tRNA Modification: Is Cancer Having a Wobble?

Rapino, Francesca; Delaunay, Sylvain; Zhou, Zhaoli; Chariot, Alain; Close, Pierre

doi:10.1016/j.trecan.2017.02.004

Cited by 47 publications

(47 citation statements)

References 16 publications

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“…The mcm 5 s 2 U modification is catalyzed by a cascade of enzymes including ELP3, ALKBH8, and CTU1/2 which sequentially modify U34 to generate cm 5 U, mcm 5 U, and mcm 5 s 2 U, respectively (Rapino et al , ). Upon ERα depletion in BM67 cells, Elp3 ( P = 0.03) showed a reduction in the amount of polysome‐associated mRNA (data from polysome profiling in Figs and EV1).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, selective alterations of transfer RNAs (tRNAs) were recently described to affect translation of mRNAs based on their codon usage (Goodarzi et al, 2016). Moreover, recent reports highlight alterations of tRNA modifications as an important mechanism underlying selective translation (Chan et al, 2015;Delaunay et al, 2016;Rapino et al, 2017Rapino et al, , 2018 which are thought to act by maintaining protein homeostasis or driving an adaptive proteome (Nedialkova & Leidel, 2015). Estrogen receptor alpha (ERa) is a key steroid receptor and transcription factor which drives tumorigenesis in hormone-dependent cancers (Shanle & Xu, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

et al. 2019

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Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer‐associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5′UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome association remains unaltered are enriched in codons requiring U34‐modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34‐modifying enzymes and thereby controls levels of U34‐modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα‐dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone‐dependent cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

et al. 2019

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“…Deletion of this loop and subsequent crystallization in the presence of acetyl-CoA allowed to determine a second structure at 2. 6 A resolution (PDB ID 5L7L). Although the electron density for acetyl-CoA was too weak to describe its binding mode in detail, this additional structure suggests that the protein does not undergo strong structural rearrangements during the acetyl-CoA binding step.…”

Section: Elongator Protein 3 (Elp3)mentioning

confidence: 99%

“…Subsequently, two highly similar crystal structures (PDB ID 4A8J and 4EJS) of the assembled Elp456 subcomplex were solved at 2.1 and 2. 6 A resolution [54,62] (Fig. 1A).…”

Section: Elongator Subcomplex Elp456mentioning

confidence: 99%

Structural asymmetry in the eukaryotic Elongator complex

et al. 2017

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Edited by Wilhelm JustNucleoside modifications in tRNA anticodons regulate ribosome dynamics during translation elongation and, thereby, fine-tune global protein synthesis rates. The highly conserved eukaryotic Elongator complex conducts specific C5-substitutions in tRNA wobble base uridines. It harbors two copies of each of its six individual subunits, which are all equally important for its activity. Here, we summarize recent developments focusing on the architecture of the Elongator complex, showing an asymmetric subunit arrangement, and its functional implications. In addition, we discuss the role of its proposed active site, its individual subunits and temporarily associated regulatory factors. Finally, we aim to provide mechanistic explanations for the link between mutations in Elongator subunits and the onset of several severe human pathologies.

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“…Modifications around the anticodon loop of the tRNA are known to affect translation fidelity, speed, and tendency to frameshift [11][12][13][14] . Modification levels are regulated and can change in a dynamic manner across physiological conditions [15][16][17] , in cancer 18,19 , and during development 20 . Yet the dynamics, regulation and biological function, both at the molecular and physiological level, of most such modifications are not well-characterized.…”

Section: Introductionmentioning

confidence: 99%

Dynamic changes in tRNA modifications and abundance during T-cell activation

Rak

Polonsky

Eizenberg

et al. 2020

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The tRNA pool determines the efficiency, throughput, and accuracy of translation. Previous studies have identified dynamic changes in the tRNA supply and mRNA demand during cancerous proliferation. Yet, dynamic changes may occur also during physiologically normal proliferation, and these are less characterized. We examined the tRNA and mRNA pools of Tcells during their vigorous proliferation and differentiation upon triggering of the T cell antigen receptor. We observe a global signature of switch in demand for codon at the early proliferation phase of the response, accompanied by corresponding changes in tRNA expression levels. In the later phase, upon differentiation of the T cells, the response of the tRNA pool is relaxed back to basal level, potentially restraining excessive proliferation. Sequencing of tRNAs allowed us to also evaluate their diverse base-modifications. We found that two types of tRNA modifications, Wybutosine and ms 2 t6A, are reduced dramatically during T-cell activation. These modifications occur in the anti-codon loops of two tRNAs that decode "slippery codons", that are prone to ribosomal frameshifting. Attenuation of these frameshift-protective modifications is expected to increase proteome-wide frameshifting during T-cell proliferation. Indeed, human cell lines deleted of a Wybutosine writer showed increased ribosomal frameshifting, as detected with a reporter that consists of a critical frameshifting site taken from the HIV gag-pol slippery codon motif. These results may explain HIV's specificity to proliferating T-Cells since it requires ribosomal frameshift exactly on this codon for infection. The changes in tRNA expression and modifications uncover a new layer of translation regulation during T-cell proliferation and exposes a potential trade-off between cellular growth and translation fidelity.The tRNA pool decodes genetic information during translation. As such, it is subject to intricate physiological regulation in all species, across different physiological conditions. Here we show for the first time a program that governs the tRNA pool and its interaction with the transcriptome upon a physiological cellular proliferation-T-cells activation. We found that upon antigenic activation of T-cells, their tRNA and mRNA pools undergo coordinated and complementary changes, which relex when cells reduces their proliferation rate. We also found a reduction in two particular tRNA modifications that have a role in governing translation fidelity and frameshift prevention. This exposes a vulnerability in activated T-cells that may be utilized by HIV for its replication.

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tRNA Modification: Is Cancer Having a Wobble?

Cited by 47 publications

References 16 publications

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

Structural asymmetry in the eukaryotic Elongator complex

Dynamic changes in tRNA modifications and abundance during T-cell activation

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