Adenosine-to-inosine RNA editing

Abstract

Ribonucleic acid (RNA) editing is a mechanism that generates RNA and protein diversity, which is not directly encoded in the genome. The most common type of RNA editing in vertebrates is the conversion of adenosine to inosine in double-stranded RNA which occurs in the higher eukaryotes. This editing is carried out by the family of adenosine deaminase acting on RNA (ADAR) proteins. The most-studied substrates of ADAR proteins undergo editing which is very consistent, highly conserved, and functionally important. However, editing causes changes in protein-coding regions only at a small proportion of all editing sites. The vast majority of editing sites are in noncoding sequences. This includes microRNAs, as well as the introns and 3' untranslated regions of messenger RNAs, which play important roles in the RNA-mediated regulation of gene expression.

FIGURE 1

Deamination of adenosine by adenosine deaminases acting on RNAs (ADARs) alters base-pairing preferences. (a) Hydrolytic deamination of adenosine yields inosine. (b) While adenosine base pairs with uridine, inosine forms Watson–Crick base pairing with cytidine, analogous to that of guanosine.

FIGURE 2

Human ADAR proteins. All three proteins share the deaminase domain (filled ovals), which catalyzes the editing reaction, and two or more double-stranded (ds) RNA-binding domains (filled rectangles), which mediate binding to the substrate RNA. The Z-DNA-binding domains (unfilled circles) of ADAR1 may localize it to newly synthesized transcripts, or assist in binding of short RNAs. The two isoforms of this protein are the result of alternative splicing that causes translation from different start codons. The R domain (unfilled rectangle) of ADAR3 has been reported to bind to single-stranded RNA, but the protein's function remains unknown.

FIGURE 3

Effects of A-to-I RNA editing on protein-coding transcripts. (a) Codon changes that can result from A-to-I RNA editing, based on interpretation of inosine as guanosine by translational machinery. Amino acids are grouped according to charge and hydrophobic properties. (b) Generation of alternative splice isoforms by RNA editing. The solid bent line indicates the intron which is removed in the absence of editing. Dotted lines indicate alternative splice isoforms resulting from editing. Editing can create new 5′ donor or 3′ acceptor sites, or eliminate splicing altogether by editing the internal branch point adenosine; 3′ acceptor sites can also be abolished. (Reprinted with permission from Ref 3. Copyright 2005 Elsevier).

FIGURE 4

Effects of A-to-I RNA editing on noncoding transcripts. (a) primary microRNA (pri-miRNAs) are subject to editing by ADARs, which may block the drosha cleavage step and subject the transcript to degradation by Tudor-SN (tudor staphylococcal nuclease), as in the case of miR142. (b) If drosha cutting is unaffected by editing, or if the pre-miRNA itself is edited, processing by dicer may be blocked as in the case of miR151. (c) If mature edited miRNAs are produced, (d) the targets of the miRNA can be changed, as in the case of miR376a-5p. (e) Alterations in miRNA stability could hypothetically affect active-strand selection. (f) Long dsRNAs, such as viral RNAs, are very efficiently and nonspecifically edited by ADARs, resulting in inhibition of RNAi, and degradation by Tudor-SN., (g) ADAR1p150 can tightly bind small interfering RNAs (siRNAs) without editing them, reducing their concentration and thereby decreasing the effectiveness of RNA interference (RNAi).