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tRNA methylation

John J Guardiola, Juliane I Beier, K Cameron Falkner, Benjamin Wheeler, Craig James McClain, Matt Cave
BACKGROUND: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. METHODS: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS(2) analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed...
October 17, 2016: Toxicology and Applied Pharmacology
Fange Liu, Wesley Clark, Guanzheng Luo, Xiaoyun Wang, Ye Fu, Jiangbo Wei, Xiao Wang, Ziyang Hao, Qing Dai, Guanqun Zheng, Honghui Ma, Dali Han, Molly Evans, Arne Klungland, Tao Pan, Chuan He
tRNA is a central component of protein synthesis and the cell signaling network. One salient feature of tRNA is its heavily modified status, which can critically impact its function. Here, we show that mammalian ALKBH1 is a tRNA demethylase. It mediates the demethylation of N(1)-methyladenosine (m(1)A) in tRNAs. The ALKBH1-catalyzed demethylation of the target tRNAs results in attenuated translation initiation and decreased usage of tRNAs in protein synthesis. This process is dynamic and responds to glucose availability to affect translation...
October 20, 2016: Cell
Tao Long, Jing Li, Hao Li, Mi Zhou, Xiao-Long Zhou, Ru-Juan Liu, En-Duo Wang
Human NSun6 is an RNA methyltransferase that catalyses the transfer of the methyl group from S-adenosyl-L-methionine (SAM) to C72 of tRNAThr and tRNACys. In the current study, we used mass spectrometry to demonstrate that human NSun6 indeed introduces 5-methylcytosine (m5C) into tRNA, as expected. To further reveal the tRNA recognition mechanism of human NSun6, we measured the methylation activity of human NSun6 and its kinetic parameters for different tRNA substrates and their mutants. We showed that human NSun6 requires a well-folded, full-length tRNA as its substrate...
October 4, 2016: Journal of Biological Chemistry
Juthamas Jaroensuk, Sopapan Atichartpongkul, Yok Hian Chionh, Yee Hwa Wong, Chong Wai Liew, Megan E McBee, Narumon Thongdee, Erin G Prestwich, Michael S DeMott, Skorn Mongkolsuk, Peter C Dedon, Julien Lescar, Mayuree Fuangthong
Bacteria respond to environmental stresses using a variety of signaling and gene expression pathways, with translational mechanisms being the least well understood. Here, we identified a tRNA methyltransferase in Pseudomonas aeruginosa PA14, trmJ, which confers resistance to oxidative stress. Analysis of tRNA from a trmJ mutant revealed that TrmJ catalyzes formation of Cm, Um, and, unexpectedly, Am. Defined in vitro analyses revealed that tRNA(Met(CAU)) and tRNA(Trp(CCA)) are substrates for Cm formation, tRNA(Gln(UUG)), tRNA(Pro(UGG)), tRNA(Pro(CGG)) and tRNA(His(GUG)) for Um, and tRNA(Pro(GGG)) for Am...
September 28, 2016: Nucleic Acids Research
William E Pierson, Eric D Hoffer, Hannah E Keedy, Carrie L Simms, Christine M Dunham, Hani S Zaher
Termination of protein synthesis on the ribosome is catalyzed by release factors (RFs), which share a conserved glycine-glycine-glutamine (GGQ) motif. The glutamine residue is methylated in vivo, but a mechanistic understanding of its contribution to hydrolysis is lacking. Here, we show that the modification, apart from increasing the overall rate of termination on all dipeptides, substantially increases the rate of peptide release on a subset of amino acids. In the presence of unmethylated RFs, we measure rates of hydrolysis that are exceptionally slow on proline and glycine residues and approximately two orders of magnitude faster in the presence of the methylated factors...
September 27, 2016: Cell Reports
Gagandeep S Saggu, Zarna R Pala, Shilpi Garg, Vishal Saxena
The MEP (Methyl Erythritol Phosphate) isoprenoids biosynthesis pathway is an attractive drug target to combat malaria, due to its uniqueness and indispensability for the parasite. It is functional in the apicoplast of Plasmodium and its products get transported to the cytoplasm, where they participate in glycoprotein synthesis, electron transport chain, tRNA modification and several other biological processes. Several compounds have been tested against the enzymes involved in this pathway and amongst them Fosmidomycin, targeted against IspC (DXP reductoisomerase) enzyme and MMV008138 targeted against IspD enzyme have shown good anti-malarial activity in parasite cultures...
2016: Frontiers in Microbiology
Yiyan Wang, Meng-Lin Tsao
A new method has been developed to reassign the rare codon AGA in Escherichia coli by engineering an orthogonal tRNA/aminoacyl-tRNA synthetase pair derived from Methanocaldococcus jannaschii. The tRNA mutant was introduced with a UCU anticodon, and the synthetase was evolved to correctly recognize the modified tRNA anticodon loop and to selectively charge a target noncanonical amino acid (NAA) onto the tRNA. In order to maximize the efficiency of AGA codon reassignment, while avoiding the lethal effects caused by global codon reassignment in cellular proteins, an inducible promoter (araBAD) was utilized to provide temporal controls for overexpression of the aminoacyl-tRNA synthetase and switch on codon reassignment...
September 20, 2016: Chembiochem: a European Journal of Chemical Biology
Dan Bar-Yaacov, Idan Frumkin, Yuka Yashiro, Takeshi Chujo, Yuma Ishigami, Yonatan Chemla, Amit Blumberg, Orr Schlesinger, Philipp Bieri, Basil Greber, Nenad Ban, Raz Zarivach, Lital Alfonta, Yitzhak Pilpel, Tsutomu Suzuki, Dan Mishmar
The mitochondrial ribosome, which translates all mitochondrial DNA (mtDNA)-encoded proteins, should be tightly regulated pre- and post-transcriptionally. Recently, we found RNA-DNA differences (RDDs) at human mitochondrial 16S (large) rRNA position 947 that were indicative of post-transcriptional modification. Here, we show that these 16S rRNA RDDs result from a 1-methyladenosine (m1A) modification introduced by TRMT61B, thus being the first vertebrate methyltransferase that modifies both tRNA and rRNAs. m1A947 is conserved in humans and all vertebrates having adenine at the corresponding mtDNA position (90% of vertebrates)...
September 2016: PLoS Biology
Caiyan Wang, Qian Jia, Ran Chen, Yuming Wei, Juntao Li, Jie Ma, Wei Xie
tRNA methyltransferase Trm5 catalyses the transfer of a methyl group from S-adenosyl-L-methionine to G37 in eukaryotes and archaea. The N1-methylated guanosine is the product of the initial step of the wyosine hypermodification, which is essential for the maintenance of the reading frame during translation. As a unique member of this enzyme family, Trm5a from Pyrococcus abyssi (PaTrm5a) catalyses not only the methylation of N1, but also the further methylation of C7 on 4-demethylwyosine at position 37 to produce isowyosine, but the mechanism for the double methylation is poorly understood...
2016: Scientific Reports
Wesley C Clark, Molly E Evans, Dan Dominissini, Guanqun Zheng, Tao Pan
Eukaryotic transfer RNAs contain on average 14 modifications. Investigations of their biological functions require the determination of the modification sites and the dynamic variations of the modification fraction. Base methylation represents a major class of tRNA modification. Although many approaches have been used to identify tRNA base methylations, including sequencing, they are generally qualitative and do not report the information on the modification fraction. Dynamic mRNA modifications have been shown to play important biological roles; yet, the extent of tRNA modification fractions has not been reported systemically...
September 9, 2016: RNA
Mingxing Wang, Yuwei Zhu, Chongyuan Wang, Xiaojiao Fan, Xuguang Jiang, Mohammad Ebrahimi, Zhi Qiao, Liwen Niu, Maikun Teng, Xu Li
The N(1) methylation of adenine at position 58 (m(1)A58) of tRNA is an important post-transcriptional modification, which is vital for maintaining the stability of the initiator methionine tRNAi(Met). In eukaryotes, this modification is performed by the TRM6-TRM61 holoenzyme. To understand the molecular mechanism that underlies the cooperation of TRM6 and TRM61 in the methyl transfer reaction, we determined the crystal structure of TRM6-TRM61 holoenzyme from Saccharomyces cerevisiae in the presence and absence of its methyl donor S-Adenosyl-L-methionine (SAM)...
2016: Scientific Reports
Thomas Christian, Reiko Sakaguchi, Agata P Perlinska, Georges Lahoud, Takuhiro Ito, Erika A Taylor, Shigeyuki Yokoyama, Joanna I Sulkowska, Ya-Ming Hou
Proteins with knotted configurations, in comparison with unknotted proteins, are restricted in conformational space. Little is known regarding whether knotted proteins have sufficient dynamics to communicate between spatially separated substrate-binding sites. TrmD is a bacterial methyltransferase that uses a knotted protein fold to catalyze methyl transfer from S-adenosyl methionine (AdoMet) to G37-tRNA. The product, m(1)G37-tRNA, is essential for life and maintains protein-synthesis reading frames. Using an integrated approach of structural, kinetic, and computational analysis, we show that the structurally constrained TrmD knot is required for its catalytic activity...
October 2016: Nature Structural & Molecular Biology
Sara Haag, Katherine E Sloan, Namit Ranjan, Ahmed S Warda, Jens Kretschmer, Charlotte Blessing, Benedikt Hübner, Jan Seikowski, Sven Dennerlein, Peter Rehling, Marina V Rodnina, Claudia Höbartner, Markus T Bohnsack
Mitochondrial gene expression uses a non-universal genetic code in mammals. Besides reading the conventional AUG codon, mitochondrial (mt-)tRNA(M)(et) mediates incorporation of methionine on AUA and AUU codons during translation initiation and on AUA codons during elongation. We show that the RNA methyltransferase NSUN3 localises to mitochondria and interacts with mt-tRNA(M)(et) to methylate cytosine 34 (C34) at the wobble position. NSUN3 specifically recognises the anticodon stem loop (ASL) of the tRNA, explaining why a mutation that compromises ASL basepairing leads to disease...
October 4, 2016: EMBO Journal
Roland Klassen, Akif Ciftci, Johanna Funk, Alexander Bruch, Falk Butter, Raffael Schaffrath
Using budding yeast, we investigated a negative interaction network among genes for tRNA modifications previously implicated in anticodon-codon interaction: 5-methoxy-carbonyl-methyl-2-thio-uridine (mcm(5)s(2)U34: ELP3, URM1), pseudouridine (Ψ38/39: DEG1) and cyclic N6-threonyl-carbamoyl-adenosine (ct(6)A37: TCD1). In line with functional cross talk between these modifications, we find that combined removal of either ct(6)A37 or Ψ38/39 and mcm(5)U34 or s(2)U34 results in morphologically altered cells with synthetic growth defects...
August 5, 2016: Nucleic Acids Research
Raghuvaran Shanmugam, Jacob Fierer, Steffen Kaiser, Mark Helm, Tomasz P Jurkowski, Albert Jeltsch
The Dnmt2 RNA methyltransferase catalyses the methylation of C38 in the anticodon loop of tRNA-Asp, but the molecular role of this methylation is unknown. Here, we report that mouse aspartyl-tRNA synthetase shows a four to fivefold preference for C38-methylated tRNA-Asp. Consistently, a 30% reduced charging level of tRNA-Asp was observed in Dnmt2 knockout (KO) murine embryonic fibroblast cells. Gene expression analysis with fluorescent reporter proteins fused to an N-terminal poly-Asp sequence showed that protein synthesis of poly-Asp-tagged reporter proteins was reduced in Dnmt2 KO cells as well...
2015: Cell Discovery
Yalan Yang, Rong Zhou, Yulian Mu, Xinhua Hou, Zhonglin Tang, Kui Li
DNA methylation is a crucial epigenetic modification involved in diverse biological processes. There is significant phenotypic variance between Chinese indigenous and western pig breeds. Here, we surveyed the genome-wide DNA methylation profiles of blood leukocytes from three pig breeds (Tongcheng, Landrace, and Wuzhishan) by methylated DNA immunoprecipitation sequencing. The results showed that DNA methylation was enriched in gene body regions and repetitive sequences. LINE/L1 and SINE/tRNA-Glu were the predominant methylated repeats in pigs...
2016: Scientific Reports
Andrew Schuster, Michael K Skinner, Wei Yan
Exposure to the agricultural fungicide vinclozolin during gestation promotes a higher incidence of various diseases in the subsequent unexposed F3 and F4 generations. This phenomenon is termed epigenetic transgenerational inheritance and has been shown to in part involve alterations in DNA methylation, but the role of other epigenetic mechanisms remains unknown. The current study investigated the alterations in small noncoding RNA (sncRNA) in the sperm from F3 generation control and vinclozolin lineage rats...
2016: Environmental Epigenetics
Tetsuya Harada, Van Chinh Dang, Do Phuc Nguyen, Thi Anh Dao Nguyen, Mitsuo Sakamoto, Moriya Ohkuma, Daisuke Motooka, Shota Nakamura, Kotaro Uchida, Michio Jinnai, Shinya Yonogi, Ryuji Kawahara, Masashi Kanki, Takao Kawai, Yuko Kumeda, Yoshimasa Yamamoto
Two Gram-positive strains, VE80T and VE116, which were resistant to vancomycin, were isolated from retail chicken meat and liver in Ho Chi Minh, Vietnam, respectively. These strains were characterised by the sequence analyses of 16S rRNA, RNA polymerase α-subunit (rpoA), ATP synthase α-subunit (atpA), and phenylalanyl-tRNA synthase α-subunit (pheS) genes, determination of DNA G+C content, cellular fatty acid methyl ester analysis, DNA-DNA hybridisation, and conventional morphological and biochemical tests...
June 30, 2016: International Journal of Systematic and Evolutionary Microbiology
Lindsey Van Haute, Sabine Dietmann, Laura Kremer, Shobbir Hussain, Sarah F Pearce, Christopher A Powell, Joanna Rorbach, Rebecca Lantaff, Sandra Blanco, Sascha Sauer, Urania Kotzaeridou, Georg F Hoffmann, Yasin Memari, Anja Kolb-Kokocinski, Richard Durbin, Johannes A Mayr, Michaela Frye, Holger Prokisch, Michal Minczuk
Epitranscriptome modifications are required for structure and function of RNA and defects in these pathways have been associated with human disease. Here we identify the RNA target for the previously uncharacterized 5-methylcytosine (m(5)C) methyltransferase NSun3 and link m(5)C RNA modifications with energy metabolism. Using whole-exome sequencing, we identified loss-of-function mutations in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of NSun3...
2016: Nature Communications
Aneeshkumar G Arimbasseri, James Iben, Fan-Yan Wei, Keshab Rijal, Kazuhito Tomizawa, Markus Hafner, Richard J Maraia
Post-transcriptional modifications of anticodon loop (ACL) nucleotides impact tRNA structure, affinity for the ribosome, and decoding activity, and these activities can be fine-tuned by interactions between nucleobases on either side of the anticodon. A recently discovered ACL modification circuit involving positions 32, 34, and 37 is disrupted by a human disease-associated mutation to the gene encoding a tRNA modification enzyme. We used tRNA-HydroSeq (-HySeq) to examine (3)methyl-cytidine-32 (m(3)C32), which is found in yeast only in the ACLs of tRNAs(Ser) and tRNAs(Thr) In contrast to that reported for Saccharomyces cerevisiae in which all m(3)C32 depends on a single gene, TRM140, the m(3)C32 of tRNAs(Ser) and tRNAs(Thr) of the fission yeast S...
September 2016: RNA
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