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      Complete chemical structures of human mitochondrial tRNAs

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          Abstract

          Mitochondria generate most cellular energy via oxidative phosphorylation. Twenty-two species of mitochondrial (mt-)tRNAs encoded in mtDNA translate essential subunits of the respiratory chain complexes. mt-tRNAs contain post-transcriptional modifications introduced by nuclear-encoded tRNA-modifying enzymes. They are required for deciphering genetic code accurately, as well as stabilizing tRNA. Loss of tRNA modifications frequently results in severe pathological consequences. Here, we perform a comprehensive analysis of post-transcriptional modifications of all human mt-tRNAs, including 14 previously-uncharacterized species. In total, we find 18 kinds of RNA modifications at 137 positions (8.7% in 1575 nucleobases) in 22 species of human mt-tRNAs. An up-to-date list of 34 genes responsible for mt-tRNA modifications are provided. We identify two genes required for queuosine (Q) formation in mt-tRNAs. Our results provide insight into the molecular mechanisms underlying the decoding system and could help to elucidate the molecular pathogenesis of human mitochondrial diseases caused by aberrant tRNA modifications.

          Abstract

          Mitochondrial tRNA modifications are important for tRNA stability and accurate decoding. By employing RNA mass spectrometry and deep sequencing, here the authors provide a comprehensive analysis of post-transcriptional modifications of 22 species of human mitochondrial tRNAs.

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          Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells

          Post-transcriptional modification of RNA nucleosides occurs in all living organisms. Pseudouridine, the most abundant modified nucleoside in non-coding RNAs 1 , enhances the function of transfer RNA and ribosomal RNA by stabilizing RNA structure 2–8 . mRNAs were not known to contain pseudouridine, but artificial pseudouridylation dramatically affects mRNA function – it changes the genetic code by facilitating non-canonical base pairing in the ribosome decoding center 9,10 . However, without evidence of naturally occurring mRNA pseudouridylation, its physiological was unclear. Here we present a comprehensive analysis of pseudouridylation in yeast and human RNAs using Pseudo-seq, a genome-wide, single-nucleotide-resolution method for pseudouridine identification. Pseudo-seq accurately identifies known modification sites as well as 100 novel sites in non-coding RNAs, and reveals hundreds of pseudouridylated sites in mRNAs. Genetic analysis allowed us to assign most of the new modification sites to one of seven conserved pseudouridine synthases, Pus1–4, 6, 7 and 9. Notably, the majority of pseudouridines in mRNA are regulated in response to environmental signals, such as nutrient deprivation in yeast and serum starvation in human cells. These results suggest a mechanism for the rapid and regulated rewiring of the genetic code through inducible mRNA modifications. Our findings reveal unanticipated roles for pseudouridylation and provide a resource for identifying the targets of pseudouridine synthases implicated in human disease 11–13 .
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            Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases.

            Mitochondria are eukaryotic organelles that generate most of the energy in the cell by oxidative phosphorylation (OXPHOS). Each mitochondrion contains multiple copies of a closed circular double-stranded DNA genome (mtDNA). Human (mammalian) mtDNA encodes 13 essential subunits of the inner membrane complex responsible for OXPHOS. These mRNAs are translated by the mitochondrial protein synthesis machinery, which uses the 22 species of mitochondrial tRNAs (mt tRNAs) encoded by mtDNA. The unique structural features of mt tRNAs distinguish them from cytoplasmic tRNAs bearing the canonical cloverleaf structure. The genes encoding mt tRNAs are highly susceptible to point mutations, which are a primary cause of mitochondrial dysfunction and are associated with a wide range of pathologies. A large number of nuclear factors involved in the biogenesis and function of mt tRNAs have been identified and characterized, including processing endonucleases, tRNA-modifying enzymes, and aminoacyl-tRNA synthetases. These nuclear factors are also targets of pathogenic mutations linked to various diseases, indicating the functional importance of mt tRNAs for mitochondrial activity.
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              Efficient and quantitative high-throughput transfer RNA sequencing

              Despite its biological importance, transfer RNA (tRNA) could not be adequately sequenced by standard methods due to abundant post-transcriptional modifications and stable structure, which interfere with cDNA synthesis. We achieve efficient and quantitative tRNA sequencing using engineered demethylases to remove base methylations and a highly processive thermostable group II intron reverse transcriptase to overcome these obstacles (DM-TGIRT-seq). Our method should be applicable to investigations of tRNA in all organisms.
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                Author and article information

                Contributors
                ts@chembio.t.u-tokyo.ac.jp
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                28 August 2020
                28 August 2020
                2020
                : 11
                : 4269
                Affiliations
                [1 ]GRID grid.26999.3d, ISNI 0000 0001 2151 536X, Department of Chemistry and Biotechnology, Graduate School of Engineering, , University of Tokyo, ; Bunkyo-ku, Tokyo, 113-8656 Japan
                [2 ]GRID grid.7597.c, ISNI 0000000094465255, RNA System Biochemistry Laboratory, Cluster for Pioneering Research, , RIKEN, ; 2-1 Hirosawa, Wako, Saitama 351-0198 Japan
                [3 ]GRID grid.26999.3d, ISNI 0000 0001 2151 536X, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, , University of Tokyo, ; Kashiwa, Chiba, 277-8562 Japan
                [4 ]GRID grid.143643.7, ISNI 0000 0001 0660 6861, Research Institute for Biomedical Sciences, , Tokyo University of Science, ; 2669 Yamazaki, Noda, Chiba 278-0022 Japan
                [5 ]GRID grid.428986.9, ISNI 0000 0001 0373 6302, State Key Laboratory of Marine Resource Utilization in South China Sea, , Hainan University, ; 570228 Haikou, Hainan P.R. China
                [6 ]GRID grid.265008.9, ISNI 0000 0001 2166 5843, Computational Medicine Center, Sidney Kimmel Medical College, , Thomas Jefferson University, ; Philadelphia, PA 19107 USA
                Author information
                http://orcid.org/0000-0001-7724-3754
                http://orcid.org/0000-0001-5232-4742
                http://orcid.org/0000-0002-9731-1731
                Article
                18068
                10.1038/s41467-020-18068-6
                7455718
                32859890
                b0ab360e-4cd0-4439-9c9f-df7e401d0a47
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 13 February 2020
                : 27 July 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001691, MEXT | Japan Society for the Promotion of Science (JSPS);
                Award ID: 18H02094
                Award ID: 18H05272
                Award ID: 26220205
                Award ID: 22227006
                Award Recipient :
                Categories
                Article
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                © The Author(s) 2020

                Uncategorized
                rna,rna modification
                Uncategorized
                rna, rna modification

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