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Ribosome dynamics and mRNA turnover, a complex relationship under constant cellular scrutiny

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Abstract Eukaryotic gene expression is closely regulated by translation and turnover of mRNAs. Recent advances highlight the importance of translation in the control of mRNA degradation, both for aberrant and apparently normal mRNAs. During translation, the information contained in mRNAs is decoded by ribosomes, one codon at a time, and tRNAs, by specifically recognizing codons, translate the nucleotide code into amino acids. Such a decoding step does not process regularly, with various obstacles that can hinder ribosome progression, then leading to ribosome stalling or collisions. The progression of ribosomes is constantly monitored by the cell which has evolved several translation‐dependent mRNA surveillance pathways, including nonsense‐mediated decay (NMD), no‐go decay (NGD), and non‐stop decay (NSD), to degrade certain problematic mRNAs and the incomplete protein products. Recent progress in sequencing and ribosome profiling has made it possible to discover new mechanisms controlling ribosome dynamics, with numerous crosstalks between translation and mRNA decay. We discuss here various translation features critical for mRNA decay, with particular focus on current insights from the complexity of the genetic code and also the emerging role for the ribosome as a regulatory hub orchestrating mRNA decay, quality control, and stress signaling. Even if the interplay between mRNA translation and degradation is no longer to be demonstrated, a better understanding of their precise coordination is worthy of further investigation. This article is categorized under: RNA Turnover and Surveillance > Regulation of RNA Stability Translation > Translation Regulation RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes
Translation termination at a normal stop codon and at a premature termination codon. (a) Normal translation termination. Panel 1: The translating 80S ribosome, composed of 60S and 40S subunits, encounters the STOP codon (red STOP sign) located near the poly(a) tail bound by PABPC1 in mammals. Ribosomal A‐site, P‐site, and E‐site are indicated. tRNAs are bound in the P‐site and E‐site. PABPC1 promotes the recruitment of the eRF1 and eRF3a release factors to the ribosomal A‐site. Panel 2: After GTP hydrolysis by eRF3a, eRF1 triggers hydrolysis of the peptidyl‐tRNA, releasing the completed nascent protein. This leaves a ribosome still bound to the mRNA, which has to be disassembled and recycled. Panel 3: The ribosome recycling factor ABCE1 is recruited and it supports, with help of other initiation factors, the dissociation of the 80S ribosome into 40S and 60S subunits, which can then be recycled for extra rounds of translation. (b) Translation termination at a premature termination codon (PTC) and induction of nonsense‐mediated mRNA decay (NMD). Panel 1: The ribosome stops at a PTC located upstream of an EJC and distant from the normal stop codon. The presence of the NMD factor UPF3B at the EJC allows the association of eRF1 and eRF3a in the ribosomal A‐site. Panel 2: A truncated protein product is released through the action of eRF3a and eRF1. Panel 3: Ribosome dissociation is mediated by ABCE1 together with UPF3B. Subsequently, UPF2 and UPF3B are thought to activate the SMG1 kinase for UPF1 phosphorylation. Panel 4: Phosphorylated UPF1 mainly associates with the SMG5‐SMG7 complex which recruits decapping and deadenylation activities (1), followed by the exoribonucleases with 5′‐to‐3′ (XRN1) and 3′‐to‐5′ (exosome or DIS3L2) activities (2). In addition, phospho‐UPF1 can recruit the endonuclease SMG6 that cleaves RNA in the vicinity of the PTC
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Ribosome‐dependent piRNA processing during mouse spermatogenesis. (a) piRNA precursors are capped and polyadenylated RNAs that reach the cytoplasm and associate with the translational machinery. Ribosomes translate the 5′ proximal short ORFs to produce short peptides of unknown function. (b) Upon reaching the stop codon of short ORFs, ribosomes fail to dissociate from the piRNA precursor and instead translocate downstream in a MOV10L1‐dependent non‐canonical manner. (c) The endonuclease PLD6 cleaves the 5′ end of the ribosome‐protected piRNA precursor, followed by the non‐canonical translocation of the ribosome to the next downstream PLD6 cleavage site. (d) A PIWI protein is recruited at the 5′‐extremity of the PLD6‐generated fragment while a second ribosome‐protected PLD6‐dependent cleavage event occurs downstream. (e) The 5′ PIWI‐bound RNA fragment is trimmed at its 3′ end by PNLDC1 to produce the mature piRNA sequence that is further chemically modified. The 3′ ribosome‐bound fragment associates with a new PIWI protein while the ribosome translocates downstream to mark the next PLD6 cleavage site
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Impact of the m6A methylation on mRNA fate. The m6A modification can regulate the fate of modified mRNAs in different ways, that is, enhanced translation, mRNA decay, and mRNA stabilization, depending on which reader protein is present, the mRNA region enriched in m6A, and the specific cellular context. The m6A readers that promote translation are YTHDF1, YTHDF3, METTL3, YTHDC2, and eIF3. The m6A readers that promote mRNA decay are YTHDF2, YTHDF3, and YTHDC2. YTHDF2 induces mRNA decay by recruiting either the CCR4–Not complex or the endonuclease RNase P/MRP via HRSP12. YTHDF3 promotes mRNA degradation by recruiting the PAN2–PAN3 deadenylase complex. YTHDC2 exerts a dual function of stimulating both translation and decay of its targeted transcripts. Also, YTHDF1/2/3 share common target mRNAs and their fate seems to be regulated in a coordinated manner. The ribosome can serve as a scaffold for the m6A reader YTHDC2. Lastly, IGF2BP1/2/3 stabilize their target mRNAs
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GC3 content, amino acid identity, and RBPs modulate translation‐dependent mRNA degradation in mammals. (a) Possible factors implicated in codon‐dependent mRNA destabilization in mammals. (b) Barplot representing the percentage of GC3 and AU3 codons among optimal and non‐optimal codons as defined for endogenous mRNAs or ORFeome reporters with fixed UTRs and variable codons in the CDS from different cell types as obtained from the literature. In most studies, optimal codons are mainly GC3, while non‐optimal codons are enriched in AU3. (c) FMRP deficiency in mouse primary neurons leads to an inversion in the GC3 and AU3 content of optimal and non‐optimal codons
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Codon‐dependent mRNA decay in yeast and zebrafish. In yeast, the kinetics of tRNA recruitment at the A‐site of elongating ribosomes is a major determinant of mRNA stability. (a) mRNAs with optimal codons (corresponding to abundant tRNAs) mediate efficient recruitment of tRNAs in the A‐site of elongating ribosomes and display long half‐lives. (b) If peptidyl transfer is slow but an optimal codon resides at the ribosome A‐site, the ribosome will bear an empty E‐site and an accommodated A‐site. This conformation allows recruitment of eIF5A to the E‐site to promote peptidyl transfer activity and rescue the stalled ribosome. (c) If a non‐optimal codon is present at the ribosome A‐site, tRNA accommodation will take longer than for an optimal codon and this increases the probability of the ribosome to bear empty E‐site and A‐site. This specific post‐translocation conformation favors the recruitment of the Ccr4–Not complex in the E‐site, which induces eS7 ubiquitination, mRNA deadenylation through the Caf1 subunit and stimulates Dhh1p recruitment to induce mRNA degradation. (d) In zebrafish, a similar Ccr4–Not‐dependent mechanism probes codon optimality to induce mRNA degradation in a translation‐dependent manner. However, in addition to codon usage, amino‐acid content can also mediate mRNA destabilization through a still uncharacterized mechanism. (e) In zebrafish, the distance between the non‐optimal codon and the poly(A) tail acts as a buffer against the deadenylase activity of the Ccr4–Not complex
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Ribosome‐associated quality control mechanisms. Upon ribosome collision induced by problematic mRNAs, EDF1 is recruited first at the disome interface (Panel 1), and then it stabilizes the interaction of ZNF598, GIGYF2, and 4EHP with collided ribosomes (Panel 2). These proteins act in two distinct ways to minimize ribosome collision: (1) GIGYF2‐4EHP represses initiation of new rounds of translation by competing with eIF4E for binding to the cap structure and marks problematic mRNAs for decay (Panel 3). (2) ZNF598 ubiquitinates several 40S ribosomal proteins and these ubiquitinations are required for the ribosome‐associated quality control involved in degradation of the nascent peptide and rescue of collided ribosomes. The ubiquitinations can be reversed by the deubiquitinases USP21 and OTUD3 (Panel 4)
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Conventional mRNA decay pathways in yeast and mammals. Cytoplasmic mRNA decay occurs independently of the translation process for the most part (a), but it can also proceed co‐translationally (b). (a) The translation‐independent mRNA decay starts with deadenylation by the CCR4–Not complex, followed by removal of the 5′‐cap by the DCP1–DCP2 complex (Panel 1). Thereafter, mRNA decay proceeds through 5′‐to‐3′ degradation by the exoribonuclease XRN1 and/or 3′‐to‐5′ degradation by the exosome assisted with the Ski complex (Panel 2). (b) Co‐translational mRNA decay is initiated when, for various reasons, a ribosome is not loaded by a new tRNA in its A‐site. As above, mRNA decay starts with deadenylation by the CCR4–Not complex, then decapping by the DCP1–DCP2 complex, leading to exonucleolytic cleavage by XRN1 (5′‐to‐3′) and the ski‐exosome complex (3′‐to‐5′). In mammals, the mRNA decay pathways are not redundant, but instead perform specialized functions. XRN1 predominantly mediates bulk mRNA decay with the aid of normal translation (Panel 1). The Ski‐exosome complex functions in global mRNA surveillance and triggers mRNA decay in the case of aberrant translation events as stalled ribosomes at a premature stop codon (Panel 2). Alternatively, mRNA decay can occur through a repeated ribosome‐associated endonucleolytic activity, for which the endonuclease remains to be identified (Panel 3)
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No‐go decay and non‐stop decay. (a) No‐go decay (NGD). Panel 1: The ribosome stops before reaching the stop codon because it encounters a stalling feature such as a stem‐loop motif, a GC‐rich tract, or rare codons. These obstacles lead to ribosome stall and potentially ribosome collision. Two different mechanisms evolved to cope with this particular event of ribosomal arrest. The first mechanism, aimed to resolve a stalled ribosome, is illustrated on panels 2 and 3. The mammalian complex Pelota‐Hbs1 (Dom34‐Hbs1 in yeast) binds to the empty ribosomal A‐site and recruits the ribosome recycling factor ABCE1 (Rli1 in yeast) and also the Cue2 endonuclease (in yeast), which cleaves the mRNA in the A‐site of the stalled ribosome, further allowing exonucleolytic decay mediated primarily by the XRN1 exonuclease rather than by the exosome assisted with the Ski complex. Panel 3: NGD closely couples decay of faulty mRNA with ribosome recycling and degradation of the nascent polypeptide. Because Pelota‐Hbs1 cannot hydrolyze the peptidyl‐tRNA bound to the P‐site, peptide release does not occur. The nascent peptide still attached to the 60S ribosomal subunit is handled by the ribosome‐associated quality control (RQC) pathway and degraded via the proteasome. Panel 4 illustrates the second mechanism aimed to resolve collided ribosomes. This event induces conformational changes of the ribosome that are recognized by the ubiquitin ligase ZNF598 (in mammals). ZNF598 ubiquitinates several ribosomal proteins and these modifications are required for robust induction of NGD. (b) Non‐stop decay (NSD). NSD relies on the same factors as NGD, but differs in its mRNA targets. Panel 1: Due to the lack of a stop codon, the ribosome translates a poly(A) sequence and translation elongation progressively slows down and eventually stops. Activation of NSD results from interactions between the positively charged lysine residues of the nascent polypeptide and the negatively charged exit channel of the ribosome. Panel 2: The complex Pelota‐Hbs1 in the A‐site recruits the endonuclease NONU‐1 (in C. elegans, homolog of Cue2 in S. cerevisiae). The interactions between positively‐charged residues with the exit channel result in the retention of the nascent peptide when the ribosome subunits are dissociated. Panel 3: Ribosome stalling caused by translation of poly(A) sequences is recognized by ZNF598. Ubiquitination of ribosomal proteins by ZNF598 are important modifications for ribosome rescue during NSD
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RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
Translation > Translation Regulation
RNA Turnover and Surveillance > Regulation of RNA Stability

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