{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:19:05Z","timestamp":1790270345323,"version":"4.1.0"},"reference-count":106,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T00:00:00Z","timestamp":1645747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01ES026856, R01ES031529,T32GM132066"],"award-info":[{"award-number":["R01ES026856, R01ES031529,T32GM132066"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Epitranscriptomic marks, in the form of enzyme catalyzed RNA modifications, play important gene regulatory roles in response to environmental and physiological conditions. However, little is known with respect to how acute toxic doses of pharmaceuticals influence the epitranscriptome. Here we define how acetaminophen (APAP) induces epitranscriptomic reprogramming and how the writer Alkylation Repair Homolog 8 (Alkbh8) plays a key gene regulatory role in the response. Alkbh8 modifies tRNA selenocysteine (tRNASec) to translationally regulate the production of glutathione peroxidases (Gpx\u2019s) and other selenoproteins, with Gpx enzymes known to play protective roles during APAP toxicity. We demonstrate that APAP increases toxicity and markers of damage, and decreases selenoprotein levels in Alkbh8 deficient mouse livers, when compared to wildtype. APAP also promotes large scale reprogramming of many RNA marks comprising the liver tRNA epitranscriptome including: 5-methoxycarbonylmethyluridine (mcm5U), isopentenyladenosine (i6A), pseudouridine (\u03a8), and 1-methyladenosine (m1A) modifications linked to tRNASec and many other tRNA\u2019s. Alkbh8 deficiency also leads to wide-spread epitranscriptomic dysregulation in response to APAP, demonstrating that a single writer defect can promote downstream changes to a large spectrum of RNA modifications. Our study highlights the importance of RNA modifications and translational responses to APAP, identifies writers as key modulators of stress responses in vivo and supports the idea that the epitranscriptome may play important roles in responses to pharmaceuticals.<\/jats:p>","DOI":"10.3390\/genes13030421","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T10:00:40Z","timestamp":1645783240000},"page":"421","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Epitranscriptomic Reprogramming Is Required to Prevent Stress and Damage from Acetaminophen"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9972-9496","authenticated-orcid":false,"given":"Sara","family":"Evke","sequence":"first","affiliation":[{"name":"Nanobioscience Constellation, College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY 12203, USA"},{"name":"The RNA Institute, University at Albany, Albany, NY 12222, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qishan","family":"Lin","sequence":"additional","affiliation":[{"name":"The RNA Institute, University at Albany, Albany, NY 12222, USA"},{"name":"Department of Biological Sciences, University at Albany, Albany, NY 12222, USA"},{"name":"RNA Epitranscriptomics and Proteomics Resource, University at Albany, Albany, NY 12222, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Andres","family":"Melendez","sequence":"additional","affiliation":[{"name":"Nanobioscience Constellation, College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY 12203, USA"},{"name":"The RNA Institute, University at Albany, Albany, NY 12222, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas John","family":"Begley","sequence":"additional","affiliation":[{"name":"The RNA Institute, University at Albany, Albany, NY 12222, USA"},{"name":"Department of Biological Sciences, University at Albany, Albany, NY 12222, USA"},{"name":"RNA Epitranscriptomics and Proteomics Resource, University at Albany, Albany, NY 12222, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.molmed.2018.07.010","article-title":"Epitranscriptomic Code and Its Alterations in Human Disease","volume":"24","author":"Kadumuri","year":"2018","journal-title":"Trends Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1074\/mcp.M115.054718","article-title":"Global Epitranscriptomics Profiling of RNA Post-Transcriptional Modifications as an Effective Tool for Investigating the Epitranscriptomics of Stress Response","volume":"15","author":"Rose","year":"2016","journal-title":"Mol. Cell. Proteom."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/bs.mie.2015.03.004","article-title":"A platform for discovery and quantification of modified ribonucleosides in RNA: Application to stress-induced reprogramming of tRNA modificiations","volume":"560","author":"Cai","year":"2016","journal-title":"Methods Enzymol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/emmm.201201161","article-title":"A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-\u03b1","volume":"5","author":"Begley","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1186\/s13059-018-1611-1","article-title":"Lifestyle modifications: Coordinating the tRNA epitranscriptome with codon bias to adapt translation during stress responses","volume":"19","author":"Chan","year":"2018","journal-title":"Genome Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1021\/acs.chemrestox.5b00004","article-title":"Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes","volume":"28","author":"Chan","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chan, C.T.Y., Dyavaiah, M., DeMott, M.S., Taghizadeh, K., Dedon, P.C., and Begley, T.J. (2010). A Quantitative Systems Approach Reveals Dynamic Control of tRNA Modifications during Cellular Stress. PLoS Genet., 6.","DOI":"10.1371\/journal.pgen.1001247"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/ncomms1938","article-title":"Reprogramming of tRNA modifications controls the oxidative stress response by codon-biased translation of proteins","volume":"3","author":"Chan","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.cell.2016.09.038","article-title":"ALKBH1-Mediated tRNA Demethylation Regulates Translation","volume":"167","author":"Liu","year":"2016","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1080\/15476286.2017.1356562","article-title":"Celebrating wobble decoding: Half a century and still much is new","volume":"15","author":"Agris","year":"2017","journal-title":"RNA Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.enz.2017.03.005","article-title":"The Importance of Being Modified: The Role of RNA Modifications in Translational Fidelity","volume":"41","author":"Agris","year":"2017","journal-title":"Enzymes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jmb.2006.11.046","article-title":"tRNA\u2019s Wobble Decoding of the Genome: 40 Years of Modification","volume":"366","author":"Agris","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41422-018-0013-y","article-title":"Modifications and functional genomics of human transfer RNA","volume":"28","author":"Pan","year":"2018","journal-title":"Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1042\/BJ20121713","article-title":"Mammalian Trit1 is a tRNA([Ser]Sec)-isopentenyl transferase required for full selenoprotein expression","volume":"450","author":"Fradejas","year":"2013","journal-title":"Biochem. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4293","DOI":"10.1093\/nar\/gkl530","article-title":"Formation of the conserved pseudouridine at position 55 in archaeal tRNA","volume":"34","author":"Roovers","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"32562","DOI":"10.1038\/srep32562","article-title":"Crystal structure of the two-subunit tRNA m1A58 methyltransferase TRM6-TRM61 from Saccharomyces cerevisiae","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Endres, L., Begley, U., Clark, R., Gu, C., Dziergowska, A.B., Ma\u0142kiewicz, A., Melendez, J.A., Dedon, P.C., and Begley, T.J. (2015). Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131335"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1074\/jbc.M111.286187","article-title":"Crystal Structure and RNA Binding Properties of the RNA Recognition Motif (RRM) and AlkB Domains in Human AlkB Homolog 8 (ABH8), an Enzyme Catalyzing tRNA Hypermodification","volume":"287","author":"Pastore","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1128\/MCB.01602-09","article-title":"Mammalian ALKBH8 Possesses tRNA Methyltransferase Activity Required for the Biogenesis of Multiple Wobble Uridine Modifications Implicated in Translational Decoding","volume":"30","author":"Leihne","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/ncomms1173","article-title":"ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA","volume":"2","author":"Born","year":"2011","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1128\/MCB.01604-09","article-title":"Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival","volume":"30","author":"Fu","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24036","DOI":"10.1074\/jbc.M116.756155","article-title":"Selenoprotein gene nomenclature","volume":"291","author":"Regina","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.freeradbiomed.2018.05.076","article-title":"Selenoprotein T is a key player in ER proteostasis, endocrine homeostasis and neuroprotection","volume":"127","author":"Anouar","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0079-6603(06)81003-2","article-title":"Selenocysteine Incorporation Machinery and the Role of Selenoproteins in Development and Health","volume":"81","author":"Hatfield","year":"2006","journal-title":"Prog. Nucleic Acid Res. Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hofstee, P., Cuffe, J.S., and Perkins, A.V. (2020). Analysis of Selenoprotein Expression in Response to Dietary Selenium Deficiency During Pregnancy Indicates Tissue Specific Differential Expression in Mothers and Sex Specific Changes in the Fetus and Offspring. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21062210"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pappas, A.C., Zoidis, E., and Chadio, S.E. (2019). Maternal Selenium and Developmental Programming. Antioxidants, 8.","DOI":"10.3390\/antiox8050145"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1089\/152308604771978336","article-title":"Regulation of the Mammalian Selenoprotein Thioredoxin Reductase 1 in Relation to Cellular Phenotype, Growth, and Signaling Events","volume":"6","year":"2004","journal-title":"Antioxid. Redox Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.nmd.2006.10.006","article-title":"Selenoprotein expression is essential in endothelial cell development and cardia muscle function","volume":"17","author":"Shrimali","year":"2008","journal-title":"Neuromuscul. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1016\/j.bbagen.2009.02.014","article-title":"Protection against reactive oxygen species by selenoproteins","volume":"1790","author":"Steinbrenner","year":"2009","journal-title":"Biochim. Biophys. Acta (BBA) Gen. Subj."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1089\/ars.2009.2890","article-title":"Selenoproteins and Protection against Oxidative Stress: Selenoprotein N as a Novel Player at the Crossroads of Redox Signaling and Calcium Homeostasis","volume":"12","author":"Arbogast","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.freeradbiomed.2018.01.028","article-title":"Roles of mammalian glutathione peroxidase and thioredoxin reductase enzymes in the cellular response to nitrosative stress","volume":"127","author":"Benhar","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1128\/MCB.00544-08","article-title":"Glutathione Peroxidase 3 Mediates the Antioxidant Effect of Peroxisome Proliferator-Activated Receptor \u03b3 in Human Skeletal Muscle Cells","volume":"29","author":"Chung","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.freeradbiomed.2016.02.028","article-title":"The role of glutathione reductase and related enzymes on cellular redox homoeostasis network","volume":"95","author":"Couto","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.ijrobp.2013.06.2063","article-title":"Selenoprotein P Inhibits Radiation-Induced Late Reactive Oxygen Species Accumulation and Normal Cell Injury","volume":"87","author":"Eckers","year":"2013","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11983","DOI":"10.1096\/fj.202000180RR","article-title":"Selenoprotein T protects against cisplatin-induced acute kidney injury through suppression of oxidative stress and apoptosis","volume":"34","author":"Huang","year":"2020","journal-title":"FASEB J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1080\/15592294.2020.1750213","article-title":"The epitranscriptomic writer ALKBH8 drives tolerance and protects mouse lungs from the environmental pollutant naphthalene","volume":"15","author":"Leonardi","year":"2020","journal-title":"Epigenetics"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zoidis, E., Seremelis, I., Kontopoulos, N., and Danezis, G.P. (2018). Selenium-Dependent Antioxidant Enzymes: Actions and Properties of Selenoproteins. Antioxidants, 7.","DOI":"10.3390\/antiox7050066"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"101375","DOI":"10.1016\/j.redox.2019.101375","article-title":"Loss of epitranscriptomic control of selenocysteine utilization engages senescence and mitochondrial reprogramming","volume":"28","author":"Lee","year":"2019","journal-title":"Redox Biol."},{"key":"ref_39","first-page":"131","article-title":"Review Article Acetaminophen-Induced Hepatotoxicity: A Comprehensive Update","volume":"4","author":"Yoon","year":"2016","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10349","DOI":"10.1074\/jbc.274.15.10349","article-title":"Acetaminophen Toxicity Opposite Effects of Two Forms of Flutathione Peroxidase","volume":"274","author":"Mirochnitchenko","year":"1999","journal-title":"Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1007\/s11095-013-1007-6","article-title":"Metabolism and Disposition of Acetaminophen: Recent Advances in Relation to Hepatotoxicity and Diagnosis","volume":"30","author":"McGill","year":"2013","journal-title":"Pharm. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Clark, R., Fisher, J.E., Sketris, I.S., and Johnston, G.M. (2012). Population prevalence of high dose paracetamol in dispensed paracetamol\/opioid prescription combinations: An observational study. BMC Clin. Pharmacol., 12.","DOI":"10.1186\/1472-6904-12-11"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"748","DOI":"10.3892\/ijmm.2017.3049","article-title":"Glutathione peroxidase 3 is a protective factor against acetaminophen-induced hepatotoxicity in vivo and in vitro","volume":"40","author":"Kanno","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0076-6879(10)77013-0","article-title":"Gene Trap Mutagenesis in the Mouse","volume":"477","author":"Friedel","year":"2010","journal-title":"Methods Enzymol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.redox.2016.10.001","article-title":"Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential","volume":"10","author":"Du","year":"2016","journal-title":"Redox Biol."},{"key":"ref_46","first-page":"e26","article-title":"Attomole quantification and global profile of RNA modifications: Epitranscriptome of human neural stem cells","volume":"44","author":"Temple","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1096\/fj.04-2330rev","article-title":"Isoprostanes: Markers and mediators of oxidative stress","volume":"18","author":"Montuschi","year":"2004","journal-title":"FASEB J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"41254","DOI":"10.1074\/jbc.M202773200","article-title":"A Comparative Study on the Hydroperoxide and Thiol Specificity of the Glutathione Peroxidase Family and Selenoprotein P","volume":"277","author":"Takebe","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7241","DOI":"10.1021\/bi015916c","article-title":"Evidence of an Odorant-Binding Protein in the Human Olfactory Mucus:\u2009 Location, Structural Characterization, and Odorant-Binding Properties","volume":"41","author":"Briand","year":"2002","journal-title":"Biochemistry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"16899","DOI":"10.1073\/pnas.242603899","article-title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences","volume":"99","author":"Strausberg","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0968-0004(96)80016-8","article-title":"Knowing when not to stop: Selenocysteine incorporation in eukaryotes","volume":"21","author":"Low","year":"1996","journal-title":"Trends Biochem. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.taap.2014.09.002","article-title":"Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase","volume":"281","author":"Du","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_55","first-page":"145","article-title":"Oxidant Stress and Lipid Peroxidation in Acetaminophen Hepaptotoxicity","volume":"5","author":"Jaeschke","year":"2018","journal-title":"React. Oxyg. Species"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1172\/JCI59755","article-title":"The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation","volume":"122","author":"McGill","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1177\/0023677215570992","article-title":"Acetaminophen-induced acute liver injury in mice","volume":"49","author":"Mossanen","year":"2015","journal-title":"Lab. Anim."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1093\/toxsci\/kfq208","article-title":"The Oxygen Tension Modulates Acetaminophen-Induced Mitochondrial Oxidant Stress and Cell Injury in Cultured Hepatocytes","volume":"117","author":"Yan","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3727\/105221618X15205260749346","article-title":"DNA Damage Response Regulates Initiation of Liver Regeneration Following Acetaminophen Overdose","volume":"18","author":"Borude","year":"2018","journal-title":"Gene Expr."},{"key":"ref_60","first-page":"157","article-title":"Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology","volume":"3","author":"Ramachandran","year":"2017","journal-title":"J. Clin. Transl. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3727\/105221617X15084371374138","article-title":"Invited Review Acetaminophen Toxicity: Novel Insights Into Mechanisms and Future Perspectives","volume":"18","author":"Ramachandran","year":"2018","journal-title":"Gene Expr."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/ncomms13302","article-title":"tRNA-mediated codon-biased translation in mycobacterial hypoxic persistence","volume":"7","author":"Chionh","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1080\/15476286.2017.1295204","article-title":"Wobble uridine modifications\u2014A reason to live, a reason to die?!","volume":"14","author":"Schaffrath","year":"2017","journal-title":"RNA Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7225","DOI":"10.1038\/s41598-017-07647-1","article-title":"Elp3 and Dph3 of Schizosaccharomyces pombe mediate cellular stress responses through tRNALys UUU modifications","volume":"7","author":"Villahermosa","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Wilkinson, E., Cui, Y.-H., and He, Y.-Y. (2021). Context-Dependent Roles of RNA Modifications in Stress Responses and Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041949"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.molcel.2007.09.021","article-title":"Trm9-Catalyzed tRNA Modifications Link Translation to the DNA Damage Response","volume":"28","author":"Begley","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41568-020-0253-2","article-title":"Role of RNA modifications in cancer","volume":"20","author":"Barbieri","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1097\/CCO.0000000000000252","article-title":"Posttranscriptional methylation of transfer and ribosomal RNA in stress response pathways, cell differentiation, and cancer","volume":"28","author":"Popis","year":"2016","journal-title":"Curr. Opin. Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/s41586-018-0243-7","article-title":"Codon-specific translation reprogramming promotes resistance to targeted therapy","volume":"558","author":"Rapino","year":"2018","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.trecan.2017.02.004","article-title":"tRNA Modification: Is Cancer Having a Wobble?","volume":"3","author":"Rapino","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"330","DOI":"10.3892\/ol.2021.12591","article-title":"Methyltransferase-like 1 regulates lung adenocarcinoma A549 cell proliferation and autophagy via the AKT\/mTORC1 signaling pathway","volume":"21","author":"Wang","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1172\/JCI0214938","article-title":"The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy","volume":"110","author":"Sadoshima","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1126\/science.1072682","article-title":"Mitogen-Activated Protein Kinase Pathways Mediated by ERK, JNK, and p38 Protein Kinases","volume":"298","author":"Johnson","year":"2002","journal-title":"Science"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"35071","DOI":"10.1074\/jbc.M111.276089","article-title":"c-Jun N-terminal Kinase (JNK)-dependent Acute Liver Injury from Acetaminophen or Tumor Necrosis Factor (TNF) Requires Mitochondrial Sab Protein Expression in Mice","volume":"286","author":"Win","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1093\/toxsci\/kfm150","article-title":"Multicenter Study of Acetaminophen Hepatotoxicity Reveals the Importance of Biological Endpoints in Genomic Analyses","volume":"99","author":"Beyer","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.freeradbiomed.2019.08.030","article-title":"Epitranscriptomic systems regulate the translation of reactive oxygen species detoxifying and disease linked selenoproteins","volume":"143","author":"Leonardi","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.bcp.2017.09.009","article-title":"Selective inhibition of endogenous antioxidants with Auranofin causes mitochondrial oxidative stress which can be countered by selenium supplementation","volume":"146","author":"Radenkovic","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Lopert, P., Day, B.J., and Patel, M. (2012). Thioredoxin Reductase Deficiency Potentiates Oxidative Stress, Mitochondrial Dysfunction and Cell Death in Dopaminergic Cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050683"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1515\/BC.2003.064","article-title":"Oxidative Stress Caused by Inactivation of Glutathione Peroxidase and Adaptive Responses","volume":"384","author":"Miyamoto","year":"2003","journal-title":"Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1021\/tx9800349","article-title":"Nitrotyrosine\u2212Protein Adducts in Hepatic Centrilobular Areas following Toxic Doses of Acetaminophen in Mice","volume":"11","author":"Hinson","year":"1998","journal-title":"Chem. Res. Toxicol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1124\/jpet.105.088898","article-title":"Peroxynitrite-Induced Mitochondrial and Endonuclease-Mediated Nuclear DNA Damage in Acetaminophen Hepatotoxicity","volume":"315","author":"Cover","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1080\/15476286.2017.1294309","article-title":"The modified base isopentenyladenosine and its derivatives in tRNA","volume":"14","author":"Schweizer","year":"2017","journal-title":"RNA Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"28110","DOI":"10.1074\/jbc.M001280200","article-title":"Inhibition of selenoprotein synthesis by selenocysteine tRNA([Ser]Sec) lacking isopentenyladenosine","volume":"275","author":"Warner","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"D262","DOI":"10.1093\/nar\/gks1007","article-title":"MODOMICS: A database of RNA modification pathways\u20142013 update","volume":"41","author":"Machnicka","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1080\/15476286.2020.1779492","article-title":"The stress specific impact of ALKBH1 on tRNA cleavage and tiRNA generation","volume":"17","author":"Rashad","year":"2020","journal-title":"RNA Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3656","DOI":"10.4161\/cc.21919","article-title":"Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response","volume":"11","author":"Patil","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e27","DOI":"10.1093\/nar\/gkaa1186","article-title":"Nucleotide resolution profiling of m3C RNA modification by HAC-seq","volume":"49","author":"Cui","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"14695","DOI":"10.1074\/jbc.M117.798298","article-title":"Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans","volume":"292","author":"Xu","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"eaaz4551","DOI":"10.1126\/sciadv.aaz4551","article-title":"METTL6 is a tRNA m 3 C methyltransferase that regulates pluripotency and tumor cell growth","volume":"6","author":"Ignatova","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"517","DOI":"10.3389\/fphar.2019.00517","article-title":"METTL3\/m6A\/miRNA-873-5p attenuated oxidative stress and apoptosis in colistin-induced kidney injury by modulating Keap1\/Nrf2 pathway","volume":"10","author":"Wang","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"113908","DOI":"10.1016\/j.envpol.2019.113908","article-title":"N6-methyladenosine mediates arsenite-induced human keratinocyte transformation by suppressing p53 activation","volume":"259","author":"Zhao","year":"2020","journal-title":"Environ. Pollut."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1111\/jcmm.14128","article-title":"N6-methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO-PGC-1\u03b1 signalling axis","volume":"23","author":"Zhuang","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"20734","DOI":"10.1074\/jbc.R115.656462","article-title":"The AlkB family of Fe(II)\/\u03b1-ketoglutarate-dependent dioxygenases: Repairing nucleic acid alkylation damage and beyond","volume":"290","author":"Fedeles","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/j.freeradbiomed.2012.07.020","article-title":"The control of histone methylation and gene expression by oxidative stress, hypoxia, and metals","volume":"53","author":"Chervona","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"7341","DOI":"10.1021\/acs.jmedchem.5b00702","article-title":"Identification of A Novel Small-Molecule Binding Site of the Fat Mass and Obesity Associated Protein (FTO)","volume":"58","author":"He","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.bbrc.2013.05.077","article-title":"A mechanistic overview of TET-mediated 5-methylcytosine oxidation","volume":"436","author":"Ponnaluri","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"258","DOI":"10.2337\/db10-0281","article-title":"FTO Is Increased in Muscle During Type 2 Diabetes, and Its Overexpression in Myotubes Alters Insulin Signaling, Enhances Lipogenesis and ROS Production, and Induces Mitochondrial Dysfunction","volume":"60","author":"Bravard","year":"2010","journal-title":"Diabetes"},{"key":"ref_98","first-page":"1004","article-title":"Fat Mass and Obesity-Associated Gene Enhances Oxidative Stress and Lipogenesis in Nonalcoholic Fatty Liver Disease","volume":"58","author":"Guo","year":"2013","journal-title":"Am. J. Dig. Dis."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e201800113","DOI":"10.26508\/lsa.201800113","article-title":"Dynamic m6A methylation facilitates mRNA triaging to stress granules","volume":"1","author":"Anders","year":"2018","journal-title":"Life Sci. Alliance"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"13040","DOI":"10.1096\/fj.201901331R","article-title":"Mettl17, a regulator of mitochondrial ribosomal RNA modifications, is required for the translation of mitochondrial coding genes","volume":"33","author":"Shi","year":"2019","journal-title":"FASEB J."},{"key":"ref_101","first-page":"2587","article-title":"NSUN2-mediated m5C methylation and METTL3\/METTL14-mediated m6A methylation cooperatively enhance p21 translation","volume":"119","author":"Li","year":"2018","journal-title":"J. Cell Biochem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3255","DOI":"10.4161\/cc.8.20.9565","article-title":"Nrf2 and p21 regulate the fine balance between life and death by controlling ROS levels","volume":"8","author":"Villeneuve","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_103","first-page":"621","article-title":"The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells","volume":"52","author":"Taketo","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2782","DOI":"10.1038\/s41467-019-10669-0","article-title":"m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade","volume":"10","author":"Yang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"20159","DOI":"10.1073\/pnas.1918986117","article-title":"ALKBH5 regulates anti\u2013PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment","volume":"117","author":"Li","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0167-4889(97)00092-X","article-title":"Replenishment of selenium deficient rats with selenium results in redistribution of the selenocysteine tRNA population in a tissue specific manner","volume":"1359","author":"Chittum","year":"1997","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/3\/421\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:27:24Z","timestamp":1760135244000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/3\/421"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,25]]},"references-count":106,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["genes13030421"],"URL":"https:\/\/doi.org\/10.3390\/genes13030421","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.08.16.456530","asserted-by":"object"}]},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,25]]}}}