Substitutional A-to-I RNA editing

Adenosine-to-inosine (A-to-I) editing catalyzed by adenosine deaminases acting on RNA (ADARs) entails the chemical conversion of adenosine residues to inosine residues within doublestranded RNA (dsRNA) substrates. Inosine base pairs as guanosine and A-to-I editing can therefore alter the structure and base pairing properties of the RNA molecule. This has a biological significance in controlling the amount of functional RNA molecules in the cell, in expanding the functionality of a limited set of transcripts, and in defending the cell against certain RNA viruses. A-to-I editing is not limited to any specific type of RNA substrate. Instead, it can affect any RNA molecule able to attain the required double-stranded structure. This includes microRNAs, small interfering RNAs, viral RNAs, and messenger RNAs with potential for recoding events and splice site modifications. An RNA molecule can be post-transcriptionally modified in many ways that affect its function in the cell, including splicing, polyadenylation, and RNA editing. RNA editing— the insertion, deletion, or chemical conversion of nucleotides—once seemed a quirk of trypanosome mitochondria but is now increasingly recognized as an important phenomenon affecting a diverse set of cellular pathways. By alteration of the RNA's sequence, properties of both the RNA molecule and of proteins translated from it can be modified. The cell uses this to control the amounts of biologically functional RNAs, to diversify the functionality of a limited set of unique transcripts, and to modulate viral replication of certain RNA viruses. Chemical conversions of nucleotides commonly take the form of deaminations. Deamination of a cytidine residue replaces it with a uridine. As shown in Figure 1, deamination of adenosine (A) creates an inosine (I), a nucleotide containing hypoxanthine in place of one of the conventional nucleobases. Inosine preferentially base pairs with cytidine, effectively equating it with guanosine. Found in most metazoa, the adenosine deaminase acting on RNA (ADAR) family catalyzes A-to-I editing in partially or perfectly double-stranded RNA. This means that the effects of ADARs, rather than being limited to any specific functional grouping of RNAs, hold significance for a wide range of cellular functions. This review focuses on the various effects of A-to-I editing by ADARs, on the biological mechanisms underlying and controlling the editing, and on the related recent discoveries.