ADATs: roles in tRNA editing and relevance to disease

Abstract

Transfer RNAs (tRNAs) play central roles in protein biosynthesis. Post-transcriptional RNA modifications affect tRNA function and stability. Among these modifications, RNA editing is a widespread RNA modification in three domains of life. Proteins of the adenosine deaminase acting on tRNA (ADAT) family were discovered more than 20 years ago. They catalyze the deamination of adenosine to inosine (A-to-I) or cytidine to uridine (C-to-U) during tRNA maturation. The most studied example is the TadA- or ADAT2/3-mediated A-to-I conversion of the tRNA wobble position in the anticodon of prokaryotic or eukaryotic tRNAs, respectively. This review provides detailed information on A-to-I and C-to-U editing of tRNAs in different domains of life, presents recent new findings on ADATs for DNA editing, and finally comments on the association of mutations in the ADAT3 gene with intellectual disability.

1. Introduction

RNA is a critical biomolecule in genetic information decoding and undergoes a series of metabolic processes after transcription, such as modification, maturation, and degradation, for normal life activities. Modified RNA nucleotides other than the four standard nucleotides have fascinated scientists since the identification of pseudouridine (ψ) as the “fifth” ribonucleotide in 1951 [1]. To date, more than 170 different types of modified ribonucleosides have been identified in RNAs from all three domains of life [2,3], and the majority of modifications occur on transfer RNA (tRNA) molecules [4,5]. tRNAs are short, ubiquitous adaptor molecules that play a central role in connecting genetic information with the protein synthesizing machinery. RNA editing is a unique modification reaction that changes RNA fate and the genomic sequence. The most common type of RNA editing is the deamination of adenosine to inosine (A-to-I) or cytidine to uridine (C-to-U) in mRNAs and non-coding RNAs (Figure 1), which expands the genetic diversity beyond the DNA-encoded sequence or has other biological significance.

Inosine was discovered in tRNAAla as early as 1965 [6], but it was not until 1987 that an A-to-I RNA editing activity was observed as a double-stranded RNA (dsRNA) unwinding activity in Xenopus laevis oocytes and embryos [7]. The enzyme was subsequently identified as an RNA adenosine deaminase (ADAR) [8]. In addition to ADARs, adenosine deaminases, known as adenosine deaminases acting on tRNAs (ADATs), function on tRNAs. In addition to carrying out A-to-I editing of tRNAs, which includes 1-methylinosine (m1I) modifications in certain organisms, ADATs also catalyze C-to-U deamination (Figure 2). Both ADARs and ADATs belong to the cytidine deaminase superfamily and require zinc ions for their activities. Although ADARs are well documented due to their crucial role in mRNA and have been the focus of several related studies [9‒12], ADATs are comparatively less understood.