Adenosine deaminases acting on RNA (ADARs) are both antiviral and proviral

Abstract

A-to-I RNA editing, the deamination of adenosine (A) to inosine (I) that occurs in regions of RNA with double-stranded character, is catalyzed by a family of Adenosine Deaminases Acting on RNA (ADARs). In mammals there are three ADAR genes. Two encode proteins that possess demonstrated deaminase activity: ADAR1, which is interferon-inducible, and ADAR2 which is constitutively expressed. ADAR3, by contrast, has not yet been shown to be an active enzyme. The specificity of the ADAR1 and ADAR2 deaminases ranges from highly site-selective to non-selective, dependent on the duplex structure of the substrate RNA. A-to-I editing is a form of nucleotide substitution editing, because I is decoded as guanosine (G) instead of A by ribosomes during translation and by polymerases during RNA-dependent RNA replication. Additionally, A-to-I editing can alter RNA structure stability as I:U mismatches are less stable than A:U base pairs. Both viral and cellular RNAs are edited by ADARs. A-to-I editing is of broad physiologic significance. Among the outcomes of A-to-I editing are biochemical changes that affect how viruses interact with their hosts, changes that can lead to either enhanced or reduced virus growth and persistence depending upon the specific virus.

Figure 1. A-to-I Editing by ADARs

Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic C-6 deamination of adenosine (A) to yield inosine (I) in RNA with double-stranded character.

Figure 2. Domain Organization of Human ADAR s

Three ADAR gene family members are known. ADAR1 and ADAR2 are active deaminase enzymes whereas ADAR3 is not known to possess deaminase activity. Alternative promoters and alternative splicing give rise to the different forms of ADAR1 and ADAR2. The p150 isoform of ADAR1 is IFN-inducible. The dsRNA binding domains (RI, RII, RIII), three present in ADAR1 p110 and p150 and two each in ADAR2 and ADAR3, are depicted in red. The C-terminal region deaminase catalytic domain is shown in yellow for ADAR1 and ADAR2, and the homologous region in stipled yellow for ADAR3 that is not yet demonstrated to be an active enzyme. The N-terminal region of the p150 form of ADAR1 possesses two Z-DNA binding domains (Zα and Zβ shown in pink, and the ADAR2R and ADAR3 proteins possess an arginine-rich domain (ARG) shown in green.

Figure 3. Mechanisms by which A-to-I RNA Editing may affect Gene Expression and Function

Deamination of adenosine (A) to produce in osine (I) in duplex RNA structures catalyzed by ADARs leads to the nucleotide substitution of an I for an A in an RNA sequence. Because I base pairs as G instead of A, A-to-I editing may effect gene expression and function in virus-infected cells by a number of ways that includes: mRNA translation, by changing codons and hence the amino acid sequence of synthesized proteins; pre-mRNA splicing, by changing a conserved A in splice site recognition sequences; RNA stability by altering sequences and structures involved in nuclease recognition; viral genome genetic stability, by changing template and thus product sequences by deamination leading to A-to-G (U-to-C) transitions during viral RNA synthesis; and RNA structure-dependent activities including microRNA production or targeting or dsRNA protein-RNA interactions involved in innate immune responses. [Adapted from Samuel 2003 with permission])