ADAR RNA editing below the backbone

Abstract

ADAR RNA editing enzymes (adenosine deaminases acting on RNA) that convert adenosine bases to inosines were first identified biochemically 30 years ago. Since then, studies on ADARs in genetic model organisms, and evolutionary comparisons between them, continue to reveal a surprising range of pleiotropic biological effects of ADARs. This review focuses on Drosophila melanogaster, which has a single Adar gene encoding a homolog of vertebrate ADAR2 that site-specifically edits hundreds of transcripts to change individual codons in ion channel subunits and membrane and cytoskeletal proteins. Drosophila ADAR is involved in the control of neuronal excitability and neurodegeneration and, intriguingly, in the control of neuronal plasticity and sleep. Drosophila ADAR also interacts strongly with RNA interference, a key antiviral defense mechanism in invertebrates. Recent crystal structures of human ADAR2 deaminase domain-RNA complexes help to interpret available information on Drosophila ADAR isoforms and on the evolution of ADARs from tRNA deaminase ADAT proteins. ADAR RNA editing is a paradigm for the now rapidly expanding range of RNA modifications in mRNAs and ncRNAs. Even with recent progress, much remains to be understood about these groundbreaking ADAR RNA modification systems.

Keywords: ADAR; Drosophila melanogaster; RNA editing; RNA modification; dsRNA; epitranscriptome.

FIGURE 1.

Summary of Drosophila Adar mutant phenotypes discussed here, with main references.

FIGURE 2.

Drosophila ADAR isoforms and effects of deaminase domain S458G editing. (A) Drosophila Adar gene structure, embryonic splicing pattern (below the gene) and adult splicing pattern (above the gene), and ADAR protein isoforms expressed in embryos and adults. (B) Structure of human ADAR2 E488Q–Bdf2 RNA complex (PDB: 5E1). The edited RNA strand runs from 5′ U1 on the left to 3′ C23 on the right. The 8-azanebularine replacing the edited A at position 12 (marked 8AZ-12) is inserted into the deaminase domain active site near the catalytic zinc atom (orange sphere), and held there as a covalent reaction intermediate analog. The serine 458 loop (red), the 5′ RNA contacting region (salmon), the amino terminus of the deaminase domain (magenta), and the GQG base flipping loop (yellow) are highlighted on the deaminase domain protein structure. Several proline residues that cause the protein backbone in the loop to make changes in direction are also shown.