mRNA Turnover

Abstract

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.
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Mitchell, Philip(Mar 2018) mRNA Turnover. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005981.pub2]