The mRNA of Human Cytoplasmic Arginyl-tRNA Synthetase Recruits Prokaryotic Ribosomes Independently

Fang, Yang; Ji, Qiu; Ruan, Liangliang; Ye, Qing; Wang, En‐Duo

doi:10.1074/jbc.m114.562454

Cited by 4 publications

(3 citation statements)

References 27 publications

(40 reference statements)

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“…The second form is the short ∼ 60 kDa N-terminal truncated form that is free in the cytoplasm and has no interaction with the MSC. [27][28][29] Kyriacou and Deutscher have shown that the 72 kDa form is essential for protein synthesis and cell growth in Chinese hamster ovary (CHO) cells, even when a functional 60 kDa RARS is present. Both the 72 and 60 kDa isoforms arise from a single mRNA through the utilisation of alternative AUG initiation codons, displaying similar catalytic properties, and contributing about equally to the total rate of RARS in vitro activity.…”

Section: Introductionmentioning

confidence: 99%

Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus–Merzbacher disease

et al. 2017

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Pelizaeus-Merzbacher disease (PMD) is a rare Mendelian disorder characterised by central nervous system hypomyelination. PMD typically manifests in infancy or early childhood and is caused by mutations in proteolipid protein-1 (PLP1). However, variants in several other genes including gap junction protein gamma 2 (GJC2) can also cause a similar phenotype and are referred to PMD-like disease (PMLD). Whole-exome sequencing in two siblings presenting with clinical symptoms of PMD revealed a homozygous variant in the arginyl-tRNA synthetase (RARS) gene: NM_002887.3: c.[5A>G] p.(Asp2Gly). Subsequent screening of a PMD cohort without a genetic diagnosis identified an unrelated individual with novel compound heterozygous variants including a missense variant c.[1367C>T] p.(Ser456Leu) and a de novo deletion c.[1846_1847delTA] p.(Tyr616Leufs*6). Protein levels of RARS and the multi-tRNA synthetase complex into which it assembles were found to be significantly reduced by 80 and 90% by western blotting and Blue native-PAGE respectively using patient fibroblast extracts. As RARS is involved in protein synthesis whereby it attaches arginine to its cognate tRNA, patient cells were studied to determine their ability to proliferate with limiting amounts of this essential amino acid. Patient fibroblasts cultured in medium with limited arginine at 30 °C and 40 °C, showed a significant decrease in fibroblast proliferation (P<0.001) compared to control cells, suggestive of inefficiency of protein synthesis in the patient cells. Our functional studies provide further evidence that RARS is a PMD-causing gene.

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Section: Introductionmentioning

confidence: 99%

Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus–Merzbacher disease

et al. 2017

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“…Similarly, that of the 62-kDa fragment of ArgRS, with the first amino acid as Ala 64 , showed that the cleavage by calpains was between Gln 63 and Ala 64 , only nine amino acid residues before the initiation site of ArgRSΔN72 synthesized by translation reinitiation ( Fig. 7 A ) ( 20 , 24 ). The truncated ArgRS was named ArgRSΔN63.…”

Section: Resultsmentioning

confidence: 83%

Calpain Cleaves Most Components in the Multiple Aminoacyl-tRNA Synthetase Complex and Affects Their Functions

Lei

Zhou

Ruan

et al. 2015

Journal of Biological Chemistry

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Background: The human multiple aminoacyl-tRNA synthetase complex (MSC) has an elongated and multiarmed structure, which might be sensitive to proteases such as calpain in vivo.Results: Partial calpain hydrolysis of MSC components generated specific fragments.Conclusion: Calpain hydrolysis could dissociate the MSC, thereby affecting its function.Significance: Calpain proteolytically degrades MSC components and might regulate the canonical and non-canonical functions of aaRS.

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“…Furthermore, a severe developmental delay was observed. RARS1 encodes cytoplasmic arginyl-tRNA synthetase, an essential part of the aminoacyl-tRNA synthetase in relation to enzymes needed for protein synthesis, which binds each amino acid to its specific tRNA (Eriani et al, 1990;Kim et al, 2014;Yang et al, 2014). RARS protein is a monomeric enzyme that belongs to the aminoacyl-tRNA synthetase class I.…”

Section: Discussionmentioning

confidence: 99%

RARS1‐related hypomyelinating leukodystrophy‐9 (HLD‐9) in two distinct Iranian families: Case report and literature review

Biglari,

Vahidnezhad,

Tabatabaiefar

et al. 2024

Molec Gen & Gen Med

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BackgroundHypomyelinating leukodystrophy‐9 (HLD‐9) is caused by biallelic pathogenic variants in RARS1, which codes for the cytoplasmic tRNA synthetase for arginine (ArgRS). This study aims to evaluate the clinical, neuroradiological, and genetic characteristics of patients with RARS1‐related disease and determine probable genotype–phenotype relationships.MethodsWe identified three patients with RARS1 homozygous pathogenic variants. Furthermore, we performed a comprehensive review of the literature.ResultsHomozygous variants of RARS1 (c.2T>C (p.Met1Thr)) were identified in three patients with HLD‐9. Clinical symptoms were severe in all patients. Following the literature review, thirty HLD‐9 cases from eight studies were found. The 33 patients' main symptoms were hypomyelination, language delay, and intellectual disability or developmental delay. The mean age of onset for HLD9 in the group of 33 patients with a known age of onset was 5.8 months (SD = 8.1). The interquartile range of age of onset was 0–10 months. Of the 25 variants identified, c.5A>G (p.Asp2Gly) was identified in 11 patients.ConclusionPathogenic variants in RARS1 decrease ArgRS activity and cause a wide range of symptoms, from severe, early onset epileptic encephalopathy with brain atrophy to a mild condition with relatively maintained myelination. These symptoms include the classic hypomyelination presentation with nystagmus and spasticity. Furthermore, the pathogenicity of the variation c.2T>C (p.Met1Thr) has been shown.

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The mRNA of Human Cytoplasmic Arginyl-tRNA Synthetase Recruits Prokaryotic Ribosomes Independently

Cited by 4 publications

References 27 publications

Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus–Merzbacher disease

Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus–Merzbacher disease

Calpain Cleaves Most Components in the Multiple Aminoacyl-tRNA Synthetase Complex and Affects Their Functions

RARS1‐related hypomyelinating leukodystrophy‐9 (HLD‐9) in two distinct Iranian families: Case report and literature review

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