Potential Nucleotide Sites for RNA Glycosylation: acp3U and Beyond

The emerging field of glycoRNAs, RNA molecules covalently modified with glycans, challenges the long-held belief that glycosylation is exclusive to proteins and lipids. The discovery of 3-(3-amino-3-carboxypropyl) uridine (acp3U) as a specific N-glycan attachment site has been a major breakthrough, establishing glycoRNA as a structurally defined and functionally relevant biopolymer. This new function of acp3U suggests its crucial regulatory node that correlates translation with other cellular processes, such as immune modulation and cell signaling. The presence of glycoRNAs on the cell surface and their interaction with immune receptors imply their involvement in cell-to-cell communication. Furthermore, studies have begun to associate altered glycoRNA patterns with conditions like cancer and inflammation, opening up possibilities for diagnostic and therapeutic applications. Despite the rapid progress in this field, several key challenges remain, including the inherent bias of current detection methods, the difficulty of isolating pure glycoRNA samples from complex cellular mixtures, and the largely unknown mechanisms of specific glycan linkages. Future research must focus on developing unbiased and sensitive analytical technologies to accurately map these modification patterns at a single-nucleotide resolution. This review summarizes the chemical and enzymatic mechanisms of RNA glycosylation sites, highlights its potential functional roles in cells, and outlines future research aimed at uncovering its full biological and therapeutic potential.