Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration

Lee, Jeong-Woong; Beebe, Kirk; Nangle, Leslie A.; Jang, Jae-Seon; Longo-Guess, Chantal M.; Cook, Susan A.; Davisson, Muriel T.; Sundberg, John P.; Schimmel, Paul; Ackerman, Susan L.

doi:10.1038/nature05096

Cited by 541 publications

(573 citation statements)

References 34 publications

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“…A similar pattern of Purkinje cell death is seen in another mouse model with an alanyl-tRNA synthetase (Aars) mutation leading to intracellular accumulation of misfolded proteins in neurons. 15 The wz mice differ from humans with MSS, since in the mice no symptoms like cataracts or myopathy have been described. 11 SIL1 is ubiquitously expressed and it still remains unknown why certain tissues and cell types, for example cerebellum and cerebellar Purkinje cells, are more vulnerable to loss of SIL1 function.…”

Section: Introductionmentioning

confidence: 99%

Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco–Sjögren syndrome

et al. 2008

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Section: Introductionmentioning

confidence: 99%

Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco–Sjögren syndrome

et al. 2008

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“…Until the discovery of a class I lysyl-tRNA synthetase (LysRS1) (4), it was believed that each amino acid was exclusively served by a single aaRS of either class I or class II. Although the aaRSs are of interest from many perspectives, including their mechanism of catalysis and proofreading (1), the intricacies of protein-RNA interactions (5), their involvement in cellular signaling functions (6), their practical applicability as potential antimicrobial targets (7), their probable role in genetic diseases (8,9), or the ability to engineer aaRSs to cotranslationally introduce unnatural amino acids into proteins (10), there remains the fundamental question about the role of these proteins in the evolution of the genetic code. The central dilemma is whether the evolution of the aaRSs is the evolution of the genetic code itself, or whether the tRNA synthetases emerged in the context of a previously established code.…”

mentioning

confidence: 99%

Emergence of the universal genetic code imprinted in an RNA record

Hohn¹,

Park²,

O’Donoghue³

et al. 2006

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

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The molecular basis of the genetic code manifests itself in the interaction of the aminoacyl-tRNA synthetases and their cognate tRNAs. The fundamental biological question regarding these enzymes' role in the evolution of the genetic code remains open. Here we probe this question in a system in which the same tRNA species is aminoacylated by two unrelated synthetases. Should this tRNA possess major identity elements common to both enzymes, this would favor a scenario where the aminoacyl-tRNA synthetases evolved in the context of preestablished tRNA identity, i.e., after the universal genetic code emerged. An experimental system is provided by the recently discovered O-phosphoseryl-tRNA synthetase (SepRS), which acylates tRNA Cys with phosphoserine (Sep), and the well known cysteinyl-tRNA synthetase, which charges the same tRNA with cysteine. We determined the identity elements of Methanocaldococcus jannaschii tRNA Cys in the aminoacylation reaction for the two Methanococcus maripaludis synthetases SepRS (forming Sep-tRNA Cys ) and cysteinyl-tRNA synthetase (forming Cys-tRNA Cys ). The major elements, the discriminator base and the three anticodon bases, are shared by both tRNA synthetases. An evolutionary analysis of archaeal, bacterial, and eukaryotic tRNA Cys sequences predicted additional SepRS-specific minor identity elements (G37, A47, and A59) and suggested the dominance of vertical inheritance for tRNA Cys from a single common ancestor. Transplantation of the identified identity elements into the Escherichia coli tRNA Gly scaffold endowed facile phosphoserylation activity on the resulting chimera. Thus, tRNA Cys identity is an ancient RNA record that depicts the emergence of the universal genetic code before the evolution of the modern aminoacylation systems.aminoacyl-tRNA synthetase ͉ evolution ͉ O-phosphoseryl-tRNA synthetase ͉ tRNA identity

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“…As stated above, cellular degeneration has been observed in vitro and in vivo as a result of genetic code ambiguity (1,2). In light of these observations, we hypothesized that mutation-causing systems might also be induced in editing-defective cells.…”

Section: Resultsmentioning

confidence: 96%

“…For example, mice that carry a mild mutation in the editing domain of alanyl-tRNA synthetase suffer from ataxia (1). The mutant alanyl-tRNA synthetase mischarges tRNA Ala with serine and, as a consequence, mistranslation occurs that leads to induction of the unfolded protein response.…”

mentioning

confidence: 99%

An editing-defective aminoacyl-tRNA synthetase is mutagenic in aging bacteria via the SOS response

Bacher

Schimmel

2007

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

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Mistranslation in bacterial and mammalian cells leads to production of statistical proteins that are, in turn, associated with specific cell or animal pathologies, including death of bacterial cells, apoptosis of mammalian cells in culture, and neurodegeneration in the mouse. A major source of mistranslation comes from heritable defects in the editing activities of aminoacyl-tRNA synthetases. These activities clear errors of aminoacylation by deacylation of mischarged tRNAs. We hypothesized that, in addition to previously reported phenotypes in bacterial and mammalian systems, errors of aminoacylation could be mutagenic and lead to disease. As a first step in testing this hypothesis, the effect of an editing defect in a single tRNA synthetase on the accumulation of mutations in aging bacteria was investigated. A striking, statistically significant, enhancement of the mutation rate in aging bacteria was found. This enhancement comes from an increase in error-prone DNA repair through induction of the bacterial SOS response. Thus, mistranslation, as caused by an editing-defective tRNA synthetase, can lead to heritable genetic changes that could, in principle, be linked to disease.aminoacylation errors ͉ error-prone DNA polymerases ͉ amino acid misincorporation ͉ genetic code ambiguity A s organisms age, mutations accumulate over time owing to direct environmental insults that are incompletely or inaccurately repaired. Recent work directed our attention to the possibility that mistranslation could play a role in producing mutations in aging populations. In particular, mistranslation can arise from editing defects in aminoacyl-tRNA synthetases. These enzymes catalyze the first step of protein synthesis, where each amino acid is linked to its cognate tRNA bearing the anticodon triplet associated with the amino acid. Because of inherent physiochemical limitations of some enzymes to discriminate between structurally similar amino acids, mischarged tRNAs, such as Val-tRNA Ile or Ser-tRNA Ala , are produced. Normally, these mischarged tRNAs are cleared by hydrolytic editing, which occurs at a distinct active site within the synthetase. But even a small defect, caused by a mutation in the editing center, can lead to extreme cell pathologies and disease.For example, mice that carry a mild mutation in the editing domain of alanyl-tRNA synthetase suffer from ataxia (1). The mutant alanyl-tRNA synthetase mischarges tRNA Ala with serine and, as a consequence, mistranslation occurs that leads to induction of the unfolded protein response. That, in turn, leads to the degeneration of Purkinje cells in the cerebellum, beginning within 3 weeks of age. Similarly, in human cell culture, an inducible, editing-defective valyl-tRNA synthetase caused cellular degradation and apoptosis (2).With these recent results in mind, we were motivated to investigate the possibility that mistranslation could also lead to heritable genetic changes. Previously, we generated a knock-in mutant allele of ileS that encodes no functional editing domain (3)....

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Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration

Cited by 541 publications

References 34 publications

Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco–Sjögren syndrome

Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco–Sjögren syndrome

Emergence of the universal genetic code imprinted in an RNA record

An editing-defective aminoacyl-tRNA synthetase is mutagenic in aging bacteria via the SOS response

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