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  • Review Article
  • Published:

DNA supercoiling — a global transcriptional regulator for enterobacterial growth?

Nature Reviews Microbiology volume 3, pages 157–169 (2005)Cite this article

Key Points

  • An important aspect of growth control in enterobacteria is regulation of production of the translational machinery.

  • Stable RNA (rRNA and tRNA) promoters are unusually dependent on high negative superhelicity for optimal expression. This superhelicity facilitates the wrapping of DNA around the polymerase and enhances its untwisting in the −10 region.

  • Stringent control and growth-rate control of stable RNA transcription are mechanistically distinct and dependent on different, but overlapping, elements of promoter structure.

  • Growth-rate control of a promoter and its dependence on negative superhelicity are correlated, while ppGpp, the effector of the stringent response, is antagonized by high negative superhelicity.

  • The transcription factor FIS acts as a topological homeostat for some stable RNA promoters by locally constraining superhelicity, thereby decreasing the sensitivity of expression to fluctuations in superhelical density.

  • The effective, or available, superhelicity of promoter DNA is determined by competition between abundant nucleoid-associated proteins, which constrain negative supercoils, and RNA polymerase, thereby balancing the compaction and availability of DNA.

  • Transcription regulation during growth-phase transitions is correlated with changes in negative superhelicity, adaptive changes in the RNA polymerase that alter the responses of transcription machinery to supercoiling, and changes in the composition of the nucleoid-associated proteins that affect the availability of negative supercoils.

  • The global control of transcription throughout the life cycle of Escherichia coli can be formalized as an interacting network of gene products and low-molecular-weight effectors that control RNA polymerase selectivity and effective superhelicity.

Abstract

A fundamental principle of exponential bacterial growth is that no more ribosomes are produced than are necessary to support the balance between nutrient availability and protein synthesis. Although this conclusion was first expressed more than 40 years ago, a full understanding of the molecular mechanisms involved remains elusive and the issue is still controversial. There is currently agreement that, although many different systems are undoubtedly involved in fine-tuning this balance, an important control, and in our opinion perhaps the main control, is regulation of the rate of transcription initiation of the stable (ribosomal and transfer) RNA transcriptons. In this review, we argue that regulation of DNA supercoiling provides a coherent explanation for the main modes of transcriptional control — stringent control, growth-rate control and growth-phase control — during the normal growth of Escherichia coli.

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Figure 1: Idealized pathway for transcription initiation by E. coli RNA polymerase.
Figure 2: Summary of regulatory pathways for the control of RNA polymerase and the effective superhelicity of promoter DNA.
Figure 3: Promoter structure and transcriptional control.
Figure 4: Global regulatory networks.
Figure 5: Alterations in the composition of the RNA polymerase holoenzyme and the nucleoid-associated proteins during the growth cycle of E.coli.

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Acknowledgements

We thank B. Peter, N. Cozzarelli and their colleagues for making available their results prior to publication and G. Mitchison for a very constructive reading of the manuscript.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Andrew Travers

  2. International University Bremen, Campus Ring 1, Research II-112, Bremen, 28759, Germany

    Georgi Muskhelishvili

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DATABASES

Entrez

Bacillus subtilis

Escherichia coli

gppA

gyrA

gyrB

hupA

hupB

leuV

rpoB

rpoC

sbmC

topA

tyrT

SwissProt

CRP

DksA

Dps

FIS

LRP

RpoZ

topoisomerase I

FURTHER INFORMATION

Andrew Travers' laboratory

Georgi Muskhelishvili's laboratory

Glossary

RHEOSTATIC CONTROL

A regulatory process for which the output is continuously variable in contrast to an on–off switch — an analogue rather than a digital response.

CLOSED COMPLEX

The complex that is formed between RNA polymerase and duplex promoter DNA, and precedes the initiation of DNA untwisting.

NUCLEATION

The initiation of DNA untwisting in a promoter. In bacterial promoters nucleation occurs in the −10 region.

OPEN COMPLEX

For transcription, the two strands of the DNA duplex must be unwound locally. An open complex is formed when RNA polymerase binds at a promoter and the duplex around the transcription start site is unwound.

R-LOOPS

An R-loop is formed when an RNA molecule hybridizes with a DNA duplex and takes the form of a bubble in which one half is a DNA–RNA duplex and the other half a single-stranded DNA of the same sequence as the hybridized RNA.

STRINGENT RESPONSE

The cessation of macromolecular synthesis on starvation of bacteria for a required amino acid. The stringent response is signalled by the production of ppGpp by the RelA protein when an uncharged tRNA binds to a ribosome.

GROWTH-RATE CONTROL

The process that coordinates the expression of promoters with the growth rate of a bacterial culture. For stable RNA promoters growth rate and expression are strongly positively correlated.

PLECTONEMIC

In the plectonemic or interwound form of supercoiled DNA, the DNA coils are wrapped around each other (see Box 1). In a circular supercoiled DNA molecule the interwindings are joined by a loop or 'apex' at each end of the structure.

ANTI-SIGMA FACTORS

A negative transcriptional regulator that acts by binding to a sigma factor and preventing its activity.

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Travers, A., Muskhelishvili, G. DNA supercoiling — a global transcriptional regulator for enterobacterial growth?. Nat Rev Microbiol 3, 157–169 (2005). https://doi.org/10.1038/nrmicro1088

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