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Quiescence, a key aspect of resistance, may also be regulated by a yet unidentified epigenetic pathway. Transfer RNA modification reprogramming and codon bias translation is a conserved epitranscriptomic translational control mechanism that allows cells to rapidly respond to stress. We report a role for this mechanism in ART-resistant parasites by combining tRNA modification, proteomic and codon usage analyses in ring-stage ART-sensitive and ART-resistant parasites in response to drug. Post-drug, ART-resistant parasites differentially hypomodify mcm\n                    <jats:sup>5<\/jats:sup>\n                    s\n                    <jats:sup>2<\/jats:sup>\n                    U on tRNA and possess a subset of proteins, including PfK13, that are regulated by Lys codon-biased translation. Conditional knockdown of the terminal s\n                    <jats:sup>2<\/jats:sup>\n                    U thiouridylase, PfMnmA, in an ART-sensitive parasite background led to increased ART survival, suggesting that hypomodification can alter the parasite ART response. This study describes an epitranscriptomic pathway via tRNA s\n                    <jats:sup>2<\/jats:sup>\n                    U reprogramming that ART-resistant parasites may employ to survive ART-induced stress.\n                  <\/jats:p>","DOI":"10.1038\/s41564-024-01664-3","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T06:01:58Z","timestamp":1713333718000},"page":"1483-1498","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6064-2249","authenticated-orcid":false,"given":"Jennifer L.","family":"Small-Saunders","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ameya","family":"Sinha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia S.","family":"Bloxham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"Hagenah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4331-7000","authenticated-orcid":false,"given":"Peter R.","family":"Preiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0011-3067","authenticated-orcid":false,"given":"Peter C.","family":"Dedon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6753-8938","authenticated-orcid":false,"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"key":"1664_CR1","unstructured":"World malaria report. 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