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Mrna and Trna Modifications As the Two Sides of the Same Coin?

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Mrna and Trna Modifications As the Two Sides of the Same Coin? REVIEW ARTICLE The epitranscriptome in translation regulation: mRNA and tRNA modifications as the two sides of the same coin? Namit Ranjan1 and Sebastian A. Leidel2,3 1 Department of Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany 2 Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Munster,€ Germany 3 Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland Correspondence Translation of mRNA is a highly regulated process that is tightly coordinated N. Ranjan, Department of Physical with cotranslational protein maturation. Recently, mRNA modifications and Biochemistry, Max Planck Institute for tRNA modifications – the so called epitranscriptome – have added a new Biophysical Chemistry, Goettingen, layer of regulation that is still poorly understood. Both types of modifications Germany – Tel: +49 5512012958 can affect codon anticodon interactions, thereby affecting mRNA translation E-mail: [email protected] and protein synthesis in similar ways. Here, we describe an updated view on S. A. Leidel, Department of Chemistry and how the different types of modifications can be mapped, how they affect Biochemistry, University of Bern, translation, how they trigger phenotypes and discuss how the combined action Bern, Switzerland of mRNA and tRNA modifications coordinate translation in health and Tel: +41 316314296 disease. E-mail: [email protected] (Received 2 April 2019, revised 7 June Keywords: disease; epitranscriptome; post-transcriptional modifications; 2019, accepted 11 June 2019, available ribosome; RNA modification; RNA sequencing; translation online 27 June 2019) doi:10.1002/1873-3468.13491 Edited by Maria Papatriantafyllou Protein synthesis is essential to life. Thus, it is regulated ribosome during protein synthesis, proteins begin to by a variety of sophisticated mechanisms and comprises fold into their final three-dimensional structure and four phases: (a) initiation; (b) elongation; (c) termina- acquire protein modifications [2]. tion; and (d) ribosome recycling. Initiation is the key Some of the key players in translation like mRNA, regulatory step of translation, and different mechanisms tRNA or ribosomes are RNA molecules or contain have been discovered that lead either to a global or tran- RNA molecules, essential to their function. These can be script-specific control of translation initiation [1]. How- post-transcriptionally modified by a plethora of chemical ever, translation initiation is not the only option for the modifications, which currently amount to more than a cell to regulate protein synthesis. Translation elongation hundred seventy [3–5]. Some of these RNA modifications comprises mRNA decoding, peptide-bond formation are evolutionary conserved and were linked to a human and tRNA–mRNA translocation, resulting in nascent- disease [6–8]. Since RNA modifications change the struc- peptide elongation, and each of these steps bears regula- tural and chemical properties of RNA molecules, some tory potential for translation. Furthermore, mRNA modifications of either mRNA, tRNA or rRNA are translation occurs in concert with protein maturation. thought to optimize translation dynamics in the cell, As soon as the nascent-peptide chain emerges from the whereas others may be neutral to translation [5].In Abbreviations ac4C, N4-acetylcytidine; eIF, eukaryotic initiation factor; hm5C, 5-hydroxymethylcytosine; IP, immunoprecipitation; m5C, 5-methylcytosine; 6 6 6 6 0 5 m A,N-methyladenosine; m Am,N,2 -O-dimethyladenosine; RT, reverse transcription; SAM, S-adenosyl-L-methionine; sm U, 5-taurinomethyluridine; U34, wobble uridine. FEBS Letters 593 (2019) 1483–1493 ª 2019 The Authors. FEBS Letters published by John Wiley & Sons Ltd 1483 on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. The epitranscriptome in translation regulation N. Ranjan and S. A. Leidel particular internal mRNA modifications and tRNA anti- us from understanding the in vivo roles of mRNA modi- codon modifications likely lead to very similar effects, fications and in particular from understanding their since the codon and the anticodon interact directly dur- effects during translation. ing decoding. Importantly, the reversibility of both types The most abundant internal mRNA modification is of modifications suggests a new, essentially unexplored m6A, which is present on average at 3 positions per layer of the control of gene expression that has been ter- mRNA molecule (Box 1). In addition to m6A, pseu- med the epitranscriptome [9,10].However,howparticu- douridine (Ψ), N1-methyladenosine (m1A), N6,20-O- lar mRNA or tRNA modifications affect translation is dimethyladenosine (m6Am), as well as m5C (Box 2) and largely unknown because the analysis of eukaryotic its oxidation product 5-hydroxymethylcytosine (hm5C), translation in vitro or in vivo and the identification of ac4C and 20-O-methylated nucleotides were mapped to internal mRNA modifications is very challenging. the transcriptome. Additional modifications were Here, we discuss our emerging understanding of the reported based on measurements by RNA mass spec- role of mRNA modifications [N6-methyladenosine trometry but their position has not been determined (m6A), 5-methylcytosine (m5C), N4-acetylcytidine throughout the transcriptome [9,25]. The complex modi- (ac4C), 20-O-methylation] and tRNA wobble uridine fication pattern of the transcriptome likely differs (U34) modifications in translation and how our under- between species and even between different tissues in standing of the roles of mRNA modifications is influ- one organism [26]. However, a complete map of all enced by current mapping approaches. Finally, we modifications in all cell types, still needs to be achieved comment on general implications for disease. This arti- and will require concerted efforts from many labs com- cle aims to convey a broad picture of how mRNA and parable to consortia like the ENCODE project [27]. tRNA modifications act in concert to control transla- tion. For a more focused discussion of mRNA and Internal mRNA modifications in tRNA modifications we refer the readers to several translational regulation recent reviews [9,11–20]. The recent identification of proteins that install (writ- 6 Internal mRNA modifications and their ers), recognize (readers) and remove (erasers) m A and mapping other modifications has revealed mechanisms how mRNA modifications can affect nearly every aspect of Internal modifications of mRNA and long noncoding the mRNA life cycle, as well as various cellular, devel- RNA have already been discovered in the 1970s [21–23]. opmental and disease processes. However, for under- However, due to their low abundance they generally standing their effects in translation, we currently have evaded biochemical analyses and we lacked the ability to mostly rely on biochemical and biophysical analy- to map their positions in a transcriptome-wide manner. ses. Using an in vitro protein synthesis kit containing mRNA modification mapping has become possible only the components for in vitro transcription and transla- recently, with the advent of deep sequencing and the tion, named ‘PUR-Express translation system’ with implementation of specialized sequencing-based proto- m5C, m6A, Ψ or 20-O-methylated nucleotides at each cols. In general, successful mapping approaches are position within a codon revealed that protein synthesis based on three strategies: (a) the induction or detection is strongly affected by nucleotide modifications in a of specific mutations in RNAseq experiments; (b) termi- position-specific manner [28].20-O-methylated nucleo- nation of reverse-transcription (RT) reactions and (c) tides at the 1st codon position affect translation only antibody-based enrichment of modification sites (exten- marginally; however, when placed at the 2nd position sively reviewed in [18]). Direct RNA sequencing appears the same modification causes an almost complete stop as a promising future alternative and has been shown to of protein synthesis. Introduction of multiple modified detect modified bases in synthetic RNA strands or nucleotides within one codon increased the translation abundant cellular targets [24]. However, these protocols inhibition [28]. More specifically, the presence of 20-O- have not been shown to work reliably on a transcrip- methylation at the 2nd codon position of mRNA tome-wide level, yet. It is important to realize that the strongly delays tRNA accommodation to the modified low abundance of mRNA modifications in combination codon [29]. Furthermore, 20-O-methylation impairs the with false-positive rates in their detection has remained initial and proofreading selection of aminoacyl-tRNA a challenge. Due to the lack of quantitative high-quality and the interaction between the codon–anticodon helix mRNA modification maps for most organisms we can- and ribosomal-monitoring bases [29]. Such alterations not easily correlate translational phenotypes to the of codon–anticodon interaction can even change the occurrence of mRNA modifications. This has prevented identity of the incorporated amino acid as the presence 1484 FEBS Letters 593 (2019) 1483–1493 ª 2019 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical
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