Indirect tRNA aminoacylation during accurate translation and phenotypic mistranslation

Rathnayake, Udumbara M.; Wood, Whitney N.; Hendrickson, Tamara L.

doi:10.1016/j.cbpa.2017.10.009

Cited by 16 publications

(29 citation statements)

References 37 publications

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“…In order to prevent mistranslation of Asn or Gln codons, the product of these ND-aaRSs must not be liberated before reaching the amidotransferase. This goal is achieved by forming a complex with the adT, the synthetase and the tRNA termed the transamidosome, that channels the aminoacyl-tRNA directly to the AdT (Bailly et al 2007;Rathnayake et al 2017). To ensure accurate decoding and avoid relying on a ND synthetase, some bacteria employ a set of duplicated enzymes.…”

Section: Organisms With Incomplete Sets Of Aarssmentioning

confidence: 99%

Aminoacyl-tRNA synthetases

Rubio

Ibba

2020

RNA

232

176

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The aminoacyl-tRNA synthetases are an essential and universally distributed family of enzymes that plays a critical role in protein synthesis, pairing tRNAs with their cognate amino acids for decoding mRNAs according to the genetic code. Synthetases help to ensure accurate translation of the genetic code by using both highly accurate cognate substrate recognition and stringent proofreading of noncognate products. While alterations in the quality control mechanisms of synthetases are generally detrimental to cellular viability, recent studies suggest that in some instances such changes facilitate adaption to stress conditions. Beyond their central role in translation, synthetases are also emerging as key players in an increasing number of other cellular processes, with far-reaching consequences in health and disease. The biochemical versatility of the synthetases has also proven pivotal in efforts to expand the genetic code, further emphasizing the wide-ranging roles of the aminoacyl-tRNA synthetase family in synthetic and natural biology.

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Section: Organisms With Incomplete Sets Of Aarssmentioning

confidence: 99%

Aminoacyl-tRNA synthetases

Rubio

Ibba

2020

RNA

232

176

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“…The indirect aminoacylation pathway is present in the majority of bacterial species (with the exception of some proteobacteria such as Escherichia coli ), all archaea, some mitochondria and other organelles ( Sheppard and Söll, 2008 ). Bacteria lacking specific glutamine and/or asparagine tRNA synthetases instead utilize a non-discriminatory glutamyl- (asparaginyl) synthetase that forms misacylated Glu-tRNA Gln and Asp-tRNA Asn aminoacyl complexes, respectively ( Curnow et al, 1997 ; Rathnayake et al, 2017 ). These misacylated complexes are specifically recognized by GatCAB and amidated to the cognate Gln-tRNA Gln and Asn-tRNA Asn aminoacyl tRNAs, thereby preserving the fidelity of the genetic code.…”

Section: Introductionmentioning

confidence: 99%

Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation

Chaudhuri

Zimmerman

et al. 2018

eLife

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Most bacteria use an indirect pathway to generate aminoacylated glutamine and/or asparagine tRNAs. Clinical isolates of Mycobacterium tuberculosis with increased rates of error in gene translation (mistranslation) involving the indirect tRNA-aminoacylation pathway have increased tolerance to the first-line antibiotic rifampicin. Here, we identify that the aminoglycoside kasugamycin can specifically decrease mistranslation due to the indirect tRNA pathway. Kasugamycin but not the aminoglycoside streptomycin, can limit emergence of rifampicin resistance in vitro and increases mycobacterial susceptibility to rifampicin both in vitro and in a murine model of infection. Moreover, despite parenteral administration of kasugamycin being unable to achieve the in vitro minimum inhibitory concentration, kasugamycin alone was able to significantly restrict growth of Mycobacterium tuberculosis in mice. These data suggest that pharmacologically reducing mistranslation may be a novel mechanism for targeting bacterial adaptation.

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“…We identified mutations in mycobacterial gatA that caused increased rates of mistranslation (Su et al, 2016), and showed that mutations in gatA identified from clinical isolates of M. tuberculosis also caused mistranslation, and importantly, tolerance to the antibiotic rifampicin (Su et al, 2016). This was the first identification of naturally occurring mutations from clinical bacterial isolates that supported a role for "adaptive mistranslation" (De Pouplana et al, 2014;Rathnayake et al, 2017). However, the potential roles, if any, of mutations in gatC and gatB in mediating mistranslation -and rifampicin tolerance -is completely unknown.…”

Section: Introductionmentioning

confidence: 78%

Forward Genetics Reveals a gatC-gatA Fusion Polypeptide Causes Mistranslation and Rifampicin Tolerance in Mycobacterium smegmatis

Cai¹,

Su²,

Li³

et al. 2020

Front. Microbiol.

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Most bacteria, including mycobacteria, utilize a two-step indirect tRNA aminoacylation pathway to generate correctly aminoacylated glutaminyl and asparaginyl tRNAs. This involves an initial step in which a non-discriminatory aminoacyl tRNA synthetase misacylates the tRNA, followed by a second step in which the essential amidotransferase, GatCAB, amidates the misacylated tRNA to its correct, cognate form. It had been previously demonstrated that mutations in gatA can mediate increased error rates specifically of glutamine to glutamate or asparagine to aspartate in protein synthesis. However, the role of mutations in gatB or gatC in mediating mistranslation are unknown. Here, we applied a forward genetic screen to enrich for mistranslating mutants of Mycobacterium smegmatis. The majority (57/67) of mutants had mutations in one of the gatCAB genes. Intriguingly, the most common mutation identified was an insertion in the 3 of gatC, abolishing its stop codon, and resulting in a fused GatC-GatA polypeptide. Modeling the effect of the fusion on GatCAB structure suggested a disruption of the interaction of GatB with the CCA-tail of the misacylated tRNA, suggesting a potential mechanism by which this mutation may mediate increased translational errors. Furthermore, we confirm that the majority of mutations in gatCAB that result in increased mistranslation also cause increased tolerance to rifampicin, although there was not a perfect correlation between mistranslation rates and degree of tolerance. Overall, our study identifies that mutations in all three gatCAB genes can mediate adaptive mistranslation and that mycobacteria are extremely tolerant to perturbation in the indirect tRNA aminoacylation pathway.

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Indirect tRNA aminoacylation during accurate translation and phenotypic mistranslation

Cited by 16 publications

References 37 publications

Aminoacyl-tRNA synthetases

Aminoacyl-tRNA synthetases

Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation

Forward Genetics Reveals a gatC-gatA Fusion Polypeptide Causes Mistranslation and Rifampicin Tolerance in Mycobacterium smegmatis

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