N7-Methylguanosine tRNA modification enhances oncogenic mRNA translation and promotes intrahepatic cholangiocarcinoma progression

Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm5U34) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease.

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Wobble tRNA modification and hydrophilic amino acid patterns dictate protein fate

Nature Communications ◽

10.1038/s41467-021-22254-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Francesca Rapino ◽

Zhaoli Zhou ◽

Ana Maria Roncero Sanchez ◽

Marc Joiret ◽

Christian Seca ◽

...

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

Protein Expression ◽

Protein Aggregation ◽

Critical Role ◽

Mrna Translation ◽

Trna Modification ◽

Translation Elongation ◽

Hydrophilic Amino Acid ◽

Protein Output

AbstractRegulation of mRNA translation elongation impacts nascent protein synthesis and integrity and plays a critical role in disease establishment. Here, we investigate features linking regulation of codon-dependent translation elongation to protein expression and homeostasis. Using knockdown models of enzymes that catalyze the mcm5s2 wobble uridine tRNA modification (U34-enzymes), we show that gene codon content is necessary but not sufficient to predict protein fate. While translation defects upon perturbation of U34-enzymes are strictly dependent on codon content, the consequences on protein output are determined by other features. Specific hydrophilic motifs cause protein aggregation and degradation upon codon-dependent translation elongation defects. Accordingly, the combination of codon content and the presence of hydrophilic motifs define the proteome whose maintenance relies on U34-tRNA modification. Together, these results uncover the mechanism linking wobble tRNA modification to mRNA translation and aggregation to maintain proteome homeostasis.

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Misactivation of multiple starvation responses in yeast by loss of tRNA modifications

Nucleic Acids Research ◽

10.1093/nar/gkaa455 ◽

2020 ◽

Cited By ~ 1

Author(s):

Alexander Bruch ◽

Teresa Laguna ◽

Falk Butter ◽

Raffael Schaffrath ◽

Roland Klassen

Keyword(s):

Saccharomyces Cerevisiae ◽

Mrna Translation ◽

Exponential Growth Phase ◽

Trna Modification ◽

Anticodon Loop ◽

Transcriptional Responses ◽

Trna Modifications ◽

Trna Species ◽

Transcriptional Stress ◽

Cellular Phenotypes

Abstract Previously, combined loss of different anticodon loop modifications was shown to impair the function of distinct tRNAs in Saccharomyces cerevisiae. Surprisingly, each scenario resulted in shared cellular phenotypes, the basis of which is unclear. Since loss of tRNA modification may evoke transcriptional responses, we characterized global transcription patterns of modification mutants with defects in either tRNAGlnUUG or tRNALysUUU function. We observe that the mutants share inappropriate induction of multiple starvation responses in exponential growth phase, including derepression of glucose and nitrogen catabolite-repressed genes. In addition, autophagy is prematurely and inadequately activated in the mutants. We further demonstrate that improper induction of individual starvation genes as well as the propensity of the tRNA modification mutants to form protein aggregates are diminished upon overexpression of tRNAGlnUUG or tRNALysUUU, the tRNA species that lack the modifications of interest. Hence, our data suggest that global alterations in mRNA translation and proteostasis account for the transcriptional stress signatures that are commonly triggered by loss of anticodon modifications in different tRNAs.

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

Journal of Experimental Medicine ◽

10.1084/jem.20160397 ◽

2016 ◽

Vol 213 (11) ◽

pp. 2503-2523 ◽

Cited By ~ 54

Author(s):

Sylvain Delaunay ◽

Francesca Rapino ◽

Lars Tharun ◽

Zhaoli Zhou ◽

Lukas Heukamp ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Mrna Translation ◽

Trna Modification ◽

Breast Cancers ◽

Invasion And Metastasis ◽

Functional Link ◽

Genetic Ablation ◽

Translation Fidelity ◽

Codon Composition

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 mcm5s2-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 mcm5s2-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.

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