Cytoplasmic RNA Decay

Abstract

RNA (ribonucleic acid) molecules play vital roles in the eukaryotic cells, not only as mediators of the flow of genetic information from DNA (deoxyribonucleic acid) to proteins but also as potent regulators of gene expression in general. Ubiquitous transcription of the eukaryotic genome, occurring in the cell nucleus, leads to the synthesis of multiple precursor RNA molecules, which undergo class‐dependent, very often complex processing events, eventually generating mature transcripts, such as mRNAs, tRNAs and rRNAs, serving as templates, adaptors and effectors, respectively, during translation. In addition, numerous noncoding RNAs (ncRNAs) are produced, which fine‐tune gene expression at different stages. Protein‐coding transcripts and many ncRNAs exert their functions in the cytoplasm. Levels of different RNA species are controlled by numerous cytoplasmic decay pathways, largely dependent on specific modifications of transcripts' ends and various enzymatic activities, including endo‐ and exoribonucleases. Moreover, RNA molecules are scrutinised for errors which may potentially impair their function by dedicated surveillance mechanisms.

Key Concepts

  • Eukaryotic genomes are almost entirely transcribed, giving rise to mRNAs, which code for proteins, and to multiple noncoding RNA classes, which impact gene expression at different levels.
  • Posttranscriptional regulation of RNA stability represents one of the major means of controlling expression of genetic information in eukaryotes. Cytoplasm is the site of RNA decay for those transcripts which function in this subcellular compartment.
  • Cytoplasmic mRNA decay in eukaryotes can be initiated by internal endonucleolytic cleavage or, more frequently, through digestion of nucleotides starting at the 5′‐ or the 3′‐end and carried out by 5′ to 3′ or 3′ to 5′ exoribonucleases, respectively.
  • mRNA termini are protected by the 5′‐cap structure and (with the exception of mammalian histone‐coding transcripts) 3′ poly(A) tail with bound proteins; these protective elements are usually removed before exonucleolytic degradation.
  • Poly(A) tail shortening (deadenylation) and extension with untemplated uridine residues (uridylation) are the most common signals triggering exonucleolytic mRNA degradation; nonpolyadenylated mRNA coding for replication‐dependent histones in mammals can also undergo uridylation, which may stimulate removal of the protective 3′ stem‐loop structure.
  • Deadenylation or uridylation provokes cap elimination from the 5′‐end (decapping) and 5′–3′ decay by Xrn1 enzyme; alternatively, mRNA can be degraded in the opposite (3′–5′) direction by the catalytic activities associated with the multisubunit exosome complex or in an exosome‐independent pathway controlled by DIS3L2 exonuclease, stimulated by uridylation.
  • Aberrant mRNAs, containing premature termination codons, devoid of stop codons or messengers, on which ribosomes tend to stall during translation, are removed by cytoplasmic quality control mechanisms, such as NMD, NSD and NGD. A common feature of these surveillance pathways is their dependence on ongoing protein synthesis. Notably, final phases of faulty mRNA decay in NMD/NSD/NGD are essentially carried out by the same exonucleases which control regular mRNA turnover.
  • One of the major NMD factors is Upf1 RNA helicase, which interacts with a dimer of canonical ribosome release factors, eRF3 GTPase‐eRF1, when translation terminates on premature stop codon. On the contrary, NSD and NGD are Upf1‐independent processes, employing Ski7 GTPase‐like protein and Hbs1–Dom34 complex, structurally resembling eRF3–eRF1 dimer.
  • Quality of some stable ncRNAs, such as tRNAs and rRNAs, can also be interrogated in the cytoplasm by dedicated surveillance mechanisms, which depend to some extent on regular and aberrant mRNA decay factors.
  • Decay pathways for a diversified group of unstable RNA species, generated by ubiquitous transcription or untypical processing of larger molecules, are less well characterised, and for some ncRNA classes remain obscure. Depending on the organism and transcript architecture, different enzymes can be involved in removal of such transcripts from the cytoplasm of wild‐type cells. Some ncRNAs are degraded by nucleases that control mRNA fate, such as Xrn1, exosome and DIS3L2, but for other noncoding transcripts, unique cytoplasmic degradative pathways emerged during evolution.

Keywords: RNA decay; deadenylation; uridylation; decapping; exoribonuclease; mRNA quality control; NMD; NSD; NGD; noncoding RNA (ncRNA)

Figure 1. Deadenylation and uridylation of poly(A)+ mRNAs (messenger ribonucleic acids) activate 5′–3′ decay pathway, involving decapping and Xrn1‐mediated degradation. mRNA adopts a closed‐loop structure, stabilised by interaction between eIF4F complex attached to the 5′‐cap and PABPs deposited on 3′‐terminal poly(A) tail. Its disruption can be achieved by poly(A) tail shortening (deadenylation) or untemplated addition of oligouridine tails (uridylation). Both these phenomena stimulate interaction of the Lsm1‐7‐Pat1 assembly with the mRNA 3′‐end, which targets decapping machinery to the 5′‐terminus. Conversion of cap to monophosphate (decapping) sensitises the transcript to 5′–3′ digestion by Xrn1.
Figure 2. Deadenylated and uridylated mRNAs can undergo 3′–5′ degradation, performed by the exosome complex and DIS3L2 exonuclease. Deprotection of the 3′‐end, resulting from the action of deadenylases or PUPs makes the transcript vulnerable to exonucleolytic digestion in the 3′–5′ direction. Two major cytoplasmic nucleases involved in this degradation pathways are the exosome complex (comprising DIS3/DIS3L enzyme), which works in cooperation with Ski7 protein and an accessory SKI complex, and an exosome‐independent exoribonuclease DIS3L2, evolutionary related to the main exosome catalytic subunits. The latter has a high preference towards 3′‐uridylated RNA species. Final degradation of the short capped oligonucleotide fragments is performed by a scavenger decapping enzyme.
Figure 3. Nonpolyadenylated metazoan histone‐encoding mRNAs are degraded in several parallel pathways, largely regulated by SLBP and 3′ uridylation. Histone mRNAs are not polyadenylated but instead contain a highly conserved stem‐loop (SL) structure, followed in vertebrates by an ACC sequence. SLBP binds to this stem‐loop and may interact with PUP, which uridylates 3′ terminus. This in turn stimulates decapping and 5′–3′ degradation by Xrn1. Alternatively, repetitive cycles of uridylation and digestion catalysed by ERI1 enzyme, together with activity of UPF1 RNA helicase can lead to SL removal and subsequent mRNA degradation by the exosome. Uridylated 3′ termini can also be recognised by DIS3L2 exoribonuclease.
Figure 4. NMD pathways in mammalian cells. A ribosome terminating on PTC (premature termination codon) associates with eRF1–eRF3 factors, which together with SMG1 kinase and UPF1 factor form a SURF complex. SURF is able to interact with EJC deposited on a downstream exon–exon junction via UPF2 and UPF3 factors. eRF1 and eRF3 are responsible for ribosome dissociation. A displacement of SMG8–SMG9 dimer of SMG1 interactors allows for UPF1 phosphorylation at different sites within its C‐terminal and N‐terminal domains. Depending on the UPF1 phosphorylation status, aberrant mRNA decay can be triggered by either SMG6 PIN domain endonucleolytic cleavage, SMG5–SMG7‐mediated stimulation of deadenylation, or decapping, which can be stimulated by PNRC2 factor. Final degradation phases employ exonucleases involved in normal mRNA turnover.
Figure 5. NSD (nonstop decay) and NGD (no‐go decay) quality control mechanisms are induced by ribosome stalling and are dependent mainly on Ski7 and Dom34–Hbs1–Rli1 factors. The lack of stop codon, which can be due to premature polyadenylation or cleavage of the messenger within open‐reading frame, results in the inhibition of ribosome progression during protein synthesis. Stalled ribosome associates with Ski7 protein, bridging interactions between the SKI and exosome complexes, performing degradation of the faulty nonstop mRNA, which can be catalysed by both exo‐ and endonucleolytic exosome activities. In the case of no‐go decay pathway, stalling of the ribosome induces upstream cleavage of the transcript by a yet‐unidentified endonuclease. Proximal and distal cleavage products are digested by the exosome and Xrn1, respectively. NSD and NGD converge on the involvement of Dom34–Hbs1, together with Rli1 factor, in the recycling of ribosomes stalled on nonstop or stop codon‐less mRNAs.
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Drazkowska, Karolina, and Tomecki, Rafal(Oct 2017) Cytoplasmic RNA Decay. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027365]