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Nonsense-Mediated Mrna Decay Begins Where Translation Ends

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Nonsense-Mediated Mrna Decay Begins Where Translation Ends Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Nonsense-Mediated mRNA Decay Begins Where Translation Ends Evangelos D. Karousis and Oliver Mühlemann Department of Chemistry and Biochemistry, University of Bern, CH-3012 Bern, Switzerland Correspondence: [email protected] Nonsense-mediated mRNA decay (NMD) is arguably the best-studied eukaryotic messenger RNA (mRNA) surveillance pathway, yet fundamental questions concerning the molecular mechanism of target RNA selection remain unsolved. Besides degrading defective mRNAs harboring premature termination codons (PTCs), NMD also targets many mRNAs encoding functional full-length proteins. Thus, NMD impacts on a cell’s transcriptome and is implicat- ed in a range of biological processes that affect a broad spectrum of cellular homeostasis. Here, we focus on the steps involved in the recognition of NMD targets and the activation of NMD. We summarize the accumulating evidence that tightly links NMD to translation ter- mination and we further discuss the recruitment and activation of the mRNA degradation machinery and the regulation of this complex series of events. Finally, we review emerging ideas concerning the mechanistic details of NMD activation and the potential role of NMD as a general surveyor of translation efficacy. riginally conceived as a quality control and a wealth of biochemical data characterizing Opathway that recognizes and specifically interactions between different NMD factors, degrades aberrant messenger RNAs (mRNAs) their enzymatic functions and posttranslational with premature termination codons (PTCs), it modifications, the mechanism and criteria for has meanwhile become clear that nonsense- selection of an mRNA for the NMD pathway mediated mRNA decay (NMD) contributes to are still not well understood. The slow progress posttranscriptional gene regulation in a way in deciphering the mechanism of NMD can that goes far beyond quality control. Exploring at least partially be attributed to the lack of a in which biological contexts NMD-mediated suitable in vitro system that faithfully recapitu- gene regulation plays an important role is a rel- lates the key steps of NMD. Nevertheless, work atively new but rapidly expanding area of re- from many laboratories during the last few search that has been covered in recent reviews years has provided compelling evidence that (Nasif et al. 2017; Nickless et al. 2017). Here, we NMD is tightly coupled to the process of summarize our current understanding regard- translation termination. During translation ter- ing the molecular mechanism of NMD, with the mination, it is decided whether the translated focus on data obtained from mammalian sys- mRNA shall remain intact and serve as a tem- tems. Despite more than 25 years of research plate for additional rounds of translation or Editors: Michael B. Mathews, Nahum Sonenberg, and John W.B. Hershey Additional Perspectives on Translation Mechanisms and Control available at www.cshperspectives.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a032862 1 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press E.D. Karousis and O. Mühlemann A Normal translation termination eRF3 eRF1 ABCE1 GTP GDP+Pi UAA UAA UAA UAA UAA UAA B Aberrant translation termination and NMD activation eRF3 eRF1 GTP 3 eRF3 U UPF eRF3 P UP F 3 U P F2 F UAA 1 2 F UP UAA UAA UAA UPF1 SMG8 SMG1 EJ G9 M C U S PF UP 3 F2 SMG 8 MG9 S N N UAA UAA C C mRNA degradation UPF1 UPF1 SMG6 SMG7 SMG5 Figure 1. Schematic illustration of the sequential events taking place in normal translation termination and aberrant translation termination resulting in the activation of nonsense-mediated mRNA decay (NMD). (A) The presence of a termination codon (TC) in the A site of the ribosome provides the signal for translation termination that is marked by recognition of the TC by eukaryotic release factor (eRF)1 and eRF3, a conformational change of eRF1 that facilitates hydrolysis of the terminal peptidyl-transfer RNA (tRNA) bond and the release of the nascent peptide. Subsequently, release of the ribosome from the messenger RNA (mRNA) is facilitated by ABCE1. (B) When translation termination occurs in an unfavorable environment, UPF1 is activated by UPF2 and/or UPF3 that are free in the cytoplasm or positioned nearby on an exon junction complex (EJC). UPF1 activation involves its phosphorylation by SMG1, whose kinase activity is controlled by SMG8 and SMG9. The fate of the stalled ribosomes in the context of NMD activation remains unclear. Phosphorylated UPF1 (indicated by red dots) recruits the NMD-specific SMG6 endonuclease, which cleaves the targeted mRNA nearby the TC and the SMG5/ SMG7 heterodimer that stimulates the exonucleolytic degradation of the mRNA by recruiting the CCR4/NOT complex. For clarity, a part of the NMD-activating complex (SMG1, UPF2, and UPF3) is depicted in gray to highlight the factors triggering mRNA degradation in the lower part of the panel. whether it shall be degraded by the NMD path- THE MECHANISM OF EUKARYOTIC way (He and Jacobson 2015). In a nutshell, the TRANSLATION TERMINATION AND current view is that NMD ensues when ribo- RIBOSOME RECYCLING somes at nonsense codons (hereafter called ter- Translation termination is signaled by the pres- mination codon [TC]) fail to terminate correct- ence of one of the three TCs in the A site of the ly. Because of the tight link between NMD and ribosome. Canonical translation termination is translation termination, we begin this review marked by three key events: (1) proper recogni- with a brief overview of eukaryotic translation tion of the termination signal, (2) hydrolysis of termination. For a more detailed review of the the terminal peptidyl-tRNA bond and release of mechanism of translation termination, see Hel- the nascent peptide, and (3) dissociation of the len (2018). ribosome into its 60S and 40S subunits (Fig. 1A) 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a032862 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press NMD Begins Where Translation Ends (Dever and Green 2012; Simms et al. 2017). In between S12 and rRNA on the small subunit comparison to the initiation and elongation (Kiosze-Becker et al. 2016). Additionally, ABCE1 steps, the step of translation termination is less associates with the 43S preinitiation complex well studied and accordingly much less is known (consisting of eIF1A, eIF2, eIF3, and initiator regarding its molecular mechanism. Instead tRNA) but its role in translation initiation re- of cognate aminoacylated (aa) transfer RNAs mains to be elucidated (Heuer et al. 2017). Bio- (tRNAs) that get recruited to the A site of the chemical datasuggest that ABCE1 alsoaccelerates ribosome during elongation, eukaryotic release the rate of the peptide release by eRF1 in an factor 1 (eRF)1 binds the A site when it harbors ATP-independent manner, providing a function- one of the three TCs. On terminating ribosomes, al link between translation termination and ribo- eRF1 is found as a ternary complex with the some recycling (Shoemaker and Green 2011). GTPase eRF3 and GTP. After its recruitment Most of the information concerning trans- to the A site, GTP hydrolysis by eRF3 stimulates lation termination originates from structural a large conformational change in eRF1 that studies and in vitro assays. The isolation of enhances polypeptide release by engaging the translation termination intermediates can be active site of the ribosome. Despite the extended achieved by using purified components in the conformational change of the middle and car- presence of nucleotide analogs that trap specific boxy-terminal parts of eRF1, the amino-termi- steps (Shao et al. 2016) or mutated release fac- nal part of the protein interacts stably with the tors (Alkalaeva et al. 2006; Brown et al. 2015). TC throughout the process (Alkalaeva et al. The biochemical dissection of translation termi- 2006; Becker et al. 2012; Eyler et al. 2013; Brown nation was facilitated by the establishment of a et al. 2015; Shao et al. 2016). reconstituted system with mammalian compo- Following GTP hydrolysis, eRF3 dissociates nents containing purified ribosomal subunits, from the termination complex, allowing for the translation factors, and aminoacylated tRNAs. subsequent interaction of eRF1 with the ABC- This in vitro translation system made possible type ATPase ABCE1 (Rli1 in yeast), a factor that the stepwise investigation of the configuration of stimulates the recycling of the ribosome by split- termination complexes by using the toeprinting ting the ribosomal subunits. ABCE1 contains technique, which allows the identification of two nucleotide-binding domains (NBDs) and ribosomal positions on a reporter mRNA at a unique amino-terminal FeS cluster domain single-nucleotide resolution (Alkalaeva et al. aligned by two diamagnetic [4Fe–4S]2+ clusters. 2006). However, the establishment of similar ATP hydrolysis by ABCE1 causes extended con- approaches by using mammalian cell lysates, formational changes that provide the mechani- as well as studies of translation termination in cal force leading to the dissociation of the 60S living cells, remains a challenge in the field. The from the 40S
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