Emerging roles of tRNA in adaptive translation, signalling dynamics and disease

Kirchner, Sebastian; Ignatova, Zoya

doi:10.1038/nrg3861

Cited by 443 publications

(403 citation statements)

References 159 publications

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“…Nevertheless, the detailed chemistry of the Elongator modification reaction is insufficiently described, and the role of the resulting modifications is not fully understood 11, 12, 13. In particular, it is currently unclear how tRNA is delivered to the active center and how the high modification turnover can be achieved in the context of the full complex.…”

Section: Introductionmentioning

confidence: 99%

Architecture of the yeast Elongator complex

et al. 2016

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The highly conserved eukaryotic Elongator complex performs specific chemical modifications on wobble base uridines of tRNAs, which are essential for proteome stability and homeostasis. The complex is formed by six individual subunits (Elp1‐6) that are all equally important for its tRNA modification activity. However, its overall architecture and the detailed reaction mechanism remain elusive. Here, we report the structures of the fully assembled yeast Elongator and the Elp123 sub‐complex solved by an integrative structure determination approach showing that two copies of the Elp1, Elp2, and Elp3 subunits form a two‐lobed scaffold, which binds Elp456 asymmetrically. Our topological models are consistent with previous studies on individual subunits and further validated by complementary biochemical analyses. Our study provides a structural framework on how the tRNA modification activity is carried out by Elongator.

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Section: Introductionmentioning

confidence: 99%

Architecture of the yeast Elongator complex

et al. 2016

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“…tRNA also play other roles and participate in: regulatory mechanisms during protein synthesis; regulation of gene expression; non-ribosomal peptide bond formation; post-translational protein modification; phospholipid modifications in cell membranes; targeting protein degradation; quality control surveillance pathways; stress response; regulation of metabolic processes; secondary metabolism (Huang and Hopper 2016); priming reverse transcription; inhibition of apoptosis via complexation with cytochrome C; antimicrobial and protein folding (for reviews, see Giegé 2008;Kirchner and Ignatova 2015;Duechler et al 2016). Recently, the production of fragments of some particular tRNA species (3′ or 5′ halves, and 3′ or 5′ quarters of a tRNA molecule, for instance) was associated with different cell conditions (responses to different stress conditions, hormonal effectors, or cancer processes) and could play regulatory functions (Keam and Hutvagner 2015).…”

Section: The State Of the Trna Population In The Cellmentioning

confidence: 99%

Protein folding and tRNA biology

2017

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Polypeptides can fold into tertiary structures while they are synthesized by the ribosome. In addition to the amino acid sequence, protein folding is determined by several factors within the cell. Among others, the folding pathway of a nascent polypeptide can be affected by transient interactions with other proteins, ligands, or the ribosome, as well as by the translocation through membrane pores. Particularly, the translation machinery and the population of tRNA under different physiological or adaptive responses can dramatically affect protein folding. This review summarizes the scientific evidence describing the role of translation kinetics and tRNA populations on protein folding and addresses current efforts to better understand tRNA biology. It is organized into three main parts, which are focused on: (i) protein folding in the cellular context; (ii) tRNA biology and the complexity of the tRNA population; and (iii) available methods and technical challenges in the characterization of tRNA pools. In this manner, this work illustrates the ways by which functional properties of proteins may be modulated by cellular tRNA populations.

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“…49 These new roles of tRNAs have been observed in prokaryotes as well as eukaryotes, and they are involved in various cellular phenomena, including haeme and chlorophyll biosynthesis, antibiotic cellular permeability, energy metabolism, amino acid biosynthesis and protein degradation, reverse transcription of viruses, cell apoptosis and survival, and cancer progression. 4-6 , 10 , 37 , 50-55 In this study, we investigated the novel functions of tRNAs, especially tRNA Leu , which promoted cell proliferation via RSK/MSK signaling.…”

Section: Discussionmentioning

confidence: 99%

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

et al. 2018

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While transfer-RNAs (tRNAs) are known to transport amino acids to ribosome, new functions are being unveiled from tRNAs and their fragments beyond protein synthesis. Here we show that phosphorylation of 90-kDa RPS6K (ribosomal proteins S6 kinase) was enhanced by tRNALeu overexpression under amino acids starvation condition. The phosphorylation of 90-kDa RPS6K was decreased by siRNA specific to tRNALeu and was independent to mTOR (mammalian target of rapamycin) signaling. Among the 90-kDa RPS6K family, RSK1 (ribosomal S6 kinase 1) and MSK2 (mitogen-and stress-activated protein kinase 2) were the major kinases phosphorylated by tRNALeu overexpression. Through SILAC (stable isotope labeling by/with amino acids in cell culture) and combined mass spectrometry analysis, we identified EBP1 (ErbB3-binding protein 1) as the tRNALeu-binding protein. We suspected that the overexpression of free tRNALeu would reinforce ErbB2/ErbB3 signaling pathway by disturbing the interaction between ErbB3 and EBP1, resulting in RSK1/MSK2 phosphorylation, improving cell proliferation and resistance to death. Analysis of samples from patients with breast cancer also indicated an association between tRNALeu overexpression and the ErbB2-positive population. Our results suggested a possible link between tRNALeu overexpression and RSK1/MSK2 activation and ErbB2/ErbB3 signaling.

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Emerging roles of tRNA in adaptive translation, signalling dynamics and disease

Cited by 443 publications

References 159 publications

Architecture of the yeast Elongator complex

Architecture of the yeast Elongator complex

Protein folding and tRNA biology

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

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