Co-evolution of transcriptional and post-translational cell-cycle regulation

Abstract

DNA microarray studies have shown that hundreds of genes are transcribed periodically during the mitotic cell cycle of humans1, budding yeast2,3, fission yeast4,5,6 and the plant Arabidopsis thaliana7. Here we show that despite the fact the protein complexes involved in this process are largely the same among all eukaryotes, their regulation has evolved considerably. Our comparative analysis of several large-scale data sets reveals that although the regulated subunits of each protein complex are expressed just before its time of action, the identity of the periodically expressed proteins differs significantly between organisms. Moreover, we show that these changes in transcriptional regulation have co-evolved with post-translational control independently in several lineages; loss or gain of cell-cycle-regulated transcription of specific genes is often mirrored by changes in phosphorylation of the proteins that they encode. Our results indicate that many different solutions have evolved for assembling the same molecular machines at the right time during the cell cycle, involving both transcriptional and post-translational layers that jointly control the dynamics of biological systems.

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Figure 1: Periodic expression is poorly conserved.
Figure 2: Protein complexes are regulated through different subunits in each organism.
Figure 3: Cyclin-dependent kinases preferentially phosphorylate dynamic proteins.

References

  1. 1

    Whitfield, M. L. et al. Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol. Biol. Cell 13, 1977–2000 (2002)

    CAS  Article  Google Scholar 

  2. 2

    Cho, R. J. et al. A genome-wide transcriptional analysis of the mitotic cell cycle. Mol. Cell 2, 65–73 (1998)

    CAS  Article  Google Scholar 

  3. 3

    Spellman, P. T. et al. Comprehensive identification of cell cycle-regulated genes of the yeast S. cerevisiae by microarray hybridization. Mol. Biol. Cell 9, 3273–3297 (1998)

    CAS  Article  Google Scholar 

  4. 4

    Rustici, G. et al. Periodic gene expression program of the fission yeast cell cycle. Nature Genet. 36, 809–817 (2004)

    CAS  Article  Google Scholar 

  5. 5

    Peng, X. et al. Identification of cell cycle-regulated genes in fission yeast. Mol. Biol. Cell 16, 1026–1042 (2005)

    CAS  Article  Google Scholar 

  6. 6

    Oliva, A. et al. The cell cycle-regulated genes of Schizosaccharomyces pombe. PLoS Biol. 3, e225 (2005)

    Article  Google Scholar 

  7. 7

    Menges, M., Hennig, L., Gruissem, W. & Murray, J. A. H. Genome-wide gene expression in an Arabidopsis cell suspension. Plant Mol. Biol. 53, 423–442 (2003)

    CAS  Article  Google Scholar 

  8. 8

    de Lichtenberg, U. et al. Comparison of computational methods for the identification of cell cycle regulated genes. Bioinformatics 21, 1164–1171 (2005)

    CAS  Article  Google Scholar 

  9. 9

    de Lichtenberg, U., Jensen, L. J., Brunak, S. & Bork, P. Dynamic complex formation during the yeast cell cycle. Science 307, 724–727 (2005)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Marguerat, S. et al. The more the merrier: comparative analysis of microarray studies on cell cycle-regulated genes in fission yeast. Yeast 23, 261–277 (2006)

    CAS  Article  Google Scholar 

  11. 11

    Ota, K., Goto, S. & Kanehisa, M. Comparative analysis of transcriptional regulation in eukaryotic cell cycles. Proc. Fourth Intl Workshop Bioinformatics Syst. Biol. 26–27 (2004)

  12. 12

    Sherlock, G. STARTing to recycle. Nature Genet. 36, 795–796 (2004)

    CAS  Article  Google Scholar 

  13. 13

    Dyczkowski, J. & Vingron, M. Comparative analysis of cell cycle regulated genes in eukaryotes. Genome Inform. Ser. Workshop Genome Inform. 16, 125–131 (2005)

    CAS  Google Scholar 

  14. 14

    Bell, S. P. & Dutta, A. DNA replication in eukaryotic cells. Annu. Rev. Biochem. 71, 333–374 (2002)

    CAS  Article  Google Scholar 

  15. 15

    Kearsey, S. E. & Cotterill, S. Enigmatic variations: divergent modes of regulating eukaryotic DNA replication. Mol. Cell 12, 1067–1075 (2003)

    CAS  Article  Google Scholar 

  16. 16

    Nasmyth, K. & Haering, C. H. The structure and function of SMC and kleisin complexes. Annu. Rev. Biochem. 74, 595–648 (2005)

    CAS  Article  Google Scholar 

  17. 17

    Forsburg, S. L. & Nurse, P. Cell cycle regulation in the yeasts Saccharomyces cerevisiae and Schizosaccaromyces pombe. Annu. Rev. Cell Biol. 7, 227–256 (1991)

    CAS  Article  Google Scholar 

  18. 18

    Diffley, J. F. X. Regulation of early events in chromosome replication. Curr. Biol. 14, R778–R786 (2004)

    CAS  Article  Google Scholar 

  19. 19

    Yanow, S. K., Lygerou, Z. & Nurse, P. Expression of Cdc18/Cdc6 and Cdt1 during G2 phase induces initiation of DNA replication. EMBO J. 20, 4648–4656 (2001)

    CAS  Article  Google Scholar 

  20. 20

    Ekholm-Reed, S. et al. Deregulation of cyclin E in human cells interferes with prereplication complex assembly. J. Cell Biol. 165, 789–800 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Zhu, Y., Ishimi, Y., Tanudji, M. & Lees, E. Human CDK2 inhibition modifies the dynamics of chromatin-bound minichromosome maintenance complex and replication protein A. Cell Cycle 4, 1254–1263 (2005)

    CAS  Article  Google Scholar 

  22. 22

    Diella, F. et al. Phospho.ELM: a database of experimentally verified phosphorylation sites in eukaryotic proteins. BMC Bioinformatics 5, 79 (2004)

    Article  Google Scholar 

  23. 23

    Ubersax, J. A. et al. Targets of the cyclin-dependent kinase cdk1. Nature 425, 859–864 (2003)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Loog, M. & Morgan, D. O. Cyclin specificity in the phosphorylation of cyclin-dependent kinase substrates. Nature 434, 104–108 (2005)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Blom, N., Sicheritz-Ponten, T., Gupta, R., Gammeltoft, S. & Brunak, S. Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics 4, 1633–1649 (2004)

    CAS  Article  Google Scholar 

  26. 26

    Tatusov, R. L., Koonin, E. V. & Lipman, D. J. A genomic perspective on protein families. Science 278, 631–637 (1997)

    ADS  CAS  Article  Google Scholar 

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Acknowledgements

We thank C. von Mering for assistance with detection of orthologues, and P. Nurse, E. Karsenti, J. Bähler, and members of the Bork and Brunak groups for comments on the manuscript. This work was supported by grants from the Danish National Research Foundation, the Danish Technical Research Council, and the European Commission FP6 Programme (grants DIAMONDS and BioSapiens).

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Supplementary information

Supplementary Notes

Supplementary Methods and Supplementary Results. This file provides a detailed material and methods section as well as additional results. In particular, the results for numerous protein complexes are described and compared to current knowledge. (PDF 1182 kb)

Supplementary Notes

Archive of the supplementary web site. This file contains a complete copy of all information on the supplementary web site (http://www.cbs.dtu.dk/cellcycle/). To use, unpack the zip file and open the file README.html in a web browser. (ZIP 1203 kb)

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Jensen, L., Jensen, T., de Lichtenberg, U. et al. Co-evolution of transcriptional and post-translational cell-cycle regulation. Nature 443, 594–597 (2006). https://doi.org/10.1038/nature05186

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