Deficiencies in tRNA synthetase editing activity cause cardioproteinopathy

Liu, Ye; Satz, Jakob S.; Vo, My-Nuong; Nangle, Leslie A.; Schimmel, Paul; Ackerman, Susan L.

doi:10.1073/pnas.1420196111

Cited by 80 publications

(86 citation statements)

References 34 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 .…”

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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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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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“…The editing of misacylated tRNAs prevents the accumulation of noncognate substrates that otherwise could lead to miscoding errors during mRNA translation. In the absence of misacylated tRNA editing, the frequency of errors in protein synthesis increases significantly and can lead to substantial losses in cellular viability (4,33,34). Additionally, the production of abnormal proteins in general leads to induction of the heat shock responses in E. coli (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

Translation quality control is critical for bacterial responses to amino acid stress

Bullwinkle

Ibba

2016

Proc. Natl. Acad. Sci. U.S.A.

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Gene expression relies on quality control for accurate transmission of genetic information. One mechanism that prevents amino acid misincorporation errors during translation is editing of misacylated tRNAs by aminoacyl-tRNA synthetases. In the absence of editing, growth is limited upon exposure to excess noncognate amino acid substrates and other stresses, but whether these physiological effects result solely from mistranslation remains unclear. To explore if translation quality control influences cellular processes other than protein synthesis, an Escherichia coli strain defective in Tyr-tRNA Phe editing was used. In the absence of editing, cellular levels of aminoacylated tRNA Phe were elevated during amino acid stress, whereas in the wild-type strain these levels declined under the same growth conditions. In the editing-defective strain, increased levels of aminoacylated tRNA Phe led to continued synthesis of the PheL leader peptide and attenuation of pheA transcription under amino acid stress. Consequently, in the absence of editing, activation of the phenylalanine biosynthetic operon becomes less responsive to phenylalanine limitation. In addition to raising aminoacylated tRNA levels, the absence of editing lowered the amount of deacylated tRNA Phe in the cell. This reduction in deacylated tRNA was accompanied by decreased synthesis of the second messenger guanosine tetraphosphate and limited induction of stringent response-dependent gene expression in editing-defective cells during amino acid stress. These data show that a single qualitycontrol mechanism, the editing of misacylated aminoacyl-tRNAs, provides a critical checkpoint both for maintaining the accuracy of translation and for determining the sensitivity of transcriptional responses to amino acid stress.translation | quality control | stress | stringent response

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“…In the mouse with AlaRS, an ED knockin was embryonic-lethal; a heterozygous knockin had extreme pathologies, such as cardioproteinopathy (15). Moreover, even a homozygous mild editing defect (about twofold) resulted in neurotoxicity and ataxia (5).…”

Section: Cells Valrsmentioning

confidence: 99%

“…For example, a mild editing defect of an alanyl-tRNA synthetase (AlaRS) in the mouse was shown to cause the death of Purkinje cells and result in neurodegeneration (5). More recently, cardioproteinopathy was also shown to have connections to mistranslation (15). Although the cellular and physiological importance of editing has been established, the extent of how editing defects impact major cellular mechanisms is only beginning to be clarified.…”

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p53-Dependent DNA damage response sensitive to editing-defective tRNA synthetase in zebrafish

Song

Shi

Carland

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Brain and heart pathologies are caused by editing defects of transfer RNA (tRNA) synthetases, which preserve genetic code fidelity by removing incorrect amino acids misattached to tRNAs. To extend understanding of the broader impact of synthetase editing reactions on organismal homeostasis, and based on effects in bacteria ostensibly from small amounts of mistranslation of components of the replication apparatus, we investigated the sensitivity to editing of the vertebrate genome. We show here that in zebrafish embryos, transient overexpression of editing-defective valyl-tRNA synthetase (ValRS ED ) activated DNA break-responsive H2AX and p53-responsive downstream proteins, such as cyclin-dependent kinase (CDK) inhibitor p21, which promotes cell-cycle arrest at DNA damage checkpoints, and Gadd45 and p53R2, with pivotal roles in DNA repair. In contrast, the response of these proteins to expression of ValRS ED was abolished in p53-deficient fish. The p53-activated downstream signaling events correlated with suppression of abnormal morphological changes caused by the editing defect and, in adults, reversed a shortened life span (followed for 2 y). Conversely, with normal editing activities, p53-deficient fish have a normal life span and few morphological changes. Whole-fish deep sequencing showed genomic mutations associated with the editing defect. We suggest that the sensitivity of p53 to expression of an editing-defective tRNA synthetase has a critical role in promoting genome integrity and organismal homeostasis. mistranslation | genomic fidelity | shortened lifespan | morphological changes | genomic mutations I n the first step of protein synthesis, amino acids are attached to their cognate tRNAs in reactions catalyzed by aminoacyl-tRNA synthetases (1, 2). Mistakes of aminoacylation occur with a frequency of less than 1% (3, 4), and if not corrected, will result in the insertion of a mischarged amino acid into a growing polypeptide chain at the wrong codon (5-7). This sort of error is usually corrected by a universal editing mechanism in tRNA synthetases, which hydrolytically removes the mischarged amino acid from the tRNA before the wrong amino acid is inserted into a nascent protein (8)(9)(10)(11)(12)(13)(14).Serious pathologies and cell death result from rare errors in protein synthesis (mistranslation). For example, a mild editing defect of an alanyl-tRNA synthetase (AlaRS) in the mouse was shown to cause the death of Purkinje cells and result in neurodegeneration (5). More recently, cardioproteinopathy was also shown to have connections to mistranslation (15). Although the cellular and physiological importance of editing has been established, the extent of how editing defects impact major cellular mechanisms is only beginning to be clarified. Because assaults on the genome by environmental factors lead to somatic cell mutations that cause diseases in humans, we were especially interested in the role editing might play in protecting vertebrates against DNA damage. Earlier work in bacteria was supportive of ...

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Deficiencies in tRNA synthetase editing activity cause cardioproteinopathy

Cited by 80 publications

References 34 publications

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

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

Translation quality control is critical for bacterial responses to amino acid stress

p53-Dependent DNA damage response sensitive to editing-defective tRNA synthetase in zebrafish

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