Translation Control by RNA

Abstract

Translation control by ribonucleic acid (RNA) refers to the process by which protein synthesis is regulated by structural elements in RNA (primary, secondary or tertiary), often cis‐acting in the messenger RNA encoding the protein being synthesised, and also trans‐acting in a number of systems. This article covers the historical early recognition of translation control by RNA in the RNA bacteriophage and extends the concept to include many additional examples of secondary structure control, or ‘riboswitches’, and other methods of controlling access by ribosomes to messenger ribonucleic acid (mRNA), including the role of small regulatory RNAs. Effects of RNA primary sequences on translation are also covered, including initiation signals, recoding (e.g. translational frameshifts), codon bias, translational attenuation and antisense regulation. mRNA stability is also considered, as well as an RNA‐based mechanism to facilitate translation termination, transfer‐messenger ribonucleic acid (tmRNA).

Key Concepts

  • mRNA secondary/tertiary structure can obscure or expose translation start sites and can be altered by conditions in the cell to regulate translation initiation (riboswitches).
  • Translational coupling requires translation of an upstream gene before ribosomes can translate the downstream gene. Often used to promote equimolar levels of proteins that are utilised in comparable amounts (enzyme subunits), or for inhibition of more than one gene in an operon (ribosomal protein operons).
  • Small RNAs, generally antisense RNA, can bind to mRNA to inhibit translation starts, or in some cases, to facilitate translation starts. Often requires a protein chaperone‐like Hfq.
  • Antisense RNAs often lead to degradation of the RNA target. In eukaryotes, this is termed ‘ribonucleic acid interference’ (RNAi).
  • Primary sequences in mRNA can also affect translation efficiency, including choice of start codon, or quality of the ribosome‐binding site, or as a target for a repressor protein (translational ‘operators’).
  • Primary sequences in mRNA can in some instances trigger ‘recoding’, in which the mRNA is translated in an unexpected way, such as causing translational frameshifts, or incorporation of selenocysteine in response to a UGA codon.
  • In the phenomenon of ‘translational attenuation’, the primary sequence encodes an inhibitory peptide that potentiates the ribosome to be inhibited by otherwise sub‐lethal concentrations of antibiotic, thereby exposing a downstream translation start for the antibiotic resistance gene.
  • Codon bias can affect the efficiency of translation, where common codons in a given organism are almost exclusively used for highly expressed proteins, and rare codons for that organism used at a much higher frequency in poorly expressed proteins. Usually correlates to cognate tRNA levels.
  • mRNA stability is a determinant of the amount of protein expressed; stability can be affected by both cis‐ and trans‐acting elements.
  • tmRNA (transfer‐messenger ribonucleic acid) is a mechanism in bacteria for orderly termination of translation when there is a vacant A site on the ribosome.

Keywords: RNA bacteriophage; antisense RNA; riboswitches; mRNA stability; translational coupling; translational enhancers; translational attenuation; initiation codon; codon bias; tmRNA; RNAIII

Figure 1. Translational control in RNA phage. Schematic diagram depicts the principle of how RNA structure governs relative translation of the coat and replicase protein genes. Note that protein synthesis proceeds, as always, from the 5′ to 3′ direction (indicated) on the messenger RNA (mRNA). (a) The ribosome‐binding site (RBS) and the start codon (AUG) of the coat protein are exposed and accessible to ribosomes so that translation of the coat gene proceeds readily. However, the RBS and the AUG (read right to left) of the replicase gene are buried in the RNA structure (selected hydrogen bonds are depicted as short vertical lines between the upper and lower portions of the RNA chain) and not accessible to ribosomes, so this gene is not translated unless the structure is opened up. (b) Ribosomes translating the upstream coat gene open the RNA structure when they proceed past approximately codons 30–40 (indicated earlier the upper portion of the RNA chain), allowing the replicase gene, RBS and AUG to be accessible to other ribosomes, which can now start translating the replicase gene.
Figure 2. Example of prokaryotic RNA secondary structure control. Schematic diagram depicts the principle of how alternate forms of messenger RNA (mRNA) can lead to either inhibition or expression. A longer form of the mRNA, starting from promoter P1, folds into a structure such that the ribosome‐binding site (RBS) and the start codon (AUG) are occluded in a stem–loop, and are inaccessible to ribosomes. A shorter form of the mRNA, starting from promoter P2, does not form the inhibitory structure, therefore the RBS and AUG are available for ribosomes to commence translation.
Figure 3. Model of translational attenuation. The ribosome‐binding site (RBS) and start codon (AUG) for the antibiotic resistance gene are masked by the secondary structure of the message in (a), therefore ribosomes cannot translate the message for the resistance gene. However, when ribosomes begin translation at the RBS and AUG of the upstream translation start in the leader region, and a short nascent leader peptide is synthesised, the ribosomes will stall during translation of the leader peptide in the presence of sublethal concentrations of antibiotic. This opens up the secondary structure, exposing the translation start site for the resistance gene, which is now expressed, as shown in (b).
Figure 4. Schematic drawing of how antisense RNA inhibits translation of a target message. The ribosome‐binding site (RBS) and start codon (AUG) to initiate translation of a coding region is accessible to ribosomes in (a). Antisense RNA encompassing the translation initiation region binds to the mRNA and obscures the start site from ribosomes in (b). Note that the orientation of the antisense RNA is antiparallel to mRNA, that is 5′ to 3′ is in the opposite direction.
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Further Reading

Deutscher MP (2006) Degradation of RNA in bacteria: comparison of mRNA and stable RNA. Nucleic Acids Research 34: 659–666.

Hinnebusch AG, Ivanov IP and Sonenberg N (2016) Translational control by 5′‐untranslated regions of eukaryotic mRNAs. Science 352: 1413–1416.

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Goldman, Emanuel(Apr 2019) Translation Control by RNA. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000859.pub3]