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Thinking quantitatively about transcriptional regulation

Nature Reviews Molecular Cell Biology volume 6, pages 221–232 (2005)Cite this article

Key Points

  • Transcription at the operon level is discussed as a regulatory mechanism, and can be divided into two distinct phases: initiation and elongation. Initiation differs significantly between prokaryotes and eukaryotes, whereas elongation is very similar.

  • Elongation, and its regulatory control, can be described in thermodynamic and kinetic terms, and many of these mechanisms can now be considered in terms of defined structural interactions within the RNA polymerase of the transcription complex and with its various transcriptional cofactors.

  • The transcription complex can choose between several alternative reaction pathways at each template position. These pathways include continued elongation, as well as pyrophosphorolysis, editing, termination, and short- and long-term pausing.

  • These potential reaction pathways are in kinetic competition with one another, and the outcome of this competition at any given template position can be described in terms of the relative heights of the free energy of activation barriers that lead into these various pathways.

  • Transcription factors can selectively modulate these relative barrier heights, and can therefore potentially redirect transcription down any of these different pathways. Elongation is the default pathway, and transcription pauses of defined lengths and various structural origins are generally required to allow other reaction pathways to be used.

  • Much mechanistic and structural information is available concerning the elongation, editing, termination and pyrophosphorolysis pathways, and how the elongation complex chooses between them.

  • Understanding the mechanisms of regulation of transcript elongation in Escherichia coli can function as a model for transcriptional control in higher organisms and in various developmental and disease states.

Abstract

By thinking about the chemical and physical mechanisms that are involved in the stepwise elongation of RNA transcripts, we can begin to understand the way that these mechanisms are controlled within the cell to reflect the different requirements for transcription that are posed by various metabolic, developmental and disease states. Here, we focus on the mechanistic details of the single-nucleotide addition (or excision) cycle in the transcription process, as this is the level at which many regulatory mechanisms function and can be explained in quantitative terms.

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Figure 1: The transcription cycle.
Figure 2: The thermodynamic stability of the elongation complex.
Figure 3: The elongation process in structural terms.
Figure 4: Alternative reaction pathways that are available to RNA polymerase.
Figure 5: Kinetic regulation of transcription elongation.
Figure 6: RNA polymerase can function as a decoupled helicase.
Figure 7: Termination and antitermination.

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Acknowledgements

We are grateful to our colleagues at the University of Oregon and elsewhere for many stimulating discussions of the concepts presented here. The preparation of this article was supported, in part, by National Institutes of Health research grants (to P.H.v.H.) and by an American Heart Association Postdoctoral Fellowship (to S.J.G.). P.H.v.H. is an American Cancer Society Research Professor of Chemistry.

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Authors and Affiliations

  1. Institute of Molecular Biology and Department of Chemistry, University of Oregon, Eugene, 97403, Oregon, USA

    Sandra J. Greive & Peter H. von Hippel

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  1. Sandra J. Greive
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Correspondence to Peter H. von Hippel.

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DATABASES

Swiss-Prot

α

β

β′

ω

GreA

GreB

NusA

NusB

NusE

NusG

S4

Protein data bank

1HQM

Saccharomyces genome database

SII

FURTHER INFORMATION

Protein Data Bank

Glossary

PROMOTER

A DNA-binding site for RNA polymerase at which gene transcription can be initiated.

TERMINATION

A reaction that occurs at terminator sites on the DNA template and that stops transcription by dissociating the transcription complex and releasing the nascent RNA into solution.

TRANSCRIPTION BUBBLE

A stretch of 12–14 bp that is melted within the dsDNA as a consequence of transcription-complex formation. The transcription bubble exposes the DNA template strand that is then copied by RNA polymerase to form complementary RNA.

RNA–DNA HYBRID

The double-stranded, 8–9-bp helix that forms within the transcription bubble when the 3′ end of the nascent RNA transcript interacts with the complementary sequence of the template.

SIGMA FACTOR

(σ factor). A promoter-specific transcription factor in prokaryotes that binds to core RNA polymerase and directs the binding of the resulting holoenzyme to a specific promoter or family of promoters.

FIDELITY

A measure of the accuracy with which the template sequence is copied into the complementary nascent RNA or DNA strand.

PROCESSIVITY

A measure of the average number of nucleotides that a template-dependent polymerase incorporates into a growing RNA or DNA chain before dissociating from the template DNA. Regulation of the processivity of a polymerase might involve interactions of regulatory factors with its sliding-clamp domain.

EDITING

The process of correcting a misincorporation event by cleaving a short oligonucleotide sequence that contains the misincorporated residue from the 3′ end of the elongating transcript.

PYROPHOSPHOROLYSIS

A chemical process that results in the sequential removal of single nucleotides from the 3′ end of the nascent RNA. It represents the direct chemical reversal of the single-nucleotide-addition reaction.

ANTITERMINATION

A process that decreases termination efficiency at a given terminator by increasing the rate of transcription by the RNA polymerase or by stabilizing the elongation complex, or both.

SLIDING CLAMP

A domain or protein ring that forms part of the DNA-replication complex. It holds (or 'clamps') the replication polymerase to the DNA template at the primer–template junction within the replication fork. In transcription, this function is carried out by the 'pincer' domain of the 'crab-claw' region of the RNA polymerase. These pincers clamp the dsDNA downstream of the moving transcription bubble and control the processivity of the transcription complex.

KINETIC COMPETITION

The competition that is seen between different reactions during a process that can proceed down several bifurcating reaction pathways, for which the outcome depends on the relative rate constants of the potentially competing reactions. Alteration (for example, by transcription-factor binding) of the relative heights of the free energy of activation barriers that lead into the various reaction pathways can change the outcome of the process.

FREE ENERGY OF ACTIVATION BARRIER

An idea derived from transition-state theory that defines the input of free energy that is needed to allow a given reaction to proceed.

BOLTZMANN DISTRIBUTION

Describes how the total energy (or free energy, in this case) that is available for a reaction is divided among the population of molecules or pathways that are available within the system.

ISOENERGETIC REACTION PROCESS

A process in which the beginning and ending states have equivalent energies (or free energies).

SLIDING–ZIPPERING

The diffusion-driven process through which the elongation complex — which comprises the transcription bubble, the RNA–DNA hybrid and the RNA polymerase — translocates backwards and forwards along (and through) the DNA genome.

BACK-SLIDING

The process by which RNA polymerase might become detached from the 3′ end of the elongating RNA, and is translocated 'backwards' (upstream) by diffusion along the nucleic-acid framework towards the promoter, in response to regulatory signals or events during transcription elongation.

EXONUCLEASE

An enzyme that catalyses the cleavage of a single residue from the end of an oligonucletide strand. The term 'exonuclease-like' indicates that the enzyme might remove more than one residue at a time from the end of the chain.

MISINCORPORATION

The addition of an incorrect (as defined by the complementary DNA template) nucleotide at the 3′ end of the nascent transcript.

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Greive, S., von Hippel, P. Thinking quantitatively about transcriptional regulation. Nat Rev Mol Cell Biol 6, 221–232 (2005). https://doi.org/10.1038/nrm1588

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