mRNA Stability

Abstract

The steady‐state level of a messenger ribonucleic acid (mRNA) is determined by both its rate of synthesis and degradation. The degradation of mRNA is an important tool employed by cells to control gene expression and to adjust the level of protein synthesis in response to physiological needs or environmental signals. The degradation of mRNA in all organisms is mastered by a rather restricted number of enzymes with major (endo‐ and exoribonucleases) and ancillary (e.g. RNA helicases) functions. Some of these enzymes are phylogenetically conserved across the three domains of life – bacteria, archaea and eukarya. Moreover, the main components of the RNA decay machinery can associate with each other to form multienzyme complexes, which makes it possible to coordinate and control mRNA decay in vivo.

  • The stability of individual mRNAs varies and is dependent on intrinsic properties of transcripts (i.e. specific structure and sequence) and action of trans‐encoded regulatory factors.
  • The enzymes and ancillary factors involved in mRNA decay in pro‐ and eukaryotic organisms can associate with each other to form multienzyme complexes such as degradosomes or exosomes.
  • Mechanisms of mRNA decay in pro‐ and eukaryotes share many common steps.
  • Pro‐ and eukaryotic cells use specific mechanisms to eliminate defective mRNAs.
  • Numerous noncoding RNAs control mRNA decay in pro‐ and eukaryotes.

Keywords: mRNA decay; noncoding RNAs; RNases; RNA‐binding proteins; polyadenylation

Figure 1. General mRNA decay pathways in bacteria. (a) The 5′‐dependent mRNA decay in E. coli is initiated by pyrophosphate removal, followed by endonucleolytic cleavage of the 5′‐monophosphate‐dependent RNase E. The resulting 5′ fragment is then degraded by 3′ to 5′ exonucleases like PNPase, RNase R or RNase II. On the first RNase E cleavage, the downstream fragment is endowed with a 5′‐monophosphate, which serves as a signal for the next endonucleolytic cut by RNase E. Repeated cycles of RNase E‐dependent endonucleolytic cleavages and exoribonucleolytic decay finally lead to 5′ to 3′ directional decay of the mRNA. The 3′ end of the mRNA containing a stem–loop structure might be first (1) polyadenylated by poly(A) polymerase I (PAPI) or (2) partly unfolded by RhlB helicase, and then exonucleolytically degraded. As the PNPase‐ and RNase II‐mediated processing ultimately yields short oligonucleotides, their further conversion to mononucleotides is accomplished by oligoribonuclease (OligoRNase). (b) In B. subtilis, the major pathway of mRNA decay (pathway I) starts with pyrophosphate removal followed by endonucleolytic cleavage in the 5′ part of the mRNA by RNase Y. The resulting decay intermediates are further degraded by the concerted action of 3′ to 5′ (e.g. PNPase) and 5′ to 3′ (i.e. RNase J1) exonucleases. Alternatively, due to the presence of 5′ monophosphate, which serves as a signal for the 5′ to 3′ exoribonuclease activity of RNase J1, RNA decay can commence in 5′ to 3′ direction immediately after pyrophosphate removal (pathway II).
Figure 2. Alternative (‘direct entry’) mRNA decay pathways in bacteria. In some cases, mRNA decay is directly initiated by endonucleolytic cut made by RNase E (panel a) or RNase III (panel b) in E. coli or by RNase J1 (panel c) in B. subtilis. The resulting intermediate products are further degraded in the same manner as decay intermediates produced in the 5′end dependent pathways presented in Figure .
Figure 3. Principal mRNA decay pathways in eukaryotes. After sequential removal of the 3′ poly(A) tail by Pan2/Pan3 and Ccr4/Not (panel a), the deadenylated mRNA can further be degraded according to uridylation‐independent (panel b) and uridylation‐dependent (panel c) pathways. According to the first one (panel b), deadenylation leads to assembly of the Pat1/Lsm1–7 protein complex at the 3′ end of the transcript, thus triggering decapping by DCP. Once decapped, mRNA is degraded in 5′ to 3′ direction by the exoribonuclease Xrn1 (left). Alternatively, the exosome recruited in a Ski‐dependent manner can degrade the mRNA in 3′ to 5′ direction (right). Apart from the above mechanisms, degradation of some deadenylated mRNAs includes uridylation (panel c). This modification promotes decay mediated by both Xrn1‐dependent and exosome‐dependent mechanisms.
Figure 4. Specialized mRNA decay pathways employed by pro‐ and eukaryotes to eliminate aberrant transcripts. (a) The surveillance of prokaryotic mRNAs lacking in‐frame stop codon is mediated by a tmRNA‐dependent mechanism evolutionarily conserved in bacteria. The stalling of the ribosome that reaches the end of the coding region induces ribosome interaction with tmRNA and subsequently triggers the process of trans‐translation (for details, see text). The latter facilitates RNase R binding to the 3′ end of the defect transcripts and their 3′ to 5′ exonucleolytic decay. (b) Schematically shown are the nonsense‐mediated decay (NMD), the nonstop decay (NSD) and the no‐go decay (NGD) used by eukaryotic organisms to eliminate non‐functional mRNAs. For explanations, see text.
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Further Reading

De Almeida C, Scheer H, Zuber H and Gagliardi D (2018) RNA uridylation: a key posttranscriptional modification shaping the coding and noncoding transcriptome. WIREs RNA 9: e1440.

Evguenieva‐Hackenberg E and Bläsi U (2013) Attack from both ends: mRNA degradation in the crenarchaeon Sulfolobus solfataricus. Biochemical Society Transactions 41: 379–383.

Kaberdin V and Bläsi U (2006) Translation initiation and the fate of bacterial mRNAs. FEMS Microbiology Reviews 30: 967–979.

Łabno A, Tomecki R and Dziembowski A (2016) Cytoplasmic RNA decay pathways – enzymes and mechanisms. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research 1863: 3125–3147.

Trinquier A, Durand S, Braun F and Condon C Regulation of RNA processing and degradation in bacteria. Biochimica et Biophysica Acta (BBA) – Gene Regulatory Mechanisms 2020, 1863: 194505.

Wilson RC and Doudna JA (2013) Molecular mechanisms of RNA interference. Annual Review of Biophysics 42: 217–239.

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Kaberdin, Vladimir(Aug 2020) mRNA Stability. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029146]