{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:58:39Z","timestamp":1791658719817,"version":"4.3.4"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T00:00:00Z","timestamp":1715126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"LOEWE","award":["LOEWE\/5\/A001\/519\/06\/00.002(0002)\/E02"],"award-info":[{"award-number":["LOEWE\/5\/A001\/519\/06\/00.002(0002)\/E02"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SCHA750\/20"],"award-info":[{"award-number":["SCHA750\/20"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KL2937\/1"],"award-info":[{"award-number":["KL2937\/1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HE3397\/14-2"],"award-info":[{"award-number":["HE3397\/14-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["448909517\/GRK 2749"],"award-info":[{"award-number":["448909517\/GRK 2749"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TP C03"],"award-info":[{"award-number":["TP C03"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012687","name":"University of Kassel","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012687","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Therapeutic fluoropyrimidines 5-fluorouracil (5-FU) and 5-fluorocytosine (5-FC) are in long use for treatment of human cancers and severe invasive fungal infections, respectively. 5-Fluorouridine triphosphate represents a bioactive metabolite of both drugs and is incorporated into target cells\u2019 RNA. Here we use the model fungus Saccharomyces cerevisiae to define fluorinated tRNA as a key mediator of 5-FU and 5-FC cytotoxicity when specific tRNA methylations are absent. tRNA methylation deficiency caused by loss of Trm4 and Trm8 was previously shown to trigger an RNA quality control mechanism resulting in partial destabilization of hypomodified tRNAValAAC. We demonstrate that, following incorporation into tRNA, fluoropyrimidines strongly enhance degradation of yeast tRNAValAAC lacking Trm4 and Trm8 dependent methylations. At elevated temperature, such effect occurs already in absence of Trm8 alone. Genetic approaches and quantification of tRNA modification levels reveal that enhanced fluoropyrimidine cytotoxicity results from additional, drug induced uridine modification loss and activation of tRNAValAAC decay involving the exonuclease Xrn1. These results suggest that inhibition of tRNA methylation may be exploited to boost therapeutic efficiency of 5-FU and 5-FC.<\/jats:p>","DOI":"10.1093\/nar\/gkae341","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T11:15:40Z","timestamp":1715166940000},"page":"5841-5851","source":"Crossref","is-referenced-by-count":8,"title":["Fluoropyrimidines trigger decay of hypomodified tRNA in yeast"],"prefix":"10.1093","volume":"52","author":[{"given":"Katharina","family":"G\u00f6rlitz","sequence":"first","affiliation":[{"name":"Institute of Biology, Department of Microbiology, Universit\u00e4t Kassel , Kassel\u00a0 34132 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Bessler","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-Universit\u00e4t Mainz , Mainz\u00a0 55128 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0154-0928","authenticated-orcid":false,"given":"Mark","family":"Helm","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-Universit\u00e4t Mainz , Mainz\u00a0 55128 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9484-5247","authenticated-orcid":false,"given":"Raffael","family":"Schaffrath","sequence":"additional","affiliation":[{"name":"Institute of Biology, Department of Microbiology, Universit\u00e4t Kassel , Kassel\u00a0 34132 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0809-0050","authenticated-orcid":false,"given":"Roland","family":"Klassen","sequence":"additional","affiliation":[{"name":"Institute of Biology, Department of Microbiology, Universit\u00e4t Kassel , Kassel\u00a0 34132 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,8]]},"reference":[{"key":"2024061000004649100_B1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1101\/gad.1049103","article-title":"tRNA transfers to the limelight","volume":"17","author":"Hopper","year":"2003","journal-title":"Genes Dev."},{"key":"2024061000004649100_B2","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1146\/annurev-genet-110711-155641","article-title":"Biosynthesis and function of posttranscriptional modifications of transfer RNAs","volume":"46","author":"El\u00a0Yacoubi","year":"2012","journal-title":"Annu. 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