Essentiality of threonylcarbamoyladenosine (t6A), a universal tRNA modification, in bacteria

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Abstract

Summary

Threonylcarbamoyladenosine (t6A) is a modified nucleoside universally conserved in tRNAs in all three kingdoms of life. The recently discovered genes for t6A synthesis, includingtsaCandtsaD, are essential in model prokaryotes but not essential in yeast. These genes had been identified as antibacterial targets even before their functions were known. However, the molecular basis for this prokaryotic-specific essentiality has remained a mystery. Here, we show that t6A is a strong positive determinant for aminoacylation of tRNA by bacterial-type but not by eukaryotic-type isoleucyl-tRNA synthetases and might also be a determinant for the essential enzyme tRNAIle-lysidine synthetase. We confirm that t6A is essential inEscherichia coliand a survey of genome-wide essentiality studies shows that genes for t6A synthesis are essential in most prokaryotes. This essentiality phenotype is not universal in Bacteria as t6A is dispensable inDeinococcus radiodurans,Thermus thermophilus,SynechocystisPCC6803 andStreptococcus mutans. Proteomic analysis of t6A−D. radioduransstrains revealed an induction of the proteotoxic stress response and identified genes whose translation is most affected by the absence of t6A in tRNAs. Thus, although t6A is universally conserved in tRNAs, its role in translation might vary greatly between organisms.

Threonylcarbamoyladenosine (t6A) is a modified nucleoside universally conserved in tRNAs in all three kingdoms of life. The genes for t6A synthesis are essential in model prokaryotes, and we show t6A is a determinant for aminoacylation of tRNA by bacterial-type isoleucyl-tRNA synthetases and a determinant for the essential enzyme tRNAIle-lysidine synthetase. This essentiality phenotype is not universal in Bacteria as t6A is dispensable in Deinococcus radiodurans, Thermus thermophilus, Synechocystis PCC6803 and Streptococcus mutans.

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