Exploring the roles of noise in the eukaryotic cell cycle

Edited by John Ross, Stanford University, Stanford, CA, and approved January 11, 2009
April 21, 2009
106 (16) 6471-6476


The DNA replication–division cycle of eukaryotic cells is controlled by a complex network of regulatory proteins, called cyclin-dependent kinases, and their activators and inhibitors. Although comprehensive and accurate deterministic models of the control system are available for yeast cells, reliable stochastic simulations have not been carried out because the full reaction network has yet to be expressed in terms of elementary reaction steps. As a first step in this direction, we present a simplified version of the control system that is suitable for exact stochastic simulation of intrinsic noise caused by molecular fluctuations and extrinsic noise because of unequal division. The model is consistent with many characteristic features of noisy cell cycle progression in yeast populations, including the observation that mRNAs are present in very low abundance (≈1 mRNA molecule per cell for each expressed gene). For the control system to operate reliably at such low mRNA levels, some specific mRNAs in our model must have very short half-lives (<1 min). If these mRNA molecules are longer-lived (perhaps 2 min), then the intrinsic noise in our simulations is too large, and there must be some additional noise suppression mechanisms at work in cells.

Continue Reading


We thank Mohsen Sabouri-Ghomi for his preliminary work on the model studied here. This work was supported by the National Institutes of Health Grant 1 R01 GM078989.

Supporting Information

Appendix (PDF)
Supporting Information
Recently, Zenklusen et al. (26) have shown that the high-throughput measurements of mRNA abundances underestimate these numbers by 5-fold or more. Repeating our full stochastic simulations with 5-fold higher mRNA abundances, we get statistical properties similar to Table 3, row 7a, for τX = τY = 120 s. Although these mRNA half-lives are more reasonable, they are still 5- to 10-fold shorter than generally accepted values (19).


JJ Tyson, B Novak, Temporal organization of the cell cycle. Curr Biol 18, R759–R768 (2008).
JJ Tyson, The coordination of cell growth and division: Intentional or incidental? Bioessays 2, 72–77 (1985).
PA Fantes, Control of cell size and cycle time in Schizosaccharomyces pombe. J Cell Sci 24, 51–67 (1977).
AL Koch, M Schaechter, A model for statistics of the cell division process. J Gen Microbiol 29, 435–454 (1962).
PS Swain, MB Elowitz, ED Siggia, Intrinsic and extrinsic contributions to stochasticity in gene expression. Proc Natl Acad Sci USA 99, 12795–12800 (2002).
A Sveiczer, A Csikasz-Nagy, B Gyorffy, JJ Tyson, B Novak, Modeling the fission yeast cell cycle: Quantized cycle times in wee1cdc25Δ mutant cells. Proc Natl Acad Sci USA 97, 7865–7870 (2000).
A Sveiczer, JJ Tyson, B Novak, A stochastic, molecular model of the fission yeast cell cycle: Role of the nucleocytoplasmic ratio in cycle time regulation. Biophys Chem 92, 1–15 (2001).
R Steuer, Effects of stochasticity in models of the cell cycle: From quantized cycle times to noise-induced oscillations. J Theor Biol 228, 293–301 (2004).
I Mura, A Csikasz-Nagy, Stochastic petri net extension of a yeast cell cycle model. J Theor Biol 254, 850–860 (2008).
KC Chen, et al., Integrative analysis of cell cycle control in budding yeast. Mol Biol Cell 15, 3841–3862 (2004).
Y Zhang, et al., Stochastic model of yeast cell cycle network. Physica D 219, 35–39 (2006).
S Braunewell, S Bornholdt, Superstability of the yeast cell cycle dynamics: Ensuring causality in the presence of biochemical stochasticity. J Theor Biol 245, 638–643 (2007).
H Ge, H Qian, M Qian, Synchronized dynamics and nonequilibrium steady states in a stochastic cell cycle network. Math Biosci 211, 132–152 (2008).
Y Okabe, M Sasai, Stable stochastic dynamics in yeast cell cycle. Biophys J 93, 3451–3459 (2007).
F Li, T Long, Y Lu, Q Ouyang, C Tang, The yeast cell cycle network is robustly designed. Proc Natl Acad Sci USA 101, 4781–4786 (2004).
M Sabouri-Ghomi, A Ciliberto, S Kar, B Novak, JJ Tyson, Antagonism and bistability in protein interaction networks. J Theor Biol 250, 209–218 (2008).
JJ Tyson, B Novak, Regulation of the eukaryotic cell cycle: Molecular antagonism, hysteresis and irreversible transitions. J Theor Biol 210, 249–263 (2001).
T Von der Haar, A quantitative estimation of the global translational activity in logarithmically growing yeast cells. BMC Syst Biol 2, 87 (2008).
FC Holstege, et al., Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95, 717–728 (1998).
JM Pedraza, J Paulsson, Effects of molecular memory and bursting on fluctuations in gene expression. Science 319, 339–343 (2008).
Z Darzynkiewicz, H Crissman, JW Jacobberger, Cytometry of the cell cycle: Cycling through history. Cytometry A 58, 21–32 (2004).
S Di Talia, JM Skotheim, JM Bean, ED Siggia, FR Cross, The effect of molecular noise and size control on the variability in the budding yeast cell cycle. Nature 448, 947–951 (2007).
H Miyata, M Miyata, M Ito, The cell cycle in the fission yeast, Schizosaccharomyces pombe. I. Relationship between cell size and cycle time. Cell Struct Funct 3, 39–46 (1978).
S Ghaemmaghami, et al., Global analysis of protein expression in yeast. Nature 425, 686–691 (2003).
FR Cross, V Archambault, M Miller, M Klovstad, Testing a mathematical model of the yeast cell cycle. Mol Biol Cell 13, 52–70 (2002).
D Zenklusen, DR Larson, RH Singer, Single-RNA counting reveals alternative modes of gene expression in yeast. Nat Struct Mol Biol 15, 1263–1271 (2008).

Information & Authors


Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 106 | No. 16
April 21, 2009
PubMed: 19246388


Submission history

Received: December 30, 2008
Published online: April 21, 2009
Published in issue: April 21, 2009


  1. cyclin-dependent kinase
  2. gene expression
  3. network dynamics
  4. stochastic model
  5. mRNA turnover


We thank Mohsen Sabouri-Ghomi for his preliminary work on the model studied here. This work was supported by the National Institutes of Health Grant 1 R01 GM078989.


This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0810034106/DCSupplemental.



Sandip Kar
Departments of aBiological Sciences,
William T. Baumann
Electrical and Computer Engineering, and
Mark R. Paul
Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061
John J. Tyson1 [email protected]
Departments of aBiological Sciences,


To whom correspondence should be addressed at: Department of Biological Sciences, M.C. 0406, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061. E-mail: [email protected]
Author contributions: W.T.B., M.R.P., and J.J.T. designed research; S.K. and W.T.B. performed research; S.K., W.T.B., M.R.P., and J.J.T. analyzed data; and S.K., W.T.B., M.R.P., and J.J.T. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

Metrics & Citations


Note: The article usage is presented with a three- to four-day delay and will update daily once available. Due to ths delay, usage data will not appear immediately following publication. Citation information is sourced from Crossref Cited-by service.

Citation statements



If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

Cited by


    View Options

    View options

    PDF format

    Download this article as a PDF file


    Get Access

    Login options

    Check if you have access through your login credentials or your institution to get full access on this article.

    Personal login Institutional Login

    Recommend to a librarian

    Recommend PNAS to a Librarian

    Purchase options

    Purchase this article to access the full text.

    Single Article Purchase

    Exploring the roles of noise in the eukaryotic cell cycle
    Proceedings of the National Academy of Sciences
    • Vol. 106
    • No. 16
    • pp. 6425-6879







    Share article link

    Share on social media