ADARmediated

ADAR-mediated RNA editing refers to the enzymatic conversion of adenosine to inosine in double-stranded RNA by ADAR family enzymes. Inosine is interpreted as guanosine by cellular machinery, potentially altering codons, splice sites, microRNA binding, or RNA structure. The predominant form is A-to-I editing, which can recode coding sequences or modulate RNA processing, with important consequences for neural function and innate immunity.

ADAR enzymes possess dsRNA-binding domains that recruit adenosine deaminase activity to duplex RNA. The human family includes ADAR1, ADAR2, and ADAR3. ADAR1 exists as two major isoforms, p110 (nuclear) and p150 (cytoplasmic and interferon-inducible); ADAR2 is primarily neuronal and responsible for canonical coding edits; ADAR3 is expressed in brain and lacks demonstrable catalytic activity, though its regulatory role remains under study.

Editing occurs at double-stranded regions formed by long or repetitive sequences, including exonic and intronic sites. The most well-known target is the GRIA2 (GluR2) Q/R site, whose editing affects calcium permeability of AMPA receptors. Numerous other transcripts show tissue-specific A-to-I edits that can influence splicing, stability, or protein function. The activity depends on dsRNA structure and surrounding sequence context.

ADAR-mediated editing intersects with innate immunity: ADAR1 limits endogenous dsRNA sensing by MDA5, preventing inappropriate interferon responses. Mutations in ADAR1 cause autoinflammatory diseases such as Aicardi-Goutières syndrome, and mouse models show embryonic lethality without ADAR1. Abnormal editing patterns have also been observed in autoimmune diseases and cancer.

In research and therapeutics, engineered ADAR enzymes are used to direct RNA editing in cells (programmable ADAR systems) for functional studies and potential treatments. Detection of A-to-I edits employs RNA sequencing and inosine-specific methods. Challenges include off-target editing, site selectivity, delivery, and immune responses.