Noncanonical RNA‐capping: Discovery, mechanism, and physiological role debate

Recently a new type of 5′‐RNA cap was discovered. In contrast to the specialized eukaryotic m7G cap, the novel caps are abundant cellular cofactors like NAD+. RNAs capped with cofactors are found in prokaryotes and eukaryotes. Unlike m7G cap, installed by specialized enzymes, cofactors are attached by main enzyme of transcription, RNA polymerase (RNAP). Cofactors act as noncanonical initiating substrates, provided cofactor's nucleoside base‐pairs with template DNA at the transcription start site. Adenosine—containing NAD(H), flavin adenine dinucleotide (FAD), and CoA modify transcripts on promoters starting with +1A. Similarly, uridine‐containing cell wall precursors, for example, uridine diphosphate‐N‐acetylglucosamine were shown to cap RNA in vitro on +1U promoters. Noncanonical capping is a universal feature of evolutionary unrelated RNAPs—multisubunit bacterial and eukaryotic RNAPs, and single‐subunit mitochondrial RNAP. Cellular concentrations of cofactors, for example, NAD(H) are significantly higher than their Km in transcription. Yet, only a small proportion of a given cellular RNA is noncanonically capped (if at all). This proportion is a net balance between capping, seemingly stochastic, and decapping, possibly determined by RNA folding, protein binding and transcription rate. NUDIX hydrolases in bacteria and eukaryotes, and DXO family proteins eukaryotes act as decapping enzymes for noncanonical caps. The physiological role of noncanonical RNA capping is only starting to emerge. It was demonstrated to affect RNA stability in vivo in bacteria and eukaryotes and to stimulate RNAP promoter escape in vitro in Escherichia coli. NAD+/NADH capping ratio may connect transcription to cellular redox state. Potentially, noncanonical capping affects mRNA translation, RNA‐protein binding and RNA localization.This article is categorized under: RNA Processing > Capping and 5′ End Modifications RNA Export and Localization > RNA Localization RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry