- Adenosine-to-inosine (A-to-I) RNA editing is one of the most widespread and well-studied forms of post-transcriptional RNA modification in metazoans.
- It involves the enzymatic deamination of adenosine (A) to inosine (I) within double-stranded regions of RNA molecules. Since the cellular translation machinery and many RNA-binding proteins interpret inosine as guanosine (G), this editing process can recode codons, alter splicing patterns, modify RNA stability, and change RNA–protein or RNA–RNA interactions. Thus, A-to-I editing serves as a powerful mechanism for diversifying the transcriptome and expanding proteomic complexity without altering the underlying genomic sequence.
- This modification is catalyzed by a family of enzymes known as adenosine deaminases acting on RNA (ADARs). In mammals, three ADAR genes have been identified: ADAR1, ADAR2, and ADAR3. ADAR1 and ADAR2 are catalytically active and responsible for most editing events, while ADAR3 appears to lack enzymatic activity but may regulate RNA editing through competitive binding. ADARs recognize and act upon double-stranded RNA (dsRNA) structures formed either within a single transcript (via inverted repeat sequences such as Alu elements in humans) or between complementary RNA strands. This structural requirement ensures that editing is targeted to specific sites rather than occurring randomly across the transcriptome.
- Functionally, A-to-I RNA editing has profound biological significance. In coding regions, it can lead to amino acid substitutions that impact protein function—for example, the well-characterized editing of the glutamate receptor subunit (GluA2) mRNA, which is essential for proper neurotransmission and prevention of excitotoxicity in the brain. In non-coding regions, A-to-I editing plays crucial roles in regulating splicing, RNA transport, microRNA (miRNA) processing, and silencing of repetitive elements. Because Alu elements make up a large proportion of primate genomes, A-to-I editing occurs extensively within these regions, suggesting a regulatory function in maintaining transcriptome homeostasis.
- A-to-I RNA editing is tightly regulated in a cell-type-, tissue-, and developmental-stage–specific manner, with particularly high levels in the nervous system. Dysregulation of editing has been implicated in various diseases, including neurological disorders, cancer, and autoimmune conditions. For instance, insufficient editing of GluA2 mRNA is associated with epilepsy and amyotrophic lateral sclerosis (ALS), while aberrant ADAR1 activity contributes to autoimmune diseases such as Aicardi–Goutières syndrome by triggering inappropriate activation of innate immune responses to endogenous dsRNA.
- Overall, A-to-I RNA editing represents a dynamic and versatile layer of gene regulation. By enabling post-transcriptional recoding and modulation of RNA fate, it contributes both to normal cellular physiology and to disease pathogenesis when disrupted. With advances in high-throughput sequencing and bioinformatics, the catalog of editing sites continues to expand, deepening our understanding of how this RNA modification shapes transcriptome plasticity and organismal complexity.
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