Generation of 2',3'-Cyclic Phosphate-Containing RNAs as a Hidden Layer of the Transcriptome

Cellular RNA molecules contain phosphate or hydroxyl ends. A 2',3'-cyclic phosphate (cP) is one of the 3'-terminal forms of RNAs mainly generated from RNA cleavage by ribonucleases. Although transcriptome profiling using RNA-seq has become a ubiquitous tool in biological and medical research, cP-containing RNAs (cP-RNAs) form a hidden transcriptome layer, which is infrequently recognized and characterized, because standard RNA-seq is unable to capture them. Despite cP-RNAs' invisibility in RNA-seq data, increasing evidence indicates that they are not accumulated simply as non-functional degradation products; rather, they have physiological roles in various biological processes, designating them as noteworthy functional molecules. This review summarizes our current knowledge of cP-RNA biogenesis pathways and their catalytic enzymatic activities, discusses how the cP-RNA generation affects biological processes, and explores future directions to further investigate cP-RNA biology.