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

Abstract

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.

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Acknowledgments.

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
SD1.txt
SD2.txt
SD3.txt
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).

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Information & Authors

Information

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

Classifications

Submission history

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

Keywords

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

Acknowledgments

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.

Notes

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

Authors

Affiliations

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,

Notes

1
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.

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

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