Riboswitches as versatile gene control elements

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Riboswitches are structured elements typically found in the 5′ untranslated regions of mRNAs, where they regulate gene expression by binding to small metabolites. In all examples studied to date, these RNA control elements do not require the involvement of protein factors for metabolite binding. Riboswitches appear to be pervasive in eubacteria, suggesting that this form of regulation is an important mechanism by which metabolic genes are controlled. Recently discovered riboswitch classes have surprisingly complex mechanisms for regulating gene expression and new high-resolution structural models of these RNAs provide insight into the molecular details of metabolite recognition by natural RNA aptamers.

Introduction

From microRNAs [1] to ‘riboregulators’ [2], one of the more salient concepts to have emerged from gene regulation research over the past several years is that RNA frequently plays a more direct and intimate role in controlling gene expression than previously assumed [3, 4]. It has long been known that differential folding of RNA plays a major role in transcriptional attenuation [5]. Other RNA-based regulatory mechanisms have subsequently been discovered, including pathways involving antisense [6] and tRNA–mRNA interactions [7], control of translation by temperature-dependent modulation of RNA structure [8, 9, 10, 11] and the involvement of microRNAs as trans-acting genetic factors [1]. The frequency at which these discoveries have been occurring suggests an even greater role for RNA in cellular control processes. This already appears to be true of bacteria, as recent descriptions of gene control by riboswitches are revealing a pervasive system of RNA-mediated gene control [12, 13, 14, 15, 16].

Riboswitches are widespread in bacteria, with nine classes already reported, some of which describe previously known conserved regulatory elements (e.g. [17, 18, 19]). The metabolites sensed by riboswitches are diverse, among them guanine [20], flavin mononucleotide (FMN) [21, 22] and lysine [23•, 24•, 25•]. One riboswitch class that binds thiamine pyrophosphate (TPP) [26] also has been found in plants and fungi [27•]. However, riboswitches that occur in eubacteria have been most extensively studied and this review will primarily focus on recent advances concerning bacterial representatives. For a more comprehensive overview of this research area, the reader is directed to several recent reviews [13, 14, 15, 28, 29, 30].

Section snippets

Structural and functional domains of riboswitches

Most riboswitches can be divided roughly into two structural domains: an aptamer [31, 32] and an expression platform (Figure 1) [26]. The aptamer domain is a highly folded structure that selectively binds to the target metabolite. The expression platform converts metabolite binding events into changes in gene expression by harnessing changes in RNA folding that are brought about by ligand binding. It is the distinctive sequence and structural features of each aptamer that are used to classify

New riboswitch classes

In the past year, three newly confirmed riboswitch classes have been reported (Figure 2). In all three cases, differences are observed compared to the prototypic riboswitch mechanisms described above. The first of these, an adenine-sensing riboswitch, is remarkably similar to a previously reported riboswitch that binds guanine [20, 36•, 37]. The guanine riboswitch had been shown to repress purine biosynthetic and salvage genes upon binding directly to guanine [20, 37]. However, certain RNA

High-resolution riboswitch structures

Recently, three high-resolution structural models have detailed the structural basis of ligand recognition by purine-binding riboswitches (Figure 3a,b) [43••, 44••]. One of these structures is the aptamer domain of the guanine riboswitch from the xpt-pbuX operon of B. subtilis [43••] (Figure 3a). The aptamer was crystallized in complex with hypoxanthine, a metabolite that is similar in structure to guanine, and has previously been shown to be bound by the riboswitch and to regulate gene

Conclusions

Despite the recent discoveries of new RNA genetic elements, it is likely that the current collection of known elements reflects only a small fraction of the contribution that RNA makes to the regulation of modern cells. Furthermore, it seems likely that the diversity of RNA structure and function could have been harnessed by the earliest life forms to construct sensory and regulatory RNAs. Some riboswitches could be direct descendents of ancient metabolite sensors that first emerged in the RNA

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to acknowledge Mary Stahley for assistance with structure images, and Jeffrey Barrick for discussion and comments on the review. Riboswitch research in the Breaker laboratory is funded by grants from the National Institutes of Health, the National Science Foundation and DARPA (Defense Advanced Research Projects Agency).

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