Key Points
-
Progression through the cell cycle requires the precise coordination of four important processes: DNA replication, chromosome segregation, cell division and cell growth. The aquatic, non-pathogenic bacterium Caulobacter crescentus has emerged as the main model system for analysis of the prokaryotic cell cycle.
-
In contrast to many other prokaryotes, including Escherichia coli, Caulobacter cells, like most eukaryotes, exhibit strict once-and-only-once replication of the chromosome. Cell division yields two daughter cells that are physiologically and morphologically different. One daughter cell is a stalked cell that immediately reinitiates another round of chromosome replication, whereas the other daughter cell is a swarmer cell that cannot start DNA replication until after an obligate swarmer-to-stalked cell differentiation step.
-
The use of transcriptome analysis, together with proteome analysis, to define the genes and products that are crucial for cell-cycle progression and generation and maintenance of asymmetry is described. These studies have confirmed and extended the array of genes involved in cell cycle regulation previously identified using genetic and biochemical techniques.
-
CtrA is a master regulatory protein that controls key cell-cycle events. The CtrA regulon has been mapped out — 26% of all cell-cycle-regulated genes are controlled by CtrA. The mechanisms of regulation of CtrA itself are discussed, including control of CtrA transcription, phosphorylation, proteolysis and compartmentalization.
-
The authors discuss what is meant by a cell-cycle checkpoint and review evidence for whether Caulobacter has a dedicated checkpoint system.
-
Finally, mechanisms by which Caulobacter couples morphological transitions and gene expression are described together with the future directions for research using this outstanding model system.
Abstract
Microorganisms make tractable model systems and Caulobacter crescentus has emerged as the main model for understanding the regulation of the bacterial cell cycle. Mechanisms that mediate the generation and maintenance of spatial asymmetry are being uncovered using this model bacterium. Now, the advent of genomic technologies together with the completion of the Caulobacter crescentus genome sequence is enabling global analyses that have revolutionized the pace of research into the genetic networks that control the bacterial life cycle.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nierman, W. C. et al. Complete genome sequence of Caulobacter crescentus. Proc. Natl Acad. Sci. USA 98, 4136–4141 (2001).
Laub, M. T., Chen, S. L., Shapiro, L. & McAdams, H. H. Genes directly controlled by CtrA, a master regulator of the Caulobacter cell cycle. Proc. Natl Acad. Sci. USA 99, 4632–4637 (2002).
Laub, M. T., McAdams, H. H., Feldblyum, T., Fraser, C. M. & Shapiro, L. Global analysis of the genetic network controlling a bacterial cell cycle. Science 290, 2144–2148 (2000). First application of whole-genome DNA microarrays to the study of global gene expression patterns in wild-type and mutant Caulobacter.
Grunenfelder, B. et al. Proteomic analysis of the bacterial cell cycle. Proc. Natl Acad. Sci. USA 98, 4681–4686 (2001).
Ireland, M. M., Karty, J. A., Quardokus, E. M., Reilly, J. P. & Brun, Y. V. Proteomic analysis of the Caulobacter crescentus stalk indicates competence for nutrient uptake. Mol. Microbiol. 45, 1029–1041 (2002).
Molloy, M. P. et al. Profiling the alkaline membrane proteome of Caulobacter crescentus with two-dimensional electrophoresis and mass spectrometry. Proteomics 2, 899–910 (2002).
Shapiro, L., McAdams, H. H. & Losick, R. Generating and exploiting polarity in bacteria. Science 298, 1942–1946 (2002). An outstanding review of the molecular mechanisms used to produce, maintain and use asymmetry in bacteria.
Robertson, G. T. et al. The Brucella abortus CcrM DNA methyltransferase is essential for viability, and its overexpression attenuates intracellular replication in murine macrophages. J. Bacteriol. 182, 3482–3489 (2000).
Wright, R., Stephens, C. & Shapiro, L. The CcrM DNA methyltransferase is widespread in the alpha subdivision of proteobacteria, and its essential functions are conserved in Rhizobium meliloti and Caulobacter crescentus. J. Bacteriol. 179, 5869–5877 (1997).
Kahng, L. S. & Shapiro, L. The CcrM DNA methyltransferase of Agrobacterium tumefaciens is essential, and its activity is cell cycle regulated. J. Bacteriol. 183, 3065–3075 (2001).
Kahng, L. S. & Shapiro, L. Polar localization of replicon origins in the multipartite genomes of Agrobacterium tumefaciens and Sinorhizobium meliloti. J. Bacteriol. 185, 3384–3391 (2003).
Bellefontaine, A. F. et al. Plasticity of a transcriptional regulation network among α-proteobacteria is supported by the identification of CtrA targets in Brucella abortus. Mol. Microbiol. 43, 945–960 (2002).
Brassinga, A. K. et al. Conserved response regulator CtrA and IHF binding sites in the alpha-proteobacteria Caulobacter crescentus and Rickettsia prowazekii chromosomal replication origins. J. Bacteriol. 184, 5789–5799 (2002).
Barnett, M. J., Hung, D. Y., Reisenauer, A., Shapiro, L. & Long, S. R. A homolog of the CtrA cell cycle regulator is present and essential in Sinorhizobium meliloti. J. Bacteriol. 183, 3204–3210 (2001).
Gober, J. W. & England, J. C. in Prokaryotic Development (eds. Brun, Y. V. & Shimkets, L. J.) 319–339 (ASM Press, Washington DC, 2000). A comprehensive review of the intricate mechanisms regulating flagellar assembly in Caulobacter.
Skerker, J. M. & Shapiro, L. Identification and cell cycle control of a novel pilus system in Caulobacter crescentus. EMBO J. 19, 3223–3234 (2000).
Jenal, U. & Fuchs, T. An essential protease involved in bacterial cell-cycle control. EMBO J. 17, 5658–5669 (1998).
Kelly, A. J., Sackett, M. J., Din, N., Quardokus, E. & Brun, Y. V. Cell cycle-dependent transcriptional and proteolytic regulation of FtsZ in Caulobacter. Genes Dev. 12, 880–893 (1998).
Stephens, C., Reisenauer, A., Wright, R. & Shapiro, L. A cell cycle-regulated bacterial DNA methyltransferase is essential for viability. Proc. Natl Acad. Sci. USA 93, 1210–1214 (1996).
Quon, K. C., Marczynski, G. T. & Shapiro, L. Cell cycle control by an essential bacterial two-component signal transduction protein. Cell 84, 83–93 (1996). A clever genetic screen identified the essential regulator CtrA and demonstrated its role in controlling DNA replication and cell division in Caulobacter.
Siam, R. & Marczynski, G. T. Glutamate at the phosphorylation site of response regulator CtrA provides essential activities without increasing DNA binding. Nucleic Acids Res. 31, 1775–1779 (2003).
Domian, I. J., Quon, K. C. & Shapiro, L. Cell type-specific phosphorylation and proteolysis of a transcriptional regulator controls the G1-to-S transition in a bacterial cell cycle. Cell 90, 415–424 (1997). Shows that a master regulator in Caulobacter , CtrA, is subject to multiple, redundant levels of regulation.
Reisenauer, A. & Shapiro, L. DNA methylation affects the cell cycle transcription of the CtrA global regulator in Caulobacter. EMBO J. 21, 4969–4977 (2002).
Ryan, K. R., Judd, E. M. & Shapiro, L. The CtrA response regulator essential for Caulobacter crescentus cell-cycle progression requires a bipartite degradation signal for temporally controlled proteolysis. J. Mol. Biol. 324, 443–455 (2002).
Hung, D. Y. & Shapiro, L. A signal transduction protein cues proteolytic events critical to Caulobacter cell cycle progression. Proc. Natl Acad. Sci. USA 99, 13160–13165 (2002).
Wu, J., Ohta, N. & Newton, A. An essential, multicomponent signal transduction pathway required for cell cycle regulation in Caulobacter. Proc. Natl Acad. Sci. USA 95, 1443–1448 (1998). Another sophisticated genetic screen that identified the essential master regulator CtrA and placed it in the context of previously studied two-component signalling systems.
Wu, J., Ohta, N., Zhao, J. L. & Newton, A. A novel bacterial tyrosine kinase essential for cell division and differentiation. Proc. Natl Acad. Sci. USA 96, 13068–13073 (1999).
Quon, K. C., Yang, B., Domian, I. J., Shapiro, L. & Marczynski, G. T. Negative control of bacterial DNA replication by a cell cycle regulatory protein that binds at the chromosome origin. Proc. Natl Acad. Sci. USA 95, 120–125 (1998).
Domian, I. J., Reisenauer, A. & Shapiro, L. Feedback control of a master bacterial cell-cycle regulator. Proc. Natl Acad. Sci. USA 96, 6648–6653 (1999).
Judd, E. M., Ryan, K. R., Moerner, W. E., Shapiro, L. & McAdams, H. H. Fluorescence bleaching reveals asymmetric compartment formation prior to cell division in Caulobacter. Proc. Natl Acad. Sci. USA 100, 8235–8240 (2003).
Levchenko, I., Seidel, M., Sauer, R. T. & Baker, T. A. A specificity-enhancing factor for the ClpXP degradation machine. Science 289, 2354–2356 (2000).
Zhou, Y., Gottesman, S., Hoskins, J. R., Maurizi, M. R. & Wickner, S. The RssB response regulator directly targets σS for degradation by ClpXP. Genes Dev. 15, 627–637 (2001).
Jacobs, C., Domian, I. J., Maddock, J. R. & Shapiro, L. Cell cycle-dependent polar localization of an essential bacterial histidine kinase that controls DNA replication and cell division. Cell 97, 111–120 (1999). Uses fluorescence microscopy to observe the dynamic localization of a key regulatory molecule, and shows that spatially, bacterial cells can be highly organized.
Jacobs, C., Ausmees, N., Cordwell, S. J., Shapiro, L. & Laub, M. T. Functions of the CckA histidine kinase in Caulobacter cell cycle control. Mol. Microbiol. 47, 1279–1290 (2003).
Sommer, J. M. & Newton, A. Pseudoreversion analysis indicates a direct role of cell division genes in polar morphogenesis and differentiation in Caulobacter crescentus. Genetics 129, 623–630 (1991).
Ohta, N. & Newton, A. The core dimerization domains of histidine kinases contain recognition specificity for the cognate response regulator. J. Bacteriol. 185, 4424–4431 (2003).
Hecht, G. B., Lane, T., Ohta, N., Sommer, J. M. & Newton, A. An essential single domain response regulator required for normal cell division and differentiation in Caulobacter crescentus. EMBO J. 14, 3915–3924 (1995).
Burbulys, D., Trach, K. A. & Hoch, J. A. Initiation of sporulation in B. subtilis is controlled by a multicomponent phosphorelay. Cell 64, 545–552 (1991).
Reisenauer, A., Quon, K. & Shapiro, L. The CtrA response regulator mediates temporal control of gene expression during the Caulobacter cell cycle. J. Bacteriol. 181, 2430–2439 (1999).
Sackett, M. J., Kelly, A. J. & Brun, Y. V. Ordered expression of ftsQA and ftsZ during the Caulobacter crescentus cell cycle. Mol. Microbiol. 28, 421–434 (1998).
Ren, B. et al. Genome-wide location and function of DNA binding proteins. Science 290, 2306–2309 (2000).
Iyer, V. R. et al. Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nature 409, 533–538 (2001).
Simon, I. et al. Serial regulation of transcriptional regulators in the yeast cell cycle. Cell 106, 697–708 (2001).
Osley, M. A. & Newton, A. Temporal control of the cell cycle in Caulobacter crescentus: roles of DNA chain elongation and completion. J. Mol. Biol. 138, 109–128 (1980).
Hartwell, L. H. & Weinert, T. A. Checkpoints: controls that ensure the order of cell cycle events. Science 246, 629–634 (1989). An authoritative discussion of checkpoints, from a definition to how they function in controlling cell-cycle progression.
Berget, P. B. & King, J. in Bacteriophage T4 (eds Mathews, C. K., Kutter, E. M., Mosig, G. & Berget, P. B.) 246–258 (ASM Press, Washington DC, 1983).
Autret, S., Levine, A., Holland, I. B. & Seror, S. J. Cell cycle checkpoints in bacteria. Biochimie 79, 549–554 (1997).
Burton, P. & Holland, I. B. Two pathways of division inhibition in UV-irradiated E. coli. Mol. Gen. Genet. 190, 309–314 (1983).
Osley, M. A., Sheffery, M. & Newton, A. Regulation of flagellin synthesis in the cell cycle of caulobacter: dependence on DNA replication. Cell 12, 393–400 (1977).
Wortinger, M., Sackett, M. J. & Brun, Y. V. CtrA mediates a DNA replication checkpoint that prevents cell division in Caulobacter crescentus. EMBO J. 19, 4503–4512 (2000).
Mohl, D. A. & Gober, J. W. Cell cycle-dependent polar localization of chromosome partitioning proteins in Caulobacter crescentus. Cell 88, 675–684 (1997).
Mohl, D. A., Easter, J. Jr & Gober, J. W. The chromosome partitioning protein, ParB, is required for cytokinesis in Caulobacter crescentus. Mol. Microbiol. 42, 741–755 (2001).
Ward, D. & Newton, A. Requirement of topoisomerase IV parC and parE genes for cell cycle progression and developmental regulation in Caulobacter crescentus. Mol. Microbiol. 26, 897–910 (1997).
Jensen, R. B. & Shapiro, L. The Caulobacter crescentus smc gene is required for cell cycle progression and chromosome segregation. Proc. Natl Acad. Sci. USA 96, 10661–10666 (1999).
Woldringh, C. L., Mulder, E., Huls, P. G. & Vischer, N. Toporegulation of bacterial division according to the nucleoid occlusion model. Res. Microbiol. 142, 309–320 (1991).
Rudner, D. Z. & Losick, R. Morphological coupling in development: lessons from prokaryotes. Dev. Cell 1, 733–742 (2001).
Mangan, E. K., Bartamian, M. & Gober, J. W. A mutation that uncouples flagellum assembly from transcription alters the temporal pattern of flagellar gene expression in Caulobacter crescentus. J. Bacteriol. 177, 3176–3184 (1995).
Muir, R. E. & Gober, J. W. Regulation of late flagellar gene transcription and cell division by flagellum assembly in Caulobacter crescentus. Mol. Microbiol. 41, 117–130 (2001).
Muir, R. E., O'Brien, T. M. & Gober, J. W. The Caulobacter crescentus flagellar gene, fliX, encodes a novel transacting factor that couples flagellar assembly to transcription. Mol. Microbiol. 39, 1623–1637 (2001).
Muir, R. E. & Gober, J. W. Mutations in FlbD that relieve the dependency on flagellum assembly alter the temporal and spatial pattern of developmental transcription in Caulobacter crescentus. Mol. Microbiol. 43, 597–615 (2002).
Anderson, D. K. & Newton, A. Post-transcriptional regulation of Caulobacter flagellin genes by a late flagellum assembly checkpoint. J. Bacteriol. 179, 2281–2288 (1997).
Anderson, P. E. & Gober, J. W. FlbT, the post-transcriptional regulator of flagellin synthesis in Caulobacter crescentus, interacts with the 5′ untranslated region of flagellin mRNA. Mol. Microbiol. 38, 41–52 (2000).
Mangan, E. K. et al. FlbT couples flagellum assembly to gene expression in Caulobacter crescentus. J. Bacteriol. 181, 6160–6170 (1999).
Shapiro, L. & Losick, R. Dynamic spatial regulation in the bacterial cell. Cell 100, 89–98 (2000).
Wheeler, R. T. & Shapiro, L. Differential localization of two histidine kinases controlling bacterial cell differentiation. Mol. Cell 4, 683–694 (1999).
Aldridge, P., Paul, R., Goymer, P., Rainey, P. & Jenal, U. Role of the GGDEF regulator PleD in polar development of Caulobacter crescentus. Mol. Microbiol. 47, 1695–1708 (2003).
Hecht, G. B. & Newton, A. Identification of a novel response regulator required for the swarmer-to-stalked-cell transition in Caulobacter crescentus. J. Bacteriol. 177, 6223–6229 (1995).
Aldridge, P. & Jenal, U. Cell cycle-dependent degradation of a flagellar motor component requires a novel-type response regulator. Mol. Microbiol. 32, 379–391 (1999).
Sommer, J. M. & Newton, A. Turning off flagellum rotation requires the pleiotropic gene pleD: pleA, pleC, and pleD define two morphogenic pathways in Caulobacter crescentus. J. Bacteriol. 171, 392–401 (1989).
Wang, S. P., Sharma, P. L., Schoenlein, P. V. & Ely, B. A histidine protein kinase is involved in polar organelle development in Caulobacter crescentus. Proc. Natl Acad. Sci. USA 90, 630–634 (1993).
Viollier, P. H., Sternheim, N. & Shapiro, L. Identification of a localization factor for the polar positioning of bacterial structural and regulatory proteins. Proc. Natl Acad. Sci. USA 99, 13831–13836 (2002).
Hinz, A. J., Larson, D. E., Smith, C. S. & Brun, Y. V. The Caulobacter crescentus polar organelle development protein PodJ is differentially localized and is required for polar targeting of the PleC development regulator. Mol. Microbiol. 47, 929–941 (2003).
Crymes, W. B. Jr, Zhang, D. & Ely, B. Regulation of podJ expression during the Caulobacter crescentus cell cycle. J. Bacteriol. 181, 3967–3973 (1999).
Blatch, G. L. & Lassle, M. The tetratricopeptide repeat: a structural motif mediating protein–protein interactions. Bioessays 21, 932–939 (1999).
Hoch, J. A. & Silhavy, T. J. (eds) Two-Component Signal Transduction (ASM Press, Washington DC, 1995).
Loomis, W. F., Kuspa, A. & Shaulsky, G. Two-component signal transduction systems in eukaryotic microorganisms. Curr. Opin. Microbiol. 1, 643–648 (1998).
Li, Z. et al. A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells. Proc. Natl Acad. Sci. USA 100, 8164–8169 (2003).
Acknowledgements
We apologize to our colleagues whose work was not cited owing to space constraints. We thank L. Garwin and A. Greenwood for helpful comments on the manuscript. Work in the Laub laboratory is supported by the Office of Science (BER), US Department of Energy, the National Institutes of Health and the Defense Advanced Research Projects Agency.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Related links
DATABASES
Entrez
SwissProt
Glossary
- G1 PHASE
-
The period of time in the cell cycle before DNA replication starts and during which the cell contains only one copy of its genome.
- S PHASE
-
The period of time in the cell cycle in which a cell is actively synthesizing/replicating its genome.
- G2 PHASE
-
The period of time in the cell cycle after DNA replication has been completed, but before cell division.
- PULSE–CHASE STUDY
-
A technique in which a cell, or cell extract, is briefly treated with a radioactive compound (the 'pulse'). This allows incorporation of the radiolabel into cellular constituents. The pulse is followed by addition of excess, non-radioactive compound (the 'chase'). Monitoring the radiolabelled compound over time then allows its location or stability to be tracked.
- DNA METHYLATION
-
The addition of a methyl (CH3) group to adenine or cytosine bases in DNA.
- HOMOLOGY MODELLING
-
A procedure in which an unknown protein structure is modelled by matching — fitting — to the known structure of a closely related protein by matching conserved amino acids. Allows an approximation of the 3D shape and organization of the protein to be obtained.
- MULTI-COMPONENT PHOSPHORELAY
-
A signalling pathway involving two-component signal transduction molecules, in which a phosphoryl group from ATP is transferred to more than two components. Usually involves transfer from a histidine kinase to a response regulator to a histidine phosphotransferase to another response regulator.
- CLOSED-LOOP SET
-
A set of regulatory factors that regulate each other such that the overall topology produces a circle, or loop, of interactions.
- NASCENT SWARMER POLE
-
The pole opposite the stalked pole in a Caulobacter predivisional cell, where the flagellum and pilus secretion apparatus must be assembled before cell division takes place.
Rights and permissions
About this article
Cite this article
Skerker, J., Laub, M. Cell-cycle progression and the generation of asymmetry in Caulobacter crescentus. Nat Rev Microbiol 2, 325–337 (2004). https://doi.org/10.1038/nrmicro864
Issue Date:
DOI: https://doi.org/10.1038/nrmicro864
This article is cited by
-
Chromosomal gene of hybrid multisensor histidine kinase is involved in motility regulation in the rhizobacterium Azospirillum baldaniorum Sp245 under mechanical and water stress
World Journal of Microbiology and Biotechnology (2023)
-
Proteolysis dependent cell cycle regulation in Caulobacter crescentus
Cell Division (2022)
-
The genus Caulobacter and its role in plant microbiomes
World Journal of Microbiology and Biotechnology (2022)
-
Towards a synthetic cell cycle
Nature Communications (2021)
-
Asymmetric cellular memory in bacteria exposed to antibiotics
BMC Evolutionary Biology (2017)