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tRNA methylation

David Alvarez-Ponce, María Torres-Sánchez, Felix Feyertag, Asmita Kulkarni, Taylen Nappi
DNA methylation is mediated by a conserved family of DNA methyltransferases (Dnmts). The human genome encodes three active Dnmts (Dnmt1, Dnmt3a and Dnmt3b), the tRNA methyltransferase Dnmt2, and the regulatory protein Dnmt3L. Despite their high degree of conservation among different species, genes encoding Dnmts have been duplicated and/or lost in multiple lineages throughout evolution, indicating that the DNA methylation machinery has some potential to undergo evolutionary change. However, little is known about the extent to which this machinery, or the methylome, varies among vertebrates...
2018: PloS One
Lu Han, Michael P Guy, Yoshiko Kon, Eric M Phizicky
Modification defects in the tRNA anticodon loop often impair yeast growth and cause human disease. In the budding yeast Saccharomyces cerevisiae and the phylogenetically distant fission yeast Schizosaccharomyces pombe, trm7Δ mutants grow poorly due to lack of 2'-O-methylation of C32 and G34 in the tRNAPhe anticodon loop, and lesions in the human TRM7 homolog FTSJ1 cause non-syndromic X-linked intellectual disability (NSXLID). However, it is unclear why trm7Δ mutants grow poorly. We show here that despite the fact that S...
March 29, 2018: PLoS Genetics
Xiaokun Xu, Haibo Zhou, Yang Liu, Xiaotong Liu, Jun Fu, Aiying Li, Yue-Zhong Li, Yuemao Shen, Xiaoying Bian, Youming Zhang
The indole alkaloid antibiotic chuangxinmycin, from Actinobacteria Actinoplanes tsinanensis, containing a unique thiopyrano[4,3,2- cd]indole scaffold, is a potent and selective inhibitor of bacterial tryptophanyl-tRNA synthetase. The chuangxinmycin biosynthetic gene cluster was identified by in silico analysis of the genome sequence, then verified by heterologous expression. Systemic gene inactivation and intermediate identification determined the minimum set of genes for unique thiopyrano[4,3,2- cd]indole formation and the concerted action of a radical S-adenosylmethionine protein plus an unknown protein for addition of the 3-methyl group...
March 22, 2018: Journal of Natural Products
Ryota Yamagami, Ryota Miyake, Ayaka Fukumoto, Misa Nakashima, Hiroyuki Hori
TrmFO catalyzes the formation of 5-methyluridine at position 54 in tRNA and uses N5, N10-methylenetetrahydrofolate (CH2THF) as the methyl group donor. We found that the trmFO gene disruptant strain of Thermus thermophilus, an extremely-thermophilic eubacterium, can grow faster than the wild-type strain in the synthetic medium at 70 °C (optimal growth temperature). Nucleoside analysis revealed that the majority of modifications were appropriately introduced into tRNA, showing that the limited nutrients are preferentially consumed in the tRNA modification systems...
March 10, 2018: Journal of Biochemistry
Michael K Skinner, Millissia Ben Maamar, Ingrid Sadler-Riggleman, Daniel Beck, Eric Nilsson, Margaux McBirney, Rachel Klukovich, Yeming Xie, Chong Tang, Wei Yan
BACKGROUND: Environmental toxicants such as DDT have been shown to induce the epigenetic transgenerational inheritance of disease (e.g., obesity) through the germline. The current study was designed to investigate the DDT-induced concurrent alterations of a number of different epigenetic processes including DNA methylation, non-coding RNA (ncRNA) and histone retention in sperm. METHODS: Gestating females were exposed transiently to DDT during fetal gonadal development, and then, the directly exposed F1 generation, the directly exposed germline F2 generation and the transgenerational F3 generation sperm were investigated...
February 27, 2018: Epigenetics & Chromatin
Junhong Choi, Gabriele Indrisiunaite, Hasan DeMirci, Ka-Weng Ieong, Jinfan Wang, Alexey Petrov, Arjun Prabhakar, Gideon Rechavi, Dan Dominissini, Chuan He, Måns Ehrenberg, Joseph D Puglisi
Chemical modifications of mRNA may regulate many aspects of mRNA processing and protein synthesis. Recently, 2'-O-methylation of nucleotides was identified as a frequent modification in translated regions of human mRNA, showing enrichment in codons for certain amino acids. Here, using single-molecule, bulk kinetics and structural methods, we show that 2'-O-methylation within coding regions of mRNA disrupts key steps in codon reading during cognate tRNA selection. Our results suggest that 2'-O-methylation sterically perturbs interactions of ribosomal-monitoring bases (G530, A1492 and A1493) with cognate codon-anticodon helices, thereby inhibiting downstream GTP hydrolysis by elongation factor Tu (EF-Tu) and A-site tRNA accommodation, leading to excessive rejection of cognate aminoacylated tRNAs in initial selection and proofreading...
February 19, 2018: Nature Structural & Molecular Biology
Yoshihiko Iwane, Takayuki Katoh, Yuki Goto, Hiroaki Suga
In ribosomal polypeptide synthesis, the 61 sense codons redundantly code for the 20 proteinogenic amino acids. The genetic code contains eight family codon boxes consisting of synonymous codons that redundantly code for the same amino acid. Here, we describe the protocol of a recently published method to artificially divide such family codon boxes and encode multiple nonproteinogenic amino acids in addition to the 20 proteinogenic ones in a reprogrammed genetic code. To achieve this, an in vitro translation system reconstituted with 32 in vitro transcribed tRNASNN's (S = C or G; N = U, C, A or G) was first developed, where the 32 tRNA transcripts can be charged with 20 proteinogenic amino acids by aminoacyl-tRNA synthetases in situ and orthogonally decode the corresponding 31 NNS sense codons as well as the AUG initiation codon...
2018: Methods in Molecular Biology
Joshua J Hamey, Marc R Wilkins
Eukaryotic elongation factor 1A (eEF1A) is an essential and highly conserved protein involved in diverse cellular processes, including translation, cytoskeleton organisation, nuclear export, and proteasomal degradation. Recently, nine novel and site-specific methyltransferases were discovered that target eEF1A, five in yeast and four in human, making it the eukaryotic protein with the highest number of independent methyltransferases. Some of these methyltransferases show striking evolutionary conservation. Yet, they come from diverse methyltransferase families, indicating they confer competitive advantage through independent origins...
February 1, 2018: Trends in Biochemical Sciences
BiBi Fatemeh Nobakht Mothlagh Ghoochani, Rasoul Aliannejad, Afsaneh Arefi Oskouie, Mostafa Rezaei-Tavirani, Shiva Kalantari, Mohammad Taghi Naseri, Alireza Akbarzadeh Baghban, Hadi Parastar, Ghazaleh Aliakbarzadeh
Objectives: This study aims to evaluate combined proton nuclear magnetic resonance (1H NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) metabolic profiling approaches, for discriminating between mustard airway diseases (MADs) and healthy controls and for providing biochemical information on this disease. Materials and Methods: In the present study, analysis of serum samples collected from 17 MAD subjects and 12 healthy controls was performed using NMR...
January 2018: Iranian Journal of Basic Medical Sciences
Raphael J Morscher, Gregory S Ducker, Sophia Hsin-Jung Li, Johannes A Mayer, Zemer Gitai, Wolfgang Sperl, Joshua D Rabinowitz
Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, thymidine and methionine. Antifolates are important immunosuppressive and anticancer agents. In proliferating lymphocytes and human cancers, mitochondrial folate enzymes are particularly strongly upregulated. This in part reflects the need for mitochondria to generate one-carbon units and export them to the cytosol for anabolic metabolism. The full range of uses of folate-bound one-carbon units in the mitochondrial compartment itself, however, has not been thoroughly explored...
February 1, 2018: Nature
Isao Masuda, Ryuichi Takase, Ryuma Matsubara, Mellie June Paulines, Howard Gamper, Patrick A Limbach, Ya-Ming Hou
Active tRNAs are extensively post-transcriptionally modified, particularly at the wobble position 34 and the position 37 on the 3'-side of the anticodon. The 5-carboxy-methoxy modification of U34 (cmo5U34) is present in Gram-negative tRNAs for six amino acids (Ala, Ser, Pro, Thr, Leu and Val), four of which (Ala, Ser, Pro and Thr) have a terminal methyl group to form 5-methoxy-carbonyl-methoxy-uridine (mcmo5U34) for higher reading-frame accuracy. The molecular basis for the selective terminal methylation is not understood...
January 18, 2018: Nucleic Acids Research
Mi Zhou, Ling Xue, Yaru Chen, Haiying Li, Qiufen He, Bibin Wang, Feilong Meng, Meng Wang, Min-Xin Guan
Defective nucleotide modifications of mitochondrial tRNAs have been associated with several human diseases, but their pathophysiology remains poorly understood. In this report, we investigated the pathogenic molecular mechanism underlying a hypertension-associated 4435A→G mutation in mitochondrial tRNAMet The m.4435A→G mutation affected a highly conserved adenosine at position 37, 3' adjacent to the tRNA's anticodon, which is important for the fidelity of codon recognition and stabilization. We hypothesized that the m...
January 26, 2018: Journal of Biological Chemistry
Caiyan Wang, Qian Jia, Jianhua Zeng, Ran Chen, Wei Xie
The wyosine derivatives present at position 37 in transfer RNAs (tRNAs) are critical for reading frame maintenance. The methyltransferase Trm5a from Pyrococcus abyssi (PaTrm5a) plays a key role in this hypermodification process in generating m1 G37 and imG2, two products of the wyosine biosynthetic pathway, through two methyl transfers to distinct substrates, but the mechanism is currently unknown. We report two cocrystal structures of PaTrm5a in complex with tRNAPhe and reveal the structural basis for substrate recognition, which was supported by in vitro activity assays...
December 2017: Science Advances
Hsin-Jung Chou, Elisa Donnard, H Tobias Gustafsson, Manuel Garber, Oliver J Rando
Covalent nucleotide modifications in noncoding RNAs affect a plethora of biological processes, and new functions continue to be discovered even for well-known modifying enzymes. To systematically compare the functions of a large set of noncoding RNA modifications in gene regulation, we carried out ribosome profiling in budding yeast to characterize 57 nonessential genes involved in tRNA modification. Deletion mutants exhibited a range of translational phenotypes, with enzymes known to modify anticodons, or non-tRNA substrates such as rRNA, exhibiting the most dramatic translational perturbations...
December 7, 2017: Molecular Cell
Katchen Julliany P Silva, Asha M Brunings, Juliana A Pereira, Natalia A Peres, Kevin M Folta, Zhonglin Mou
BACKGROUND: Plant immune response is associated with a large-scale transcriptional reprogramming, which is regulated by numerous transcription regulators such as the Elongator complex. Elongator is a multitasking protein complex involved in diverse cellular processes, including histone modification, DNA methylation, and tRNA modification. In recent years, Elongator is emerging as a key regulator of plant immune responses. However, characterization of Elongator's function in plant immunity has been conducted only in the model plant Arabidopsis thaliana...
December 1, 2017: BMC Plant Biology
Marcus J O Johansson, Fu Xu, Anders S Byström
Naturally occurring modifications of the nucleosides in the anticodon region of tRNAs influence their translational decoding properties. Uridines present at the wobble position in eukaryotic cytoplasmic tRNAs often contain a 5-carbamoylmethyl (ncm5 ) or 5-methoxycarbonylmethyl (mcm5 ) side-chain and sometimes also a 2-thio or 2'-O-methyl group. The first step in the formation of the ncm5 and mcm5 side-chains requires the conserved six-subunit Elongator complex. Although Elongator has been implicated in several different cellular processes, accumulating evidence suggests that its primary, and possibly only, cellular function is to promote modification of tRNAs...
November 21, 2017: Biochimica et Biophysica Acta
Mie Mechta, Lars R Ingerslev, Odile Fabre, Martin Picard, Romain Barrès
Methylation of nuclear genes encoding mitochondrial proteins participates in the regulation of mitochondria function. The existence of cytosine methylation in the mitochondrial genome is debated. To investigate whether mitochondrial DNA (mtDNA) is methylated, we used both targeted- and whole mitochondrial genome bisulfite sequencing in cell lines and muscle tissue from mouse and human origin. While unconverted cytosines were detected in some portion of the mitochondrial genome, their abundance was inversely associated to the sequencing depth, indicating that sequencing analysis can bias the estimation of mtDNA methylation levels...
2017: Frontiers in Genetics
Takayuki Katoh, Yoshihiko Iwane, Hiroaki Suga
A bacterial translation factor EF-P alleviates ribosomal stalling caused by polyproline sequence by accelerating Pro-Pro formation. EF-P recognizes a specific D-arm motif found in tRNAPro isoacceptors, 9-nt D-loop closed by a stable D-stem sequence, for Pro-selective peptidyl-transfer acceleration. It is also known that the T-stem sequence on aminoacyl-tRNAs modulates strength of the interaction with EF-Tu, giving enhanced incorporation of non-proteinogenic amino acids such as some N-methyl amino acids. Based on the above knowledge, we logically engineered tRNA's D-arm and T-stem sequences to investigate a series of tRNAs for the improvement of consecutive incorporation of d-amino acids and an α, α-disubstituted amino acid...
December 15, 2017: Nucleic Acids Research
Zegang Wang, Kai Tang, Dayong Zhang, Yizhen Wan, Yan Wen, Quanyou Lu, Lei Wang
This study is the first to comprehensively characterize m6A patterns in the Arabidopsis chloroplast and mitochondria transcriptomes based on our open accessible data deposited in NCBI's Gene Expression Omnibus with GEO Series accession number of GSE72706. Over 86% of the transcripts were methylated by m6A in the two organelles. Over 550 and 350 m6A sites were mapped, with ~5.6 to ~5.8 and ~4.6 to ~4.9 m6A sites per transcript, to the chloroplast and mitochondria genome, respectively. The overall m6A methylation extent in the two organelles was greatly higher than that in the nucleus...
2017: PloS One
Lukas Trixl, Thomas Amort, Alexandra Wille, Manuela Zinni, Susanne Ebner, Clara Hechenberger, Felix Eichin, Hanna Gabriel, Ines Schoberleitner, Anming Huang, Paolo Piatti, Roxana Nat, Jakob Troppmair, Alexandra Lusser
Chemical modifications of RNA have been attracting increasing interest because of their impact on RNA fate and function. Therefore, the characterization of enzymes catalyzing such modifications is of great importance. The RNA cytosine methyltransferase NSUN3 was recently shown to generate 5-methylcytosine in the anticodon loop of mitochondrial tRNA(Met). Further oxidation of this position is required for normal mitochondrial translation and function in human somatic cells. Because embryonic stem cells (ESCs) are less dependent on oxidative phosphorylation than somatic cells, we examined the effects of catalytic inactivation of Nsun3 on self-renewal and differentiation potential of murine ESCs...
November 4, 2017: Cellular and Molecular Life Sciences: CMLS
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