Translation Elongation and Recoding in Eukaryotes

Dever, Thomas E.; Dinman, Jonathan D.; Green, Rachel

doi:10.1101/cshperspect.a032649

Cited by 186 publications

(159 citation statements)

References 192 publications

(230 reference statements)

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“…In eukaryotes, spermidine serves as a substrate for the hypusination of a conserved lysine residue in eukaryotic initiation factor 5A (eIF5A) (Park et al, 1981) (Park et al, 1981), through the action of DHPS and DOHH. EIF5A is a factor that controls translation elongation and termination (Dever et al, 2018;Saini et al, 2009), and its post-translational hypusine modification by DHPS and DOHH is critical for its function (Park et al, 2010;Park and Wolff, 2018). The only known function of DHPS and DOHH is, via a two-step process, to convert this one lysine residue in eIF5A to the amino acid hypusine (Park et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Polyamine metabolism regulates the T cell epigenome through hypusination

Baixauli

et al. 2020

Preprint

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We report here a central role for polyamines in T cell differentiation and function. Deficiency in ornithine decarboxylase (ODC), a critical enzyme for polyamine synthesis, resulted in a profound failure of CD4 + T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineagedefining transcription factors across T H 1, T H 2, T H 17, and T reg polarizing conditions, and enhanced colitogenic potential. T cells deficient in deoxyhypusine synthase (DHPS) or deoxyhypusine hydroxylase (DOHH), which sequentially utilize polyamines to generate hypusine, phenocopied Odc-deficient T cells, and mice in which T cells lacked Dhps or Dohh developed colitis. Polyamine-hypusine pathway enzyme deficiency caused widespread chromatin and transcriptional dysregulation accompanied by alterations in histone methylation, histone acetylation, and TCA cycle metabolites. Epigenetic modulation by 2-hydroxyglutarate, or histone acetyltransferase inhibition, restored CD4 + T cell subset specification. Thus, polyamine synthesis via hypusine is critical for maintaining the epigenome to focus T H cell subset fidelity.

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Section: Introductionmentioning

confidence: 99%

Polyamine metabolism regulates the T cell epigenome through hypusination

Baixauli

et al. 2020

Preprint

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“…[ 15a ] The eukaryotic elongation phase requires a network of eukaryotic elongation factors (eEFs) ( Figure 2B) interacting with aminoacyl‐tRNAs and the mRNA‐80S complex. [ 15a,26 ]…”

Section: Introductionmentioning

confidence: 99%

“…When the 80S ribosome reaches the mRNA's stop codon, the ribosome complex and a network of eukaryotic protein release factors (eRFs) (Figure 2C) terminate polypeptide synthesis and promote the release of the nascent polypeptide and subsequent dissociation of the 80S ribosome into the 40S and 60S ribosomal subunits. [ 15a,26,27 ] The small and large ribosomal subunits are recycled for a new round of translation initiation, elongation, and termination. [ 15a,26,27 ]…”

Section: Introductionmentioning

confidence: 99%

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Targeted Identification of Protein Interactions in Eukaryotic mRNA Translation

et al. 2020

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To identify protein–protein interactions and phosphorylated amino acid sites in eukaryotic mRNA translation, replicate TAP‐MudPIT and control experiments are performed targeting Saccharomyces cerevisiae genes previously implicated in eukaryotic mRNA translation by their genetic and/or functional roles in translation initiation, elongation, termination, or interactions with ribosomal complexes. Replicate tandem affinity purifications of each targeted yeast TAP‐tagged mRNA translation protein coupled with multidimensional liquid chromatography and tandem mass spectrometry analysis are used to identify and quantify copurifying proteins. To improve sensitivity and minimize spurious, nonspecific interactions, a novel cross‐validation approach is employed to identify the most statistically significant protein–protein interactions. Using experimental and computational strategies discussed herein, the previously described protein composition of the canonical eukaryotic mRNA translation initiation, elongation, and termination complexes is calculated. In addition, statistically significant unpublished protein interactions and phosphorylation sites for S. cerevisiae’s mRNA translation proteins and complexes are identified.

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“…The kinetics of translation initiation exert the strongest influence on final protein synthesis rates (5). However, translation elongation, the speed and dynamics at which ribosomes move along mRNAs, is equally heavily regulated and emerging as an important aspect to defining the fate of the encoded nascent polypeptides (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Inferring translational heterogeneity from ribosome profiling data

Bordignon

Pechmann

2019

Preprint

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Translation of messenger RNAs into proteins by the ribosome is the most important step of protein biosynthesis. Accordingly, translation is tightly controlled and heavily regulated to maintain cellular homeostasis. Ribosome profiling (Ribo-seq) has revolutionized the study of translation by revealing many of its underlying mechanisms. However, equally many aspects of translation remain mysterious, in part also due to persisting challenges in the interpretation of data obtained from Ribo-seq experiments. Here, we show that some of the variability observed in Ribo-seq data has biological origins and reflects programmed heterogeneity of translation. To systematically identify sequences that are differentially translated (DT) across mRNAs beyond what can be attributed to experimental variability, we performed a comparative analysis of Ribo-seq data from Saccharomyces cerevisiae and derived a consensus ribosome density profile that reflects consistent signals in individual experiments. Remarkably, the thus identified DT sequences link to mechanisms known to regulate translation elongation and are enriched in genes important for protein and organelle biosynthesis. Our results thus highlight examples of translational heterogeneity that are encoded in the genomic sequences and tuned to optimizing cellular homeostasis. More generally, our work highlights the power of Ribo-seq to understand the complexities of translation regulation.

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Translation Elongation and Recoding in Eukaryotes

Cited by 186 publications

References 192 publications

Polyamine metabolism regulates the T cell epigenome through hypusination

Polyamine metabolism regulates the T cell epigenome through hypusination

Targeted Identification of Protein Interactions in Eukaryotic mRNA Translation

Inferring translational heterogeneity from ribosome profiling data

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