Translation Control by RNA


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.


Arini A, Keller MP and Arber W (1997) An antisense RNA in IS30 regulates the translational expression of the transposase. Biological Chemistry 378: 1421–1431.

Baim SB and Sherman F (1988) mRNA structures influencing translation in the yeast Saccharomyces cerevisiae. Molecular and Cellular Biology 8: 1591–1601.

Baranov PV, Gesteland RF and Atkins JF (2002) Recoding: translational bifurcations in gene expression. Gene 286: 187–201.

Barrick D, Villanueba K, Childs J, et al. (1994) Quantitative analysis of ribosome binding sites in E. coli. Nucleic Acids Research 22: 1287–1295.

Bechhofer DH (1990) Triple post‐transcriptional control. Molecular Microbiology 4: 1419–1423.

Beck HJ and Janssen GR (2017) Novel translation initiation regulation mechanism in Escherichia coli ptrB mediated by a 5‐terminal AUG. Journal of Bacteriology 199: e00091‐17.

Berkhout B, Schmidt BF, van Strien A, et al. (1987) Lysis gene of bacteriophage MS2 is activated by translation termination at the overlapping coat gene. Journal of Molecular Biology 195: 517–524.

Betney R, de Silva E, Krishnan J and Stansfield I (2010) Autoregulatory systems controlling translation factor expression: thermostat‐like control of translational accuracy. RNA 16: 655–663.

Binns N and Masters M (2002) Expression of the Escherichia coli pcnB gene is translationally limited using an inefficient start codon: a second chromosomal example of translation initiated at AUU. Molecular Microbiology 44: 1287–1298.

Boisset S, Geissmann T, Huntzinger E, et al. (2007) Staphylococcus aureus RNAIII coordinately represses the synthesis of virulence factors and the transcription regulator Rot by an antisense mechanism. Genes & Development 21: 1353–1366.

Bordier B, Perala‐Heape M, Degols G, et al. (1995) Sequence‐specific inhibition of human immunodeficiency virus (HIV) reverse transcription by antisense oligonucleotides: comparative study in cell‐free assays and in HIV‐infected cells. Proceedings of the National Academy of Sciences of the United States of America 92: 9383–9387.

Brown L and Elliott T (1997) Mutations that increase expression of the rpoS gene and decrease its dependence on hfq function in Salmonella typhimurium. Journal of Bacteriology 179: 656–662.

Chandler M and Fayet O (1993) Translational frameshifting in the control of transposition in bacteria. Molecular Microbiology 7: 497–503.

Chevallier A and Garel JP (1982) Differential synthesis rates of tRNA species in the silk gland of Bombyx mori are required to promote tRNA adaptation to silk messages. European Journal of Biochemistry 124: 477–482.

Chiaruttini C, Milet M and Springer M (1997) Translational coupling by modulation of feedback repression in the IF3 operon of E. coli. Proceedings of the National Academy of Sciences of the United States of America 94: 9208–9213.

Condon C (2007) Maturation and degradation of RNA in bacteria. Current Opinion in Microbiology 10: 271–278.

Dar D and Sorek R (2018) Extensive reshaping of bacterial operons by programmed mRNA decay. PLoS Genetics 14: e1007354.

Davis MA, Simons RW and Kleckner N (1985) Tn10 protects itself at two levels from fortuitous activation by external promoters. Cell 43: 379–387.

Flynn A and Proud CG (1996) The role of eIF4 in cell proliferation. Cancer Surveys 27: 293–310.

Foley PL, Hsieh PK, Luciano DJ and Belasco JG (2015) Specificity and evolutionary conservation of the Escherichia coli RNA pyrophosphohydrolase RppH. Journal of Biological Chemistry 290: 9478–9486.

Fröhlich KS and Vogel J (2009) Activation of gene expression by small RNA. Current Opinion in Microbiology 12: 674–682.

Gallie DR (2002) The 5′‐leader of tobacco mosaic virus promotes translation through enhanced recruitment of eIF4F. Nucleic Acids Research 30: 3401–3411.

Gao W, Tyagi S, Kramer FR and Goldman E (1997) Messenger RNA release from ribosomes during 5′‐translational blockage by consecutive low‐usage arginine but not leucine codons in E. coli. Molecular Microbiology 25: 707–716. Erratum: (1998) 27: 669.

Geballe AP and Morris DR (1994) Initiation codons within 5′‐leaders of mRNAs as regulators of translation. Trends in Biochemical Sciences 19: 159–164.

Gerdes K, Gultyaev AP, Franch T, Pedersen K and Mikkelsen ND (1997) Antisense RNA‐regulated programmed cell death. Annual Review of Genetics 31: 1–31.

Gold L (1988) Posttranscriptional regulatory mechanisms in Escherichia coli. Annual Review of Biochemistry 57: 199–233.

Golshani A, Golomehova V, Mironova R, Ivanov IG and AbouHaidar MG (1997) Does the epsilon sequence of phage T7 function as an initiator for the translation of CAT mRNA in E. coli? Biochemical and Biophysical Research Communications 236: 253–256.

Gottesman S (2004) The small RNA regulators of E. coli: roles and mechanisms. Annual Review of Microbiology 58: 303–328.

Hammer BK and Bassler BL (2007) Regulatory small RNAs circumvent the conventional quorum sensing pathway in pandemic Vibrio cholerae. Proceedings of the National Academy of Sciences of the United States of America 104: 11145–11149.

Harrod R and Lovett PS (1995) Peptide inhibitors of peptidyltransferase alter the conformation of domains IV and V of large subunit rRNA: a model for nascent peptide control of translation. Proceedings of the National Academy of Sciences of the United States of America 92: 8650–8654.

He L, Soderbom F, Wagner EG, et al. (1993) PcnB is required for the rapid degradation of RNAi, the antisense RNA that controls the copy number of ColE1‐related plasmids. Molecular Microbiology 9: 1131–1142.

Hecht A, Glasgow J, Jaschke PR, et al. (2017) Measurements of translation initiation from all 64 codons in E. coli. Nucleic Acids Research 45: 3615–3626.

van Himbergen J, van Geffen B and van Duin J (1993) Translational control by a long range RNA‐RNA interaction; a basepair substitution analysis. Nucleic Acids Research 21: 1713–1717.

Hui A, Hayflick J, Dinkelspiel K and de Boer HA (1984) Mutagenesis of the three bases preceding the start codon of the beta‐galactosidase mRNA and its effect on translation in E. coli. EMBO Journal 3: 623–629.

Ito K, Kawakami K and Nakamura Y (1993) Multiple control of E. coli lysyl‐tRNA synthetase expression involves a transcriptional repressor and a translational enhancer element. Proceedings of the National Academy of Sciences of the United States of America 90: 302–306.

Ivey‐Hoyle M and Steege DA (1992) Mutational analysis of an inherently defective translation initiation site. Journal of Molecular Biology 224: 1039–1054.

Jan E and Sarnow P (2002) Factorless ribosome assembly on the internal ribosome entry site of cricket paralysis virus. Journal of Molecular Biology 324: 889–902.

Jin X, Turcott E, Englehardt S, Mize GJ and Morris DR (2003) The two upstream open reading frames of oncogene mdm2 have different translational regulatory properties. Journal of Biological Chemistry 278: 25716–25721.

Joanny G, Le Derout J, Bréchemier‐Baey D, et al. (2007) Polyadenylation of a functional mRNA controls gene expression in E. coli. Nucleic Acids Research 35: 2494–2502.

Kane JF (1995) Effects of rare codon clusters on high‐level expression of heterologous proteins in E. coli. Current Opinion in Biotechnology 6: 494–500.

Kanjo N and Inokuchi H (1999) Genes for tRNA(Arg) located in the upstream region of the Shiga toxin II operon in enterohemorrhagic Escherichia coli O157:H7. DNA Research 6: 71–73.

Kozak M (1989) Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs. Molecular Cell. Biology 9: 5134–5142.

Liebhaber SA, Cash F and Eshleman SS (1992) Translation inhibition by an mRNA coding region secondary structure is determined by its proximity to the AUG initiation codon. Journal of Molecular Biology 226: 609–621.

Lodato PB, Rogers EJ and Lovett PS (2006) A variation of the translation attenuation model can explain the inducible regulation of the pBC16 tetracycline resistance gene in Bacillus subtilis. Journal of Bacteriology 188: 4749–4758.

Lodish HF and Robertson HD (1969) Regulation of in vitro translation of bacteriophage f2 RNA. Cold Spring Harbor Symposia on Quantitative Biology 34: 655–673.

Lovett PS (1996) Translation attenuation regulation of chloramphenicol resistance in bacteria – a review. Gene 179: 157–162.

Ma C and Simons RW (1990) The IS10 antisense RNA blocks ribosome binding at the transposase translation initiation site. EMBO Journal 9: 1267–1274.

Ma CK, Kolesnikow T, Rayner JC, et al. (1994) Control of translation by mRNA secondary structure: the importance of the kinetics of structure formation. Molecular Microbiology 14: 1033–1047.

Ma J, Campbell A and Karlin S (2002) Correlations between Shine‐Dalgarno sequences and gene features such as predicted expression levels and operon structures. Journal of Bacteriology 184: 5733–5745.

Macdonald PM, Kutter E and Mosig G (1984) Regulation of a bacteriophage T4 late gene, soc, which maps in an early region. Genetics 106: 17–27.

Martin SE and Caplen NJ (2007) Applications of RNA interference in mammalian systems. Annual Review of Genomics and Human Genetics 8: 81–108.

Matteson RJ, Biswas SJ and Steege DA (1991) Distinctive patterns of translational reinitiation in the lac repressor mRNA: bridging of long distances by out‐of‐frame translation and RNA secondary structure, effects of primary sequence. Nucleic Acids Research 19: 3499–3506.

Mattheakis L, Vu L, Sor F and Nomura M (1989) Retroregulation of the synthesis of ribosomal proteins L14 and L24 by feedback repressor S8 in E. coli. Proceedings of the National Academy of Sciences of the United States of America 86: 448–452.

McPheeters DS, Christensen A, Young ET, Stormo G and Gold L (1986) Translational regulation of expression of the bacteriophage T4 lysozyme gene. Nucleic Acids Research 14: 5813–5826.

Min Jou W, Haegeman G, Ysebaert M and Fiers W (1972) Nucleotide sequence of the gene coding for the bacteriophage MS2 coat protein. Nature 237: 82–88.

Moore SD and Sauer RT (2007) The tmRNA system for translational surveillance and ribosome rescue. Annual Review of Biochemistry 76: 101–124.

Morita M, Kanemori M, Yanagi H and Yura T (1999a) Heat‐induced synthesis of sigma32 in E. coli: structural and functional dissection of rpoH mRNA secondary structure. Journal of Bacteriology 181: 401–410.

Morita MT, Tanaka Y, Kodama TS, et al. (1999b) Translational induction of heat shock transcription factor sigma32: evidence for a built‐in RNA thermosensor. Genes & Development 13: 655–665.

Nakatogawa H, Murakami A and Ito K (2004) Control of SecA and SecM translation by protein secretion. Current Opinion in Microbiology 7: 145–150.

Nivinskas R, Malys N, Klausa V, Vaiskunaite R and Gineikiene E (1999) Post‐transcriptional control of bacteriophage T4 gene 25 expression: mRNA secondary structure that enhances translational initiation. Journal of Molecular Biology 288: 291–304.

O'Connor M, Asai T, Squires CL and Dahlberg AE (1999) Enhancement of translation by the downstream box does not involve base pairing of mRNA with the penultimate stem sequence of 16S rRNA. Proceedings of the National Academy of Sciences of the United States of America 96: 8973–8978.

O'Connor M and Dahlberg AE (2001) Enhancement of translation by the epsilon element is independent of the sequence of the 460 region of 16S rRNA. Nucleic Acids Research 29: 1420–1425.

Olins PO and Rangwala SH (1989) A novel sequence element derived from bacteriophage T7 mRNA acts as an enhancer of translation of the lacZ gene in E. coli. Journal of Biological Chemistry 264: 16973–16976.

Peabody DS (1993) The RNA binding site of bacteriophage MS2 coat protein. EMBO Journal 12: 595–600.

Rex G, Surin B, Besse G, Schneppe B and McCarthy JE (1994) The mechanism of translational coupling in E. coli. Higher order structure in the atpHA mRNA acts as a conformational switch regulating the access of de novo initiating ribosomes. Journal of Biological Chemistry 269: 18118–18127.

Ringquist S, Shinedling S, Barrick D, et al. (1992) Translation initiation in Escherichia coli: sequences within the ribosome‐binding site. Molecular Microbiology 6: 1219–1229.

Rojiani M and Goldman E (1986) Dependence of MS2 and T4 phage growth upon host amino acid biosynthesis during infections of E. coli. Virology 150: 313–317.

Sacerdot C, Chiaruttini C, Engst K, et al. (1996) The role of the AUU initiation codon in the negative feedback regulation of the gene for translation initiation factor IF3 in Escherichia coli. Molecular Microbiology 21: 331–346.

Saito K, Mattheakis LC and Nomura M (1994) Post‐transcriptional regulation of the str operon in E. coli. Ribosomal protein S7 inhibits coupled translation of S7 but not its independent translation. Journal of Molecular Biology 235: 111–124.

Satchidanandam V and Shivashankar Y (1997) Availability of a second upstream AUG can completely overcome inhibition of protein synthesis initiation engendered by mRNA secondary structure encompassing the start codon. Gene 196: 231–237.

Schmeissner U, McKenney K, Rosenberg M and Court D (1984) Removal of a terminator structure by RNA processing regulates int gene expression. Journal of Molecular Biology 176: 39–53.

Schmidt H, Scheef J, Janetzki‐Mittmann C, Datz M and Karch H (1997) An ileX tRNA gene is located close to the Shiga toxin II operon in enterohemorrhagic Escherichia coli O157 and non‐O157 strains. FEMS Microbiology Letters 149: 39–44.

Schulz VP and Reznikoff WS (1990) In vitro secondary structure analysis of mRNA from lacZ translation initiation mutants. Journal of Molecular Biology 211: 427–445.

Schulz VP and Reznikoff WS (1991) Translation initiation of IS50R read‐through transcripts. Journal of Molecular Biology 221: 65–80.

Sengupta DJ, Wickens M and Fields S (1999) Identification of RNAs that bind to a specific protein using the yeast three‐hybrid system. RNA 5: 596–601.

Serganov A and Nudler E (2013) A decade of riboswitches. Cell 152: 17–24.

Sor F, Bolotin‐Fukuhara M and Nomura M (1987) Mutational alterations of translational coupling in the L11 ribosomal protein operon of E. coli. Journal of Bacteriology 169: 3495–3507.

Sprengart ML, Fuchs E and Porter AG (1996) The downstream box: an efficient and independent translation initiation signal in E. coli. EMBO Journal 15: 665–674.

Starck SR, Jiang V, Pavon‐Eternod M, et al. (2012) Leucine‐tRNA initiates at CUG start codons for protein synthesis and presentation by MHC class I. Science 336: 1719–1723.

Strome S and Young ET (1980) Translational discrimination against bacteriophage T7 gene 0.3 messenger RNA. Journal of Molecular Biology 136: 433–450.

Thomas LK, Dix DB and Thompson RC (1988) Codon choice and gene expression: synonymous codons differ in their ability to direct aminoacylated‐transfer RNA binding to ribosomes in vitro. Proceedings of the National Academy of Sciences of the United States of America 85: 4242–4246.

Tikole S and Sankararamakrishnan R (2006) A survey of mRNA sequences with a non‐AUG start codon in RefSeq database. Journal of Biomolecular Structure and Dynamics 24: 33–42.

Tu KC and Bassler BL (2007) Multiple small RNAs act additively to integrate sensory information and control quorum sensing in Vibrio harveyi. Genes & Development 21: 221–233.

Urban JH and Vogel J (2008) Two seemingly homologous noncoding RNAs act hierarchically to activate glmS mRNA translation. PLoS Biology 6: e64.

Wakita T, Moradpour D, Tokushihge K and Wands JR (1999) Antiviral effects of antisense RNA on hepatitis C virus RNA translation and expression. Journal of Medical Virology 57: 217–222.

Wikstrom PM, Lind LK, Berg DE and Bjork GR (1992) Importance of mRNA folding and start codon accessibility in the expression of genes in a ribosomal protein operon of E. coli. Journal of Molecular Biology 224: 949–966.

Yasueda H, Takechi S, Sugiyama T and Itoh T (1994) Control of ColE2 plasmid replication: negative regulation of the expression of the plasmid‐specified initiator protein, Rep, at a posttranscriptional step. Molecular & General Genetics 244: 41–48.

Yoshida T, Qin L, Egger LA and Inouye M (2006) Transcription regulation of ompF and ompC by a single transcription factor, OmpR. Journal of Biological Chemistry 281: 17114–17123.

Zahn K and Landy A (1996) Modulation of lambda integrase synthesis by rare arginine tRNA. Molecular Microbiology 21: 69–76.

Zhang SP, Zubay G and Goldman E (1991) Low‐usage codons in E. coli, yeast, fruit fly and primates. Gene 105: 61–72.

Zhang J and Deutscher MP (1992) A uridine‐rich sequence required for translation of prokaryotic mRNA. Proceedings of the National Academy of Sciences of the United States of America 89: 2605–2609.

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.

Jackson RJ (2005) Alternative mechanisms of initiating translation of mammalian mRNAs. Biochemical Society Transactions 33: 1231–1241.

Lindahl L and Hinnebusch A (1992) Diversity of mechanisms in the regulation of translation in prokaryotes and lower eukaryotes. Current Opinion in Genetics and Development 2: 720–726.

Lodish HF (1976) Translational control of protein synthesis. Annual Review of Biochemistry 45: 39–72.

Mathews MB, Sonenberg N and Hershey JWB (eds) (2018) Translation Mechanisms and Control. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.

McCarthy JE and Gualerzi C (1990) Translational control of prokaryotic gene expression. Trends in Genetics 6: 78–85.

Papenfort K and Vanderpool CK (2015) Target activation by regulatory RNAs in bacteria. FEMS Microbiology Review 39: 362–378.

Quax TE, Claassens NJ, Söll D and van der Oost J (2015) Codon bias as a means to fine‐tune gene expression. Molecular Cell 59: 149–161.

Rana TM (2007) Illuminating the silence: understanding the structure and function of small RNAs. Nature Reviews. Molecular Cell Biology 8: 23–36.

de Smit MH and van Duin J (1990) Control of prokaryotic translational initiation by mRNA secondary structure. Progress in Nucleic Acid Research and Molecular Biology 38: 1–35.

Storz G, Altuvia S and Wassarman KM (2005) An abundance of RNA regulators. Annual Review of Biochemistry 74: 199–217.

Wagner EG and Simons RW (1994) Antisense RNA control in bacteria, phages, and plasmids. Annual Review of Microbiology 48: 713–742.

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