Double-sieving-defective aminoacyl-tRNA synthetase causes protein mistranslation and affects cellular physiology and development

Lu, Jiongming; Bergert, Martin; Walther, Anita; Suter, Beat

doi:10.1038/ncomms6650

Cited by 68 publications

(106 citation statements)

References 62 publications

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“…The importance of tRNA synthetase editing including editing by the alanyl tRNA synthetase ( Aars ; AlaRS) has been shown in multiple organisms 6, 7, 8, 9, 10, 11 . Although AlaRS misactivates both glycine and serine, misactivation of serine appears to have more serious consequences, perhaps due to the presence of D-aminoacyl-tRNA deacylases which act on Gly-tRNA Ala 12, 13, 14 .…”

mentioning

confidence: 99%

ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

Terrey

Lee

et al. 2018

Nature

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Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aarssti mutant mice resulted in an increased production of serine-mischarged tRNAAla and degeneration of cerebellar Purkinje cells. By positional cloning, we identified Ankrd16, which acts epistatically with the Aarssti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific, ankyrin repeat-containing protein, binds directly to the catalytic domain of AlaRS. Serine misactivated by AlaRS is captured by lysine side chains of ANKRD16, preventing the charging of serine adenylates to tRNAAla and precluding serine misincorporation in nascent peptides. Deletion of Ankrd16 in the Aarssti/sti brain causes widespread protein aggregation and neuron loss. These results identify a novel amino acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery essential for preventing severe pathologies that arise from defects in editing.

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confidence: 99%

ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

Terrey

Lee

et al. 2018

Nature

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“…Mutations in the active and editing sites of the Drosophila phenylalanyl tRNA synthetase increased the mischarging of tRNA Phe with tyrosine, which resulted in misincorporation of tyrosine at phenylalanine codons. Mutant flies were sensitive to diets high in tyrosine and had increased endoplasmic reticulum stress, impaired locomotion, and neurodegeneration, a phenotype reminiscent of the sticky mice (Lu et al, 2014). …”

Section: Defects In Aminoacyl Trna Synthetase Function In Neurodegenementioning

confidence: 99%

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

Kapur

Monaghan

Ackerman

2017

Neuron

179

167

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SUMMARY Dynamic regulation of mRNA translation initiation and elongation is essential for the survival and function of neural cells. Global reductions in translation initiation resulting from mutations in the translational machinery or inappropriate activation of the integrated stress response may contribute to pathogenesis in a subset of neurodegenerative disorders. Aberrant proteins generated by non-canonical translation initiation may be a factor in the neuron death observed in the nucleotide repeat expansion diseases. Dysfunction of central components of the elongation machinery, such as the tRNAs and their associated enzymes, can cause translation infidelity and ribosome stalling, resulting in neurodegeneration. Taken together, dysregulation of mRNA translation is emerging as a unifying mechanism underlying the pathogenesis of many neurodegenerative disorders.

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“…In this case, restoration of protein activity is used as a proxy for misincorporation rate. Protein reporters for this experimental approach have included β-lactamase, GFP, luciferase, and β-Galactosidase [10–13]. However, these reporters often lack the sensitivity necessary to accurately detect low level misincorporation events.…”

Section: Introductionmentioning

confidence: 99%

MS-READ: Quantitative measurement of amino acid incorporation

Mohler

Aerni

Gassaway

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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Ribosomal protein synthesis results in the genetically programmed incorporation of amino acids into a growing polypeptide chain. Faithful amino acid incorporation that accurately reflects the genetic code is critical to the structure and function of proteins as well as overall proteome integrity. Errors in protein synthesis are generally detrimental to cellular processes yet emerging evidence suggest that proteome diversity generated through mistranslation may be beneficial under certain conditions. Cumulative translational error rates have been determined at the organismal level, however codon specific error rates and the spectrum of misincorporation errors from system to system remain largely unexplored. In particular, until recently technical challenges have limited the ability to detect and quantify comparatively rare amino acid misincorporation events, which occur orders of magnitude less frequently than canonical amino acid incorporation events. We now describe a technique for the quantitative analysis of amino acid incorporation that provides the sensitivity necessary to detect mistranslation events during translation of a single codon at frequencies as low as 1 in 10,000 for all 20 proteinogenic amino acids, as well as non-proteinogenic and modified amino acids.

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Double-sieving-defective aminoacyl-tRNA synthetase causes protein mistranslation and affects cellular physiology and development

Cited by 68 publications

References 62 publications

ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

MS-READ: Quantitative measurement of amino acid incorporation

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