mRNA Turnover


mRNA stability is an important facet of regulated gene expression and RNA surveillance systems. mRNA turnover is intimately coupled to the process of translation; the stability of normal mRNAs broadly correlates with their efficiency of translation, while the mechanisms that initiate nonsense‐mediated decay and no‐go/nonstop decay mRNA quality control systems are closely linked to the events of normal translation termination. The general mechanisms of mRNA turnover are well conserved throughout eukaryotic systems and the enzymes involved are closely related to those that act in mRNA degradation in bacterial systems. Notwithstanding this, metazoan systems have developed more diverse and specialised systems. Notably, mammalian transcripts are subject to regulation through factors involved in ARE‐mediated decay and a set of decapping activities. Capping of transcripts with NAD appears to reflect a widespread quality control mechanism throughout biological systems.

Key Concepts

  • mRNA stability plays an important role in regulated gene expression.
  • mRNA surveillance mechanisms act on both aberrant and physiological transcripts.
  • mRNA turnover mechanisms involve multiple redundant pathways.
  • mRNA degradation is cotranslational.
  • The mRNA cap structure is the target of several quality control systems.

Keywords: exonuclease; deadenylase; mRNA surveillance; m7G cap; poly(A) binding protein

Figure 1. Pathways for nonstop decay in bacteria and eukaryotic systems. (a) The tmRNA/SmpB complex is recruited to the empty A site of a ribosome stalled at the end of the mRNA. Transpeptidation transfers the translated polypeptide to the alanyl residue at the 3′ end of tmRNA and a degron tag is added to the C‐terminal end by translation of the short ORF within tmRNA (indicated in green). Upon RF1/RF3‐mediated termination, the tagged polypeptide product is released and the ribosomal subunits dissociate. Proteases such as tail‐specific protease Tsp degrade the degron‐tagged polypeptide, while the exonuclease RNase R degrades the released mRNA. (b) The Ski7/exosome complex is recruited to the A site of ribosome complexes that are stalled at the end of the mRNA. The SKI complex, comprising the RNA helicase Ski2 (shown in red), Ski3 (shown in pale blue) and two copies of Ski8 (shown in pale green), is then recruited to the exosome. Hbs1 and Dom34 factors are important for ribosome subunit dissociation. The exosome/SKI complex degrades the mRNA, the Ski2 helicase unfolding the RNA and threading it through the core of the exosome to the catalytic subunit Rrp44 (also known as Dis3). The polypeptide product is targeted to ubiquitylation and degradation by the proteasome.
Figure 2. mRNA stability correlates with the mRNA translation elongation rate. (a) mRNAs containing optimal codons, which are efficiently translated and allow fast elongation rates, can produce high yields of protein and are stable. (b) In contrast, mRNAs that contain nonoptimal codons undergo decreased elongation rates, produce less protein and are more rapidly degraded. The RNA helicase Dhh1 is required for the accelerated degradation of mRNAs with nonoptimal codons. Dhh1 preferentially interacts with nonoptimal mRNAs and binds nonspecifically along the length of the transcript. The degradation of nonoptimal mRNAs reflects ‘stacking up’ of slowly elongating ribosomes along the mRNA. Notably, the degradation pathway of nonoptimal mRNAs is distinct from other established pathways such as NGD. The recruitment of an RNA helicase to ribosomes in a poor context for translation (elongation) is reminiscent of the role of Upf1 in NMD.
Figure 3. Quality control pathways of mRNA capping. (a) Capping of the mRNA normally occurs when the RNA polymerase II (pol II) transcript is ∼30 nucleotides long. The capping complex is recruited to the carboxy‐terminal domain of pol II and introduces the m7G cap through a three‐step process involving hydrolysis of the terminal γ‐phosphate, addition of a guanylate moiety, and methylation of the guanyl cap. (b) Noncapped transcripts or capped but nonmethylated transcripts can be degraded through the recruitment of decapping activities. (c) In the absence of the canonical capping reaction, transcripts can be capped with NAD. ‘NADding’ promotes mRNA degradation in human cells by the decapping/exonuclease enzyme DXO.


Atkins JF and Gesteland RF (1996) A case for trans translation. Nature 379: 769–771.

Beelman CA, Stevens A, Caponigro G, et al. (1996) An essential component of the decapping enzyme required for normal rates of mRNA turnover. Nature 382: 642–646.

Bird JG, Zhang Y, Tian Y, et al. (2016) The mechanism of RNA 5' capping with NAD+, NADH and desphospho‐CoA 5. Nature 535: 444–447.

Bregman A, Avraham‐Kelbert M, Barkai O, et al. (2011) Promoter elements regulate cytoplasmic mRNA decay. Cell 147: 1473–1483.

Brengues M, Teixeira D and Parker R (2005) Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies. Science 310: 486–489.

Cahová H, Winz M‐L, Höfer K, Nübel G and Jäschke A (2014) NAD captureSeq indicates NAD as a bacterial cap for a subset of regulatory RNAs. Nature 519: 374–377.

Carpousis AJ (2002) The Escherichia coli RNA degradosome: structure, function and relationship in other ribonucleolytic multienzyme complexes. Biochemical Society Transactions 30: 150–155.

Celik A, Baker R, He F and Jacobson A (2017) High‐resolution profiling of NMD targets in yeast reveals translational fidelity as a basis for substrate selection. RNA 23: 735–748.

Chang JH, Jiao X, Chiba K, et al. (2012) Dxo1 is a new type of eukaryotic enzyme with both decapping and 5′‐3′ exoribonuclease activity. Nature Structural & Molecular Biology 19: 1011–1017.

Chen CY and Shyu AB (1995) AU‐rich elements: characterization and importance in mRNA degradation. Trends in Biochemical Sciences 20: 465–470.

Chlebowski A, Lubas M, Jensen TH and Dziembowski A (2013) RNA decay machines: the exosome. Biochimica et Biophysica Acta 1829: 552–560.

Chou C‐F, Mulky A, Maitra S, et al. (2006) Tethering KSRP, a decay‐promoting AU‐rich element‐binding protein, to mRNAs elicits mRNA decay. Molecular and Cellular Biology 26: 3695–3706.

Coller J and Parker R (2005) General translational repression by activators of mRNA decapping. Cell 122: 875–886.

Daugeron MC, Mauxion F and Séraphin B (2001) The yeast POP2 gene encodes a nuclease involved in mRNA deadenylation. Nucleic Acids Research 29: 2448–2455.

Decker CJ and Parker R (1993) A turnover pathway for both stable and unstable mRNAs in yeast: evidence for a requirement for deadenylation. Genes & Development 7: 1632–1643.

van Dijk E, Cougot N, Meyer S, et al. (2002) Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures. EMBO Journal 21: 6915–6924.

Doma MK and Parker R (2006) Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature Cell Biology 440: 561–564.

Fabian MR, Mathonnet G, Sundermeier T, et al. (2009) Mammalian miRNA RISC recruits CAF1 and PABP to affect PABP‐dependent deadenylation. Molecular Cell 35: 868–880.

Fabian MR, Cieplak MK, Frank F, et al. (2011) miRNA‐mediated deadenylation is orchestrated by GW182 through two conserved motifs that interact with CCR4‐NOT. Nature Structural & Molecular Biology 18: 1211–1217.

Gherzi R, Lee K‐Y, Briata P, et al. (2004) A KH domain RNA binding protein, KSRP, promotes ARE‐directed mRNA turnover by recruiting the degradation machinery. Molecular Cell 14: 571–583.

Halbach F, Reichelt P, Rode M and Conti E (2013) The yeast ski complex: crystal structure and RNA channeling to the exosome complex. Cell 154: 814–826.

Hilleren P and Parker R (1999) mRNA surveillance in eukaryotes: kinetic proofreading of proper translation termination as assessed by mRNP domain organization? RNA 5: 711–719.

van Hoof A, Frischmeyer PA, Dietz HC and Parker R (2002) Exosome‐mediated recognition and degradation of mRNAs lacking a termination codon. Science 295: 2262–2264.

Hu W, Sweet TJ, Chamnongpol S, Baker KE and Coller J (2009) Co‐translational mRNA decay in Saccharomyces cerevisiae. Nature 461: 225–229.

Hu W, Petzold C, Coller J and Baker KE (2010) Nonsense‐mediated mRNA decapping occurs on polyribosomes in Saccharomyces cerevisiae. Nature Structural & Molecular Biology 17: 244–247.

Huter P, Müller C, Arenz S, Beckert B and Wilson DN (2017) Structural basis for ribosome rescue in bacteria. Trends in Biochemical Sciences 42: 669–680.

Ishigaki Y, Li X, Serin G and Maquat LE (2001) Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense‐mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell 106: 607–617.

Jiao X, Xiang S, Oh C, et al. (2010) Identification of a quality‐control mechanism for mRNA 59‐end capping. Nature 467: 608–611.

Jiao X, Chang JH, Kilic T, Tong L and Kiledjian M (2013) A mammalian pre‐mRNA 5′ prime end capping quality control mechanism and an unexpected link of capping to pre‐mRNA processing. Molecular Cell 50: 104–115.

Jiao X, Doamekpor SK, Bird JG, et al. (2017) End nicotinamide adenine dinucleotide cap in human cells promotes RNA decay through DXO‐mediated deNADding. Cell 168: 1015–1027.

Körner CG and Wahle E (1997) Poly(A) tail shortening by a mammalian poly(A)‐specific 3'‐exoribonuclease. Journal of Biological Chemistry 272: 10448–10456.

Kurosaki T, Li W, Hoque M, et al. (2014) A post‐translational regulatory switch on UPF1 controls targeted mRNA degradation. Genes & Development 28: 1900–1916.

Le Hir H, Izaurralde E, Maquat LE and Moore MJ (2000) The spliceosome deposits multiple proteins 20–24 nucleotides upstream of mRNA exon‐exon junctions. EMBO Journal 19: 6860–6869.

Liu H, Rodgers ND, Jiao X and Kiledjian M (2002) The scavenger mRNA decapping enzyme DcpS is a member of the HIT family of pyrophosphatases. EMBO Journal 21: 4699–4708.

Maquat LE (1995) When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. RNA 1: 453–465.

Maquat LE, Tarn W‐Y and Isken O (2010) The pioneer round of translation: features and functions. Cell 142: 368–374.

Mauer J, Luo X, Blanjoie A, et al. (2017) Reversible methylation of m6Am in the 5' cap controls mRNA stability. Nature 541: 371–375.

Pelechano V, Wei W and Steinmetz LM (2015) Widespread co‐translational RNA decay reveals ribosome dynamics. Cell 161: 1400–1412.

Presnyak V, Alhusaini N, Chen Y‐H, et al. (2015) Codon optimality is a major determinant of mRNA stability. Cell 160: 1111–1124.

Radhakrishnan A, Chen Y‐H, Martin S, et al. (2016) The DEAD‐Box Protein Dhh1p Couples mRNA Decay and Translation by Monitoring Codon Optimality. Cell 167: 122–128.e9.

Schmidt C, Kowalinski E, Shanmuganathan V, et al. (2016) The cryo‐EM structure of a ribosome‐Ski2‐Ski3‐Ski8 helicase complex. Science 354: 1431–1433.

Sheth U and Parker R (2003) Decapping and decay of messenger RNA occur in cytoplasmic processing bodies. Science 300: 805–808.

Shyu AB, Belasco JG and Greenberg ME (1991) Two distinct destabilizing elements in the c‐fos message trigger deadenylation as a first step in rapid mRNA decay. Genes & Development 5: 221–231.

Song M‐G, Li Y and Kiledjian M (2010) Multiple mRNA decapping enzymes in mammalian cells. Molecular Cell 40: 423–432.

Song MG, Bail S and Kiledjian M (2013) Multiple Nudix family proteins possess mRNA decapping activity. RNA 19: 390–399.

Tsuboi T, Kuroha K, Kudo K, et al. (2012) Dom34:Hbs1 plays a general role in quality control systems by dissociation of a stalled ribosome at the 3' end of aberrant mRNA. Molecular Cell 46: 518–529.

Tucker M, Valencia‐Sanchez MA, Staples RR, et al. (2001) The transcription factor associated Ccr4 and Caf1 proteins are components of the major cytoplasmic mRNA deadenylase in Saccharomyces cerevisiae. Cell 104: 377–386.

Walters RW, Matheny T, Mizoue LS, et al. (2017) Identification of NAD+ capped mRNAs in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America 109 (941–946): 114.

Wang Z and Kiledjian M (2001) Functional link between the mammalian exosome and mRNA decapping. Cell 107: 751–762.

Further Reading

Graille M and Séraphin B (2012) Surveillance pathways rescuing eukaryotic ribosomes lost in translation. Nature Reviews. Molecular Cell Biology 13: 727–735.

Grudzien‐Nogalska E and Kiledjian M (2016) New insights into decapping enzymes and selective mRNA decay. WIREs RNA 8: e1379.

Hui MP, Foley PL and Belasco JG (2014) Messenger RNA degradation in bacterial cells. Annual Review of Genetics 48: 537–559.

Iwakawa H‐O and Tomari Y (2015) The functions of MicroRNAs: mRNA decay and translational repression. Trends in Cell Biology 25: 651–665.

Kurosaki T and Maquat LE (2016) Nonsense‐mediated mRNA decay in humans at a glance. Journal of Cell Science 129: 461–467.

Lykke‐Andersen S and Jensen TH (2015) Nonsense‐mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nature Reviews. Molecular Cell Biology 16: 665–677.

Molleston J and Cherry S (2017) Attacked from all sides: RNA decay in antiviral defense. Viruses 9: 2.

Singh G, Pratt G, Yeo GW and Moore MJ (2015) The clothes make the mRNA: past and present trends in mRNP fashion. Annual Review of Biochemistry 84: 325–354.

Wu X and Brewer G (2012) The regulation of mRNA stability in mammalian cells: 2.0. Gene 500: 10–21.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Mitchell, Philip(Mar 2018) mRNA Turnover. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005981.pub2]