{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T01:52:32Z","timestamp":1792720352000,"version":"4.5.0"},"reference-count":101,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T00:00:00Z","timestamp":1734912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"BMBF","doi-asserted-by":"publisher","award":["FKZ 01K12012"],"award-info":[{"award-number":["FKZ 01K12012"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"BMBF","doi-asserted-by":"publisher","award":["01KD2101D"],"award-info":[{"award-number":["01KD2101D"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["390713860"],"award-info":[{"award-number":["390713860"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["210879364"],"award-info":[{"award-number":["210879364"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Increasing antifungal drug resistance is a major concern associated with human fungal pathogens like Aspergillus fumigatus. Genetic mutation and epimutation mechanisms clearly drive resistance, yet the epitranscriptome remains relatively untested. Here, deletion of the A. fumigatus transfer RNA (tRNA)-modifying isopentenyl transferase ortholog, Mod5, led to altered stress response and unexpected resistance against the antifungal drug 5-fluorocytosine (5-FC). After confirming the canonical isopentenylation activity of Mod5 by liquid chromatography-tandem mass spectrometry and Nano-tRNAseq, we performed simultaneous profiling of transcriptomes and proteomes to reveal a comparable overall response to 5-FC stress; however, a premature activation of cross-pathway control (CPC) genes in the knockout was further increased after antifungal treatment. We identified several orthologues of the Aspergillus nidulans Major Facilitator Superfamily transporter nmeA as specific CPC-client genes in A. fumigatus. Overexpression of Mod5-target tRNATyrG\u03a8A in the \u0394mod5 strain rescued select phenotypes but failed to reverse 5-FC resistance, whereas deletion of nmeA largely, but incompletely, reverted the resistance phenotype, implying additional relevant exporters. In conclusion, 5-FC resistance in the absence of Mod5 and i6A likely originates from multifaceted transcriptional and translational changes that skew the fungus towards premature CPC-dependent activation of antifungal toxic-intermediate exporter nmeA, offering a potential mechanism reliant on RNA modification to facilitate transient antifungal resistance.<\/jats:p>","DOI":"10.1093\/nar\/gkae1205","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T10:26:38Z","timestamp":1734949598000},"source":"Crossref","is-referenced-by-count":8,"title":["tRNA hypomodification facilitates 5-fluorocytosine resistance via cross-pathway control system activation in <i>Aspergillus fumigatus<\/i>"],"prefix":"10.1093","volume":"53","author":[{"given":"Alexander","family":"Bruch","sequence":"first","affiliation":[{"name":"Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology\u2014Hans Kn\u00f6ll Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11A, 07745\u00a0 Jena ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Lazarova","sequence":"additional","affiliation":[{"name":"Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology\u2014Hans Kn\u00f6ll Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11A, 07745\u00a0 Jena ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Berg","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe University Frankfurt , Max-von-Laue-Stra\u00dfe 9, 60438 Frankfurt am Main ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kr\u00fcger","sequence":"additional","affiliation":[{"name":"Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology\u2014Hans Kn\u00f6ll Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11A, 07745 Jena ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3862-6546","authenticated-orcid":false,"given":"Sascha","family":"Sch\u00e4uble","sequence":"additional","affiliation":[{"name":"Department of Microbiome Dynamics, Leibniz Institute for Natural Product Research and Infection Biology\u2014Hans Kn\u00f6ll Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11A, 07745\u00a0 Jena ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulrahman\u00a0A","family":"Kelani","sequence":"additional","affiliation":[{"name":"Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology\u2014Hans Kn\u00f6ll Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11A, 07745\u00a0 Jena 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and Infection Biology\u2014Hans Kn\u00f6ll Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11A, 07745 Jena ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3224-7502","authenticated-orcid":false,"given":"Stefanie","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe University Frankfurt , Max-von-Laue-Stra\u00dfe 9, 60438 Frankfurt am Main ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0128-3076","authenticated-orcid":false,"given":"Gianni","family":"Panagiotou","sequence":"additional","affiliation":[{"name":"Department of Microbiome Dynamics, Leibniz Institute for Natural Product Research and Infection Biology\u2014Hans Kn\u00f6ll Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11A, 07745\u00a0 Jena ,","place":["Germany"]},{"name":"Friedrich-Schiller-University, Faculty of Biological Sciences , F\u00fcrstengraben 1, 07743\u00a0 Jena ,","place":["Germany"]},{"name":"Cluster of Excellence Balance of the Microverse, Friedrich-Schiller-University , F\u00fcrstengraben 1, 07743\u00a0 Jena ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9257-8648","authenticated-orcid":false,"given":"Fabio","family":"Gsaller","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, Biocenter, Medical University of Innsbruck , Fritz-Pregl-Stra\u00dfe 3, 6020 Innsbruck ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8015-9019","authenticated-orcid":false,"given":"Matthew\u00a0G","family":"Blango","sequence":"additional","affiliation":[{"name":"Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology\u2014Hans Kn\u00f6ll Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11A, 07745\u00a0 Jena ,","place":["Germany"]},{"name":"Cluster of Excellence Balance of the Microverse, Friedrich-Schiller-University , F\u00fcrstengraben 1, 07743\u00a0 Jena ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,12,23]]},"reference":[{"key":"2025020516033601800_B1","doi-asserted-by":"crossref","first-page":"165rv113","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden killers: human fungal infections","volume":"4","author":"Brown","year":"2012","journal-title":"Sci. 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Mech."},{"key":"2025020516033601800_B15","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1101\/gad.1956510","article-title":"tRNA biology charges to the front","volume":"24","author":"Phizicky","year":"2010","journal-title":"Genes Dev."},{"key":"2025020516033601800_B16","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":"2025020516033601800_B17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0378-1119(00)00421-2","article-title":"Cloning of a human tRNA isopentenyl transferase","volume":"258","author":"Golovko","year":"2000","journal-title":"Gene"},{"key":"2025020516033601800_B18","first-page":"177","article-title":"Isolation and characterization of MOD5, a gene required for isopentenylation of cytoplasmic and mitochondrial tRNAs of Saccharomyces cerevisiae","volume":"7","author":"Dihanich","year":"1987","journal-title":"Mol. 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