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Review
. 2021 Feb;56(1):54-87.
doi: 10.1080/10409238.2020.1856768. Epub 2020 Dec 27.

To protect and modify double-stranded RNA - the critical roles of ADARs in development, immunity and oncogenesis

Emily A Erdmann  1 , Ananya Mahapatra  1 , Priyanka Mukherjee  2 , Boyoon Yang  3 , Heather A Hundley  2
Affiliations
Review

To protect and modify double-stranded RNA - the critical roles of ADARs in development, immunity and oncogenesis

Emily A Erdmann et al. Crit Rev Biochem Mol Biol. 2021 Feb.

Abstract

Adenosine deaminases that act on RNA (ADARs) are present in all animals and function to both bind double-stranded RNA (dsRNA) and catalyze the deamination of adenosine (A) to inosine (I). As inosine is a biological mimic of guanosine, deamination by ADARs changes the genetic information in the RNA sequence and is commonly referred to as RNA editing. Millions of A-to-I editing events have been reported for metazoan transcriptomes, indicating that RNA editing is a widespread mechanism used to generate molecular and phenotypic diversity. Loss of ADARs results in lethality in mice and behavioral phenotypes in worm and fly model systems. Furthermore, alterations in RNA editing occur in over 35 human pathologies, including several neurological disorders, metabolic diseases, and cancers. In this review, a basic introduction to ADAR structure and target recognition will be provided before summarizing how ADARs affect the fate of cellular RNAs and how researchers are using this knowledge to engineer ADARs for personalized medicine. In addition, we will highlight the important roles of ADARs and RNA editing in innate immunity and cancer biology.

Keywords: ADAR; Double-stranded RNA (dsRNA); RNA editing; RNA modification; cancer; dsRBP; innate immunity; inosine.

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Figures

Figure 1.
Figure 1.. Domain structure of ADARs from various organisms.
Overall domain structure of human (Homo sapiens, hs), fly (Drosophila melanogaster, dm), squid (Doryteuthis opalescens, sq), and nematode (Caenorhabditis elegans, ce) ADAR proteins. Structures highlighted include dsRNA binding domains (purple), C-terminal catalytic (deaminase) domains (blue), Z-DNA binding motifs (red, hsADAR1 only), and the arginine-rich R-domain (yellow, hsADAR3 only). Domain boundaries and protein length data was obtained from the UniProt database, accession numbers are as follows: hsADAR1 (P55265), hsADAR2 (P78563), hsADAR3 (Q9NS39), dmADAR (Q9NII1), sqADAR2a (C1JAR3), sqADAR2b (C1JAR4), ceADR-1 (Q9U3D6), ceADR-2 (Q22618).
Figure 2.
Figure 2.. Multiple sequence alignment of dsRNA binding domains of ADARs.
Sequences of the dsRBDs for the indicated proteins were obtained from UniProt database using the accession numbers described for Figure 1. Domain boundaries were adjusted based on structural data. The final figure was produced using ESPript 3 (Robert and Gouet, 2014). Sequences that are identical are shown in a red-filled box, while those meet consensus (> 70%, <100%) are boxed with consensus residues in red font. The residues important for dsRNA binding (Masliah, Barraud, and Allain, 2013) and the secondary structure elements (conserved αβββα fold) are shown below. The conserved GPxH motif and di-alanine residues (AA) as well as the aromatic residues that reside within the hydrophobic core (HC) of the dsRBD are indicated above the alignment.
Figure 3.
Figure 3.. Influence of ADARs and editing on cellular fate of RNAs.
A) A-to-I editing within coding regions can lead to codon changes, resulting in altered protein sequence and, potentially, changes in protein structure and function. B) Editing can affect splicing by disrupting the 3’ splice site or the branch point adenosine, or by creating novel 5’ or 3’ splice sites. C) A-to-I editing can interfere with miRNA biogenesis and processing. Editing can also alter miRNA specificity and binding to the 3’ UTRs of target genes. D) ADARs may cause nuclear retention of target transcripts, either by binding transcripts and competing with RNA shuttling factors or by editing transcripts, allowing them to be targeted and bound by the nuclear p54nrb complex. E) Inosine-containing RNA can recruit the Vigilin complex, which promotes heterochromatic gene silencing. F) Certain endonucleases specifically target and cleave inosine-containing RNA, suggesting that editing may mark certain transcripts for degradation.
Figure 4.
Figure 4.. ADAR binding and editing of endogenous dsRNA prevents aberrant sensing of self dsRNA in nematodes, flies and mammals.
ADARs can have both binding and editing effects that prevent the sensing of endogenous dsRNA structures by the indicated sensor proteins. Loss of ADAR leads to upregulation of antiviral, innate immune and interferon stimulated genes.
Figure 5.
Figure 5.. Conservation of the deaminase domain sequences between human ADAR1, Drosophila ADAR and C. elegans ADR-2.
Sequences of the deaminase domains for the indicated proteins were obtained from UniProt database using the accession numbers described for Figure 1. Sequences that are identical are shown in a red-filled box, while those meet consensus (> 70%, <100%) are boxed with consensus residues in red font. Variants in human ADAR1 p150 deaminase domain known to cause AGS (Rice et al., 2012) are indicated using symbols: A870T (#), I872T (*), R892H (!), K999N (^), G1007R(&), Y1112H (+) and D1113H ($). Please refer to Table 1 for detailed information about the consequences of these mutations on ADAR1 function.
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