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Review
. 2022 Oct;28(10):1281-1297.
doi: 10.1261/rna.079266.122. Epub 2022 Jul 21.

ADAR2 enzymes: efficient site-specific RNA editors with gene therapy aspirations

Khadija Hajji  1 , Jiří Sedmík  1 , Anna Cherian  1 , Damiano Amoruso  1 , Liam P Keegan  1 , Mary A O'Connell  1
Affiliations
Review

ADAR2 enzymes: efficient site-specific RNA editors with gene therapy aspirations

Khadija Hajji et al. RNA. 2022 Oct.

Abstract

The adenosine deaminase acting on RNA (ADAR) enzymes are essential for neuronal function and innate immune control. ADAR1 RNA editing prevents aberrant activation of antiviral dsRNA sensors through editing of long, double-stranded RNAs (dsRNAs). In this review, we focus on the ADAR2 proteins involved in the efficient, highly site-specific RNA editing to recode open reading frames first discovered in the GRIA2 transcript encoding the key GLUA2 subunit of AMPA receptors; ADAR1 proteins also edit many of these sites. We summarize the history of ADAR2 protein research and give an up-to-date review of ADAR2 structural studies, human ADARBI (ADAR2) mutants causing severe infant seizures, and mouse disease models. Structural studies on ADARs and their RNA substrates facilitate current efforts to develop ADAR RNA editing gene therapy to edit disease-causing single nucleotide polymorphisms (SNPs). Artificial ADAR guide RNAs are being developed to retarget ADAR RNA editing to new target transcripts in order to correct SNP mutations in them at the RNA level. Site-specific RNA editing has been expanded to recode hundreds of sites in CNS transcripts in Drosophila and cephalopods. In Drosophila and C. elegans, ADAR RNA editing also suppresses responses to self dsRNA.

Keywords: ADAR; ADARB1; dsRNA; neurons; recoding RNA editing.

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Figures

FIGURE 1.
FIGURE 1.
The consequences of GRIA2 Q/R site editing by ADAR2. The editing of GRIA2 pre-mRNA at the Q/R site affects the properties of the resultant GLUA2 protein, which assembles with other subunits to form AMPA receptors. The edited GRIA2 codes for GLUA2 protein with arginine in the pore-forming region, which regulates receptor assembly and blocks Ca2+ entry through AMPA receptors. Unedited GLUA2 protein has glutamine in the pore-forming region, and it assembles to form Ca2+-permeable AMPA receptors (CP-AMPARs). Aberrantly increased production of unedited GLUA2 and the subsequent increase in Ca2+-permeable CP-AMPARs leads to epilepsy in mice and humans.
FIGURE 2.
FIGURE 2.
The domain structure of major ADAR2 protein isoforms. Human ADAR2 has two major isoforms: ADAR2a (ADAR2S) and ADAR2b (ADAR2L). Both isoforms have two amino-terminal dsRBDs (pink) and a carboxy-terminal deaminase domain (light yellow), as well as an NLS (lilac) at the amino terminus. The longer isoform ADAR2b (ADAR2L) has an extra Alu-derived insert (light blue) in the deaminase domain. ADAR2 has further isoforms differing at the carboxyl terminus, with either a long (blue) or short (yellow; C-ter. S) terminus that is generated by alternative splicing. The adult Drosophila ADAR is the ortholog of mammalian ADAR2, with a slightly shorter deaminase domain.
FIGURE 3.
FIGURE 3.
ADAR2 recognizes the editing site as an asymmetric deaminase domain dimer with one positioned dsRBD 2. The ADAR2 catalytic deaminase domain in red is shown behind the dsRNA in this view of the ADAR2 deaminase domain plus dsRBD 2 protein complex with a GLI1 substrate RNA containing 8-azanebularine (8-AZ) at the edited A (Thuy-Boun et al. 2020). The dsRBD 2 of the catalytic deaminase monomer is not resolved in the structure. The adenosine-analog, 8-AN, editing target base, is on the yellow edited strand where the phosphate backbone is slightly kinked, and the 8-AN base is seen flipped back out through the dsRNA minor groove and down towards the blue sphere of the catalytic site zinc atom. A short dimerization helix on the catalytic deaminase domain holds the second, noncatalytic deaminase domain, in green. This second, noncatalytic deaminase domain then positions its associated dsRBDII, shown in orange, for normal dsRBD binding to the dsRNA, without contacting the catalytic deaminase domain.
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