Frederick R. Cross.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains the Supplementary Materials and Methods, Supplementary Discussion, Supplementary Tables S1- S12 and Supplementary Figures S1-S12. The discussion concerns the statistical analysis of the correlation of αT and ln(Mbirth), the analysis of the independence of the two regulatory steps of Start and a more detailed analysis of movies in glycerol/ethanol. The Supplementary Tables show the cell cycle timing analysis, the analysis of cell size at budding and of growth rates of individual cells. The Supplementary Figures show additional data concerning noise reduction by ploidy and gene dosage, the effect of CLN2 gene on Start and the distribution of growth rates of individual cells. (PDF 916 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Talia, S., Skotheim, J., Bean, J. et al. The effects of molecular noise and size control on variability in the budding yeast cell cycle. Nature 448, 947–951 (2007). https://doi.org/10.1038/nature06072

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06072

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing