Leveraging genetics to understand ADAR1-mediated RNA editing in health and disease

Endogenous, long double-stranded RNA (dsRNA) can resemble viral dsRNA and be recognized by cytosolic dsRNA sensors, triggering autoimmunity. Genetic studies of rare, inherited human diseases and experiments using mouse models have established the importance of adenosine-to-inosine RNA editing by the enzyme adenosine deaminase acting on RNA 1 (ADAR1) as a critical safeguard against autoinflammatory responses to cellular dsRNA. More recently, human genetic studies have revealed that dsRNA editing and sensing mechanisms are involved in common inflammatory diseases, emphasizing the broader role of dsRNA in modulating immune responses and disease pathogenesis. These findings have highlighted the therapeutic potential of targeting dsRNA editing and sensing, as exemplified by the emergence of ADAR1 inhibition in cancer therapy. ADAR1-mediating RNA editing enables the cell to distinguish between endogenous and viral RNA. Li and Walkley review findings from human and mouse genetics that have revealed the mechanisms of ADAR1-mediated RNA editing, which are now providing insights for the development of potential therapies that target these mechanisms.