A-to-I mRNA editing: Why not simply incorporate inosine during mRNA synthesis?

Adenosine-to-inosine (A-to-I) mRNA editing, catalyzed by ADAR enzymes, is a pervasive post-transcriptional mechanism that diversifies transcriptomes and protects against innate immune activation. This study asks a fundamental "why not" question: why organisms edit adenosine to inosine rather than directly incorporating inosine during mRNA synthesis? We argue that while inosine triphosphate (ITP) could theoretically serve as a transcriptional substrate, its biochemical, regulatory, and evolutionary constraints potentially make this mechanism less feasible. Direct inosine incorporation might replace guanosine instead of adenosine, disrupt editing precision, abolish transcriptomic diversity, and reduce transcriptional/translational efficiency. The universal ITP-to-IMP pathway might reflect the evolutionary pressure to prevent inosine accumulation. Thus, A-to-I RNA editing seems to be a safer, spatially confined solution that reconciles molecular flexibility with genomic fidelity. Understanding why life edits rather than encodes inosine reveals the deep evolutionary logic guiding RNA modification systems.