Abstract
Cells regulate responses to external stimuli and control cell fate through reversible modifications on proteins, DNA, and RNA typically introduced by enzymes. Next to these well-known enzymatically installed modifications, covalent modifications can also occur on these same biomolecules through spontaneous reaction with small molecules taken up from external sources or generated endogenously, e.g. byproducts of metabolic processes. These so-called non-enzymatic covalent modifications (NECMs) have been mainly studied on proteins and DNA, yet their biological role on RNA remains mostly underexplored. This review surveys identified and predicted RNA NECMs, explores their impact on RNA structure, stability, and function, and examines their potential link to diseases. Finally, we discuss regulation mechanisms of non-enzymatically modified RNAs and their potential significance on cellular dynamics.