Ribozymes, riboswitches and beyond: regulation of gene expression without proteins

Abstract

Although various functions of RNA are carried out in conjunction with proteins, some catalytic RNAs, or ribozymes, which contribute to a range of cellular processes, require little or no assistance from proteins. Furthermore, the discovery of metabolite-sensing riboswitches and other types of RNA sensors has revealed RNA-based mechanisms that cells use to regulate gene expression in response to internal and external changes. Structural studies have shown how these RNAs can carry out a range of functions. In addition, the contribution of ribozymes and riboswitches to gene expression is being revealed as far more widespread than was previously appreciated. These findings have implications for understanding how cellular functions might have evolved from RNA-based origins.More than 40 years of extensive research has revealed that RNAs participate in a range of cellular functions. Some RNAs, despite being composed of only four chemically similar nucleotides, can fold into distinct three-dimensional architectures. In many cases, these constitute simple scaffolds that provide binding sites for proteins that function together with the RNAs. However, the discovery of the first catalytic RNAs -later named RNA enzymes, or ribozymes -in the 1980s demonstrated that RNAs can also have important functional roles in their own right 1,2 . The list of naturally occuring ribozymes is short, and additions over the years have been rare, with each new discovery eliciting considerable excitement in the field.Studies of molecular evolution suggest that RNA molecules significantly influenced the development of modern organisms by mediating the genetic flow from DNA to proteins, as well as through their own contribution to catalytic functions. The 'RNA world' hypothesis implies that RNA molecules appeared before DNA and proteins 3 . Nevertheless, even with a head start, RNA catalysts do not prevail in the modern world. Moreover, most ubiquitous ribozymes require proteins for efficient catalysis in vivo, and most true protein-devoid catalytic RNAs have been found in only a few viral-like sources, suggesting that the contribution of protein-free RNAs to the functions of modern cells has been limited.Correspondence to A.S. or D.J.P. serganoa@mskcc.org; pateld@mskcc.org. Competing interests statementThe authors declare no competing financial interests. HHS Public AccessAuthor manuscript Nat Rev Genet. Author manuscript; available in PMC 2015 December 23. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe discovery of riboswitches 4-6 and other RNA-based sensors reignited interest in the roles of protein-devoid RNA-based elements. These RNA sensors can be broadly defined as mRNA regions that are capable of modulating gene expression in response to internal and external inputs, without the initial participation of proteins. Unlike ribozymes, many of these sensors direct gene expression purely through changes in RNA conformation. For instance, riboswitches alter their conformations in response to small metabolite...

Towards deciphering the principles underlying an mRNA recognition code

“…We propose dividing all such complexes into three categories (Table 1): (1) structure-specific recognition of folded RNAs ( Figure 1a); (2) sequence-specific recognition of single-stranded RNAs ( Figure 1b); (3) non-specific recognition of single-stranded RNAs (Figure 1c). …”

“…The mRNA recognition signatures, therefore, could be considered a special 'code', contributing, along with other layers of gene expression control, to the final pattern of gene expression. This code, however, is unlikely to be universal due to dramatic differences in transcription and mRNA processing amongst evolutionary distant groups, as well as occurrence of species-specific mRNA-recognition systems necessary for adaptation to particular environmental cues [1]. Due to the immense potential and opportunities for manipulation of gene expression at the post-transcriptional level, many structural biology groups have focused their ongoing research efforts towards determination of structures that would uncover the complex network of relationships between mRNA and its partners, thereby contributing towards a comprehensive understanding of the principles underlying a 'mRNA recognition code'.…”

Folding of the SAM-I riboswitch

“…8 While the very conserved aptamer domain is involved in signal detection, the expression platform varies widely as it controls gene expression at various biological levels, such as transcription or translation. 9 Ligand binding causes the riboswitch to undergo a global conformational change leading to the modulation of gene expression. Because riboswitches are able to sense cellular signals and regulate gene expression, they provide a direct response mechanism for metabolic stress.…”

“…4,6,[8][9][10][11][12][13][14][15][16][17][18] Although various riboswitch apo forms have recently been described in reference 19-23, a complete knowledge is still lacking about subsequent conformational changes occurring as a result of ligand binding. 17,24 Intriguingly, some crystal structures of ligand-free aptamers are highly similar to those obtained in their bound form, suggesting that free aptamers may sample various conformations resembling those adopted in presence of the ligand.…”

Entropic origin of Mg 2+ -facilitated RNA folding

“…RNA secondary structure prediction from the known thermodynamics is quite reliable (3), though correspondingly accurate prediction of tertiary structure remains a major challenge (1). Static tertiary structure data alone are also not enough to predict RNA functionality, as time-dependent conformational dynamics occur during biochemical processes (4,5). As a result, one needs the full free energy, enthalpy, and entropy landscapes for folding.…”