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https://hdl.handle.net/10356/180037
Title: | tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum | Authors: | Small-Saunders, Jennifer L. Sinha, Ameya Bloxham, Talia S. Hagenah, Laura M. Sun, Guangxin Preiser, Peter Rainer Dedon, Peter C. Fidock, David A. |
Keywords: | Medicine, Health and Life Sciences | Issue Date: | 2024 | Source: | Small-Saunders, J. L., Sinha, A., Bloxham, T. S., Hagenah, L. M., Sun, G., Preiser, P. R., Dedon, P. C. & Fidock, D. A. (2024). tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum. Nature Microbiology, 9(6), 1483-1498. https://dx.doi.org/10.1038/s41564-024-01664-3 | Project: | MOE2018-T2-2-13 | Journal: | Nature Microbiology | Abstract: | Plasmodium falciparum artemisinin (ART) resistance is driven by mutations in kelch-like protein 13 (PfK13). 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 mcm5s2U on tRNA and possess a subset of proteins, including PfK13, that are regulated by Lys codon-biased translation. Conditional knockdown of the terminal s2U 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 s2U reprogramming that ART-resistant parasites may employ to survive ART-induced stress. | URI: | https://hdl.handle.net/10356/180037 | ISSN: | 2058-5276 | DOI: | 10.1038/s41564-024-01664-3 | Schools: | School of Biological Sciences | Organisations: | Singapore MIT Alliance for Research and Technology | Rights: | © 2024 The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/. | Fulltext Permission: | open | Fulltext Availability: | With Fulltext |
Appears in Collections: | SBS Journal Articles |
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