A Direct Chemical Repair of Etheno‐Type RNA Damages

Etheno damages in RNA represent a unique class of structural alterations that arise from exposure to various environmental stressors or endogenous processes. They significantly distort the RNA structure and affect crucial biological functions, including RNA-protein interactions, ribosome function, and translation fidelity. However, repair mechanisms for those etheno damages in RNA are still being elucidated. Here, a synthetic flavin derivative PS9 has been identified as the first example of chemical repair approach for this type of RNA damages. It efficiently managed the removal of etheno-type ϵA and ϵC damages in nucleosides, oligonucleotides in vitro, and in E. coli RNA in vivo under blue light irradiation. The capacity of the chemical approach relies on a unique cycloaddition activation of the etheno-bridge with singlet oxygen, which is distinct from traditional epoxidation of the C=C double bonds by proteins from the AlkB family. The understanding and effective manipulation of etheno damages in RNA with chemical tools hold implications for deciphering their role in mutagenesis and RNA biology, potentially opening avenues for targeted therapeutic interventions and biomarker development.