On the reversibility of RNA deamination versus RNA methylation: exploring the proximate and ultimate causes.

RNA modifications play a crucial role in regulating gene expression, splicing, decoding, translation, and degradation. Among the most studied modifications are adenosine-to-inosine (A-to-I) RNA editing and N⁶-methyladenosine (m⁶A). While m⁶A is reversible, enabling dynamic regulation of gene expression; A-to-I editing is irreversible, leading to permanent changes in RNA sequences. This raises a thought-provoking question: why do different RNA modifications have such distinct reversibility? Is this feature random or governed by evolutionary constraints? We interrogate the mechanistic (proximate cause) and evolutionary (ultimate cause) reasons for how and why inosine cannot be reversed by adding an amino group but m⁶A remains reversible, despite both modifications have the option to be degraded along with host RNAs. We also discuss whether inosine can have reader proteins like m⁶A to exert dynamic and regulatory control. Finally, we explore the evolutionary significance of these differences and their implications for future research in RNA modifications.