Adenosine Deaminases Acting on RNA, RNA Editing, and Interferon Action

Abstract

Adenosine deaminases acting on RNA (ADARs) catalyze adenosine (A) to inosine (I) editing of RNA that possesses double-stranded (ds) structure. A-to-I RNA editing results in nucleotide substitution, because I is recognized as G instead of A both by ribosomes and by RNA polymerases. A-to-I substitution can also cause dsRNA destabilization, as I:U mismatch base pairs are less stable than A:U base pairs. Three mammalian ADAR genes are known, of which two encode active deaminases (ADAR1 and ADAR2). Alternative promoters together with alternative splicing give rise to two protein size forms of ADAR1: an interferon-inducible ADAR1-p150 deaminase that binds dsRNA and Z-DNA, and a constitutively expressed ADAR1-p110 deaminase. ADAR2, like ADAR1-p110, is constitutively expressed and binds dsRNA. A-to-I editing occurs with both viral and cellular RNAs, and affects a broad range of biological processes. These include virus growth and persistence, apoptosis and embryogenesis, neurotransmitter receptor and ion channel function, pancreatic cell function, and posttranscriptional gene regulation by microRNAs. Biochemical processes that provide a framework for understanding the physiologic changes following ADAR-catalyzed A-to-I ( ¼ G) editing events include mRNA translation by changing codons and hence the amino acid sequence of proteins; pre-mRNA splicing by altering splice site recognition sequences; RNA stability by changing sequences involved in nuclease recognition; genetic stability in the case of RNA virus genomes by changing sequences during viral RNA replication; and RNAstructure-dependent activities such as microRNA production or targeting or protein-RNA interactions.

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

“…However, unlike PKR, ADAR1 uses dsRNA as a substrate (32). ADAR1 catalyzes the C6 deamination of adenosine (A) in dsRNA structures to generate inosine (I), a process known as A-to-I editing (33,34) samuel@lifesci.ucsb.edu.…”

“…However, unlike PKR, ADAR1 uses dsRNA as a substrate (32). ADAR1 catalyzes the C6 deamination of adenosine (A) in dsRNA structures to generate inosine (I), a process known as A-to-I editing (33,34) samuel@lifesci.ucsb.edu.2 The abbreviations used are: SG, stress granule; ADAR1, adenosine deaminase acting on RNA1; MEF, mouse embryo fibroblast; mmPCR-seq, microfluidics-based multiplex PCR and deep sequencing; RIG, retinoic acid-inducible gene. …”

Host Response to Polyomavirus Infection Is Modulated by RNA Adenosine Deaminase ADAR1 but Not by ADAR2

“…Two size forms of ADAR1 protein are expressed by a mechanism involving alternative adar1 promoter usage and alternative exon 1 splicing: a short (p110) nuclear form that is constitutively made and a long (p150) form that is interferon inducible and present in both the cytoplasm and nucleus (7,8,36,37). The mouse adar2 gene maps to chromosome 10 C1, is constitutively expressed, and is not known to be regulated by IFN or infection (10,16,29). The ADARs possess multiple copies of the canonical double-stranded RNA (dsRNA) binding motif first discovered in the PKR kinase (30), with three copies present in both ADAR1 p110 and p150 and two copies in ADAR2 (33,46).…”

“…In contrast to the highly selective A-to-I editing seen with GluR-B, 5HT-2cR, and HDV RNAs, nonselective and multiple-site adenosine deamination of viral and cellular RNAs has been observed when RNA substrates possesses extensive duplex character (10,17). Two examples of the hyperediting of viral RNAs during lytic and persistent infection include measles virus, where biased A-to-I (G) hypermutations were first described (6), and mouse polyomavirus (22).…”

“…Inosine-containing dsRNA is reported to bind a stressgranule-like complex and downregulate gene expression in trans (40), but the possible occurrence of such downregulation in PyV-infected cells mediated by edited viral RNA species is not yet known. Both ADAR1 and ADAR2 in mammalian cells are active enzymes and generate I-containing RNA (10,38); however, possibly the catalytic activity of only one of the two proteins is required, with the other ADAR protein being necessary but having a catalytically independent role.…”