Codon-specific translation reprogramming promotes resistance to targeted therapy

Francesca Rapino, Sylvain Delaunay, Florian Rambow, Zhaoli Zhou, Lars Tharun, Pascal De Tullio, Olga Sin, Kateryna Shostak, Sebastian Schmitz, Jolanda Piepers, Bart Ghesquiere, Latifa Karim, Benoit Charloteaux, Diane Jamart, Alexandra Florin, Charles Lambert, Andree Rorive, Guy Jerusalem, Eleonora Leucci, Michael DewaeleMarc Vooijs, Sebastian A. Leidel, Michel Georges, Marianne Voz, Bernard Peers, Reinhard Buttner, Jean-Christophe Marine, Alain Chariot, Pierre Close*

*Corresponding author for this work

Research output: Contribution to journalComment/Letter to the editorAcademicpeer-review

128 Citations (Web of Science)


Reprogramming of mRNA translation has a key role in cancer development and drug resistance(1). However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation(2,3). Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U-34) tRNA (U-34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF(V600E) oncogene and by resistance to targeted therapy in melanoma. We show that BRAF(V600E)-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U-34 enzymes. Mechanistically, U-34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1 alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U-34 enzymes and HIF1 alpha. Together, these results demonstrate that U-34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.
Original languageEnglish
Pages (from-to)605-609
Number of pages5
Issue number7711
Publication statusPublished - 28 Jun 2018


  • Author Correction: Codon-specific translation reprogramming promotes resistance to targeted therapy

    Rapino, F., Delaunay, S., Rambow, F., Zhou, Z., Tharun, L., De Tullio, P., Sin, O., Shostak, K., Schmitz, S., Piepers, J., Ghesquière, B., Karim, L., Charloteaux, B., Jamart, D., Florin, A., Lambert, C., Rorive, A., Jerusalem, G., Leucci, E., Dewaele, M., & 9 othersVooijs, M., Leidel, S. A., Georges, M., Voz, M., Peers, B., Büttner, R., Marine, J-C., Chariot, A. & Close, P., 25 Nov 2021, In: Nature. 599, 7886, p. E14-E14 1 p.

    Research output: Contribution to journalErratum / corrigendum / retractionsAcademic

    Open Access

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