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Title: Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer.
Authors: Delaunay, Sylvain
Rapino, Francesca
Tharun, Lars
Zhou, Zhaoli
Heukamp, Lukas
Termathe, Martin
Shostak, Kateryna
Klevernic, Iva
Florin, Alexandra
Desmecht, Hadrien
Desmet, Christophe J.
Nguyen, Laurent
Leidel, Sebastian A.
Willis, Anne E.
Büttner, Reinhard
Chariot, Alain
Close, Pierre
First Published: 10-Oct-2016
Publisher: Rockefeller University Press
Citation: Journal of Experimental Medicine, 2016, 213 (11), pp. 2503-2523
Abstract: Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Posttranscriptional modifications of transfer RNAs (tRNAs) at the wobble uridine 34 (U34) base are highly conserved and contribute to translation fidelity. Here, we show that ELP3 and CTU1/2, partner enzymes in U34 mcm(5)s(2)-tRNA modification, are up-regulated in human breast cancers and sustain metastasis. Elp3 genetic ablation strongly impaired invasion and metastasis formation in the PyMT model of invasive breast cancer. Mechanistically, ELP3 and CTU1/2 support cellular invasion through the translation of the oncoprotein DEK. As a result, DEK promotes the IRES-dependent translation of the proinvasive transcription factor LEF1. Consistently, a DEK mutant, whose codon composition is independent of U34 mcm(5)s(2)-tRNA modification, escapes the ELP3- and CTU1-dependent regulation and restores the IRES-dependent LEF1 expression. Our results demonstrate that the key role of U34 tRNA modification is to support specific translation during breast cancer progression and highlight a functional link between tRNA modification- and IRES-dependent translation during tumor cell invasion and metastasis.
DOI Link: 10.1084/jem.20160397
ISSN: 0022-1007
eISSN: 1540-9538
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution- Non Commercial-ShareAlike Licence ( ).
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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