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Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer.pdf (4 MB)

Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer.

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posted on 2017-06-07, 14:36 authored by Sylvain Delaunay, Francesca Rapino, Lars Tharun, Zhaoli Zhou, Lukas Heukamp, Martin Termathe, Kateryna Shostak, Iva Klevernic, Alexandra Florin, Hadrien Desmecht, Christophe J. Desmet, Laurent Nguyen, Sebastian A. Leidel, Anne E. Willis, Reinhard Büttner, Alain Chariot, Pierre Close
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.

History

Citation

Journal of Experimental Medicine, 2016, 213 (11), pp. 2503-2523

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biology

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  • VoR (Version of Record)

Published in

Journal of Experimental Medicine

Publisher

Rockefeller University Press

issn

0022-1007

eissn

1540-9538

Acceptance date

2016-09-02

Copyright date

2016

Available date

2017-06-07

Publisher version

http://jem.rupress.org/content/213/11/2503

Language

en

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