Abstract
The modification of adenosine to inosine at the wobble position (I34) of tRNA anticodons is an abundant and essential feature of eukaryotic tRNAs. The expansion of inosine-containing tRNAs in eukaryotes followed the transformation of the homodimeric bacterial enzyme TadA, which generates I34 in tRNAArg and tRNALeu, into the heterodimeric eukaryotic enzyme ADAT, which modifies up to eight different tRNAs. The emergence of ADAT and its larger set of substrates, strongly influenced the tRNA composition and codon usage of eukaryotic genomes. However, the selective advantages that drove the expansion of I34-tRNAs remain unknown. Here we investigate the functional relevance of I34-tRNAs in human cells and show that a full complement of these tRNAs is necessary for the translation of low-complexity protein domains enriched in amino acids cognate for I34-tRNAs. The coding sequences for these domains require codons translated by I34-tRNAs, in detriment of synonymous codons that use other tRNAs. I34-tRNA-dependent low-complexity proteins are enriched in functional categories related to cell adhesion, and depletion in I34-tRNAs leads to cellular phenotypes consistent with these roles. We show that the distribution of these low-complexity proteins mirrors the distribution of I34-tRNAs in the phylogenetic tree.
Highlights
Transfer RNAs are essential components of the translation machinery that physically connect amino acids to their cognate nucleotide triplets according to the Genetic Code
Editing of the ADAT2 allele resulted in the generation of a premature stop codon eight amino acids downstream of the edited site (Supplementary Figure S1A); while editing of the ADAT3 allele resulted in the elimination of seven residues mapping to the deaminase domain of the protein without changes in the translation reading frame (Supplementary Figure S1B)
HEK293T ADAT2 KD cells were stable in culture, but HEK293T ADAT3 KD cells rapidly reverted to the wild type (WT) sequence
Summary
Transfer RNAs (tRNAs) are essential components of the translation machinery that physically connect amino acids to their cognate nucleotide triplets (anticodons) according to the Genetic Code. Regulation of tRNA pools is a wellknown adaptive mechanism that acts in combination with codon usage to implement translational responses to internal or external cues [1]. The genetic code is essentially universal, the mechanisms that decode it are not. Inosine at position 34 of the tRNA (I34; first nucleotide of the tRNA anticodon) is produced in Bacteria and Eukarya through the deamination of adenosine (A34) [6,7] (Figure 1). In Bacteria I34 is produced by the homodimeric enzyme tRNA adenosine deaminase A (TadA), and, in Eukarya, by the heterodimeric adenosine deaminase acting on tRNA (ADAT). Eukaryotic I34 is found in eight tRNAs
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