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Review
. 2021 Jul 1;12(7):1026.
doi: 10.3390/genes12071026.

An I for an A: Dynamic Regulation of Adenosine Deamination-Mediated RNA Editing

Cornelia Vesely  1 , Michael F Jantsch  1
Affiliations
Review

An I for an A: Dynamic Regulation of Adenosine Deamination-Mediated RNA Editing

Cornelia Vesely et al. Genes (Basel). .

Abstract

RNA-editing by adenosine deaminases acting on RNA (ADARs) converts adenosines to inosines in structured RNAs. Inosines are read as guanosines by most cellular machineries. A to I editing has two major functions: first, marking endogenous RNAs as "self", therefore helping the innate immune system to distinguish repeat- and endogenous retrovirus-derived RNAs from invading pathogenic RNAs; and second, recoding the information of the coding RNAs, leading to the translation of proteins that differ from their genomically encoded versions. It is obvious that these two important biological functions of ADARs will differ during development, in different tissues, upon altered physiological conditions or after exposure to pathogens. Indeed, different levels of ADAR-mediated editing have been observed in different tissues, as a response to altered physiology or upon pathogen exposure. In this review, we describe the dynamics of A to I editing and summarize the known and likely mechanisms that will lead to global but also substrate-specific regulation of A to I editing.

Keywords: ADAR; RNA modification; RNA processing; adenosine deamination; regulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Activity and architecture of mammalian ADARs. (A) Adenosine deaminases acting on RNA convert adenosines via hydrolytic deamination to inosines. (B) Three ADAR genes can be found in mammals, ADAR1, ADAR2 and ADAR3. ADAR1 is expressed in two isoforms, ADAR1 p150 of 150 kDa, which is expressed from an interferon-inducible promoter, and ADAR1 p110, which is constitutively expressed. All ADARs contain a deaminase domain at their C-terminus. However, the catalytic domain of ADAR3 is enzymatically inactive. Substrate engagement of the ADARs is mediated via a variable number of double-stranded RNA-binding domains (dsRBDs) that interact with structured and double-stranded RNAs. The amino termini of the ADAR proteins are quite divergent. While the N-terminus of ADAR1 harbors a Z-DNA binding domain (ZBD) that is able to interact with Z-DNA and ZRNA, the long N terminus of ADAR1 p150 also harbors a nuclear export signal (NES), resulting in mostly cytoplasmic localization of this interferon-induced isoform. A nuclear localization signal (NLS) that overlaps the third dsRBD of ADAR1 is negatively regulated by RNA binding. As a consequence, the p150 isoform of ADAR1 can shuttle between the nucleus and cytoplasm. The N-terminus of ADAR2 harbors its classical nuclear localization signal. The catalytically inactive ADAR3 protein contains an N-terminally located RNA-binding domain (RBD).
Figure 2
Figure 2
Regulation of A to I editing by Adenosine Deaminases Acting on RNA (ADARs). Adar transcripts can be alternatively spliced, resulting in premature termination codons or the expression of an ADAR protein with modified editing activity. The time for ADARs to edit sites that consist of secondary structures in which intronic sequences are contained is restricted by the speed of the splicing that removes the intron. Intracellular acidic pH seems to favor the flipping out of the adenosine that is edited, resulting in higher editing rates. Overall, the editing rates for different types of editing sites (intronic, exonic and UTRs) is controlled by the ability of the ADAR proteins to shuttle between the nucleus and the cytoplasm. PIN1, a prolyl-isomerase, stabilizes ADAR2 in the nucleus and thereby regulates editing of the nuclear targets of ADAR2. Further, levels of ADARs can be regulated on a transcriptional level, by CREB for ADAR2 and by TDP-43 for ADAR1. Competitive binding of other RNA-binding proteins in general is another way to regulate editing. In many cases, however, this happens in a more tissue- or target-specific way. More broadly, the influential competitors of ADARs are ADAR3 in the brain and some proteins that have a DZF domain in common, such as NF-90 and Zn72D. Finally, ADARs can be decorated by different protein modifications (SUMOylation, phosphorylation and ubiquitination), which lead to either a reduction in available editase or compromise its editing activity.
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