Noncanonical metabolite RNA caps: Classification, quantification, (de)capping, and function

Abstract The 5′ cap of eukaryotic mRNA is a hallmark for cellular functions from mRNA stability to translation. However, the discovery of novel 5′‐terminal RNA caps derived from cellular metabolites has challenged this long‐standing singularity in both eukaryotes and prokaryotes. Reminiscent of the 7‐methylguanosine (m7G) cap structure, these noncanonical caps originate from abundant coenzymes such as NAD, FAD, or CoA and from metabolites like dinucleoside polyphosphates (NpnN). As of now, the significance of noncanonical RNA caps is elusive: they differ for individual transcripts, occur in distinct types of RNA, and change in response to environmental stimuli. A thorough comparison of their prevalence, quantity, and characteristics is indispensable to define the distinct classes of metabolite‐capped RNAs. This is achieved by a structured analysis of all present studies covering functional, quantitative, and sequencing data which help to uncover their biological impact. The biosynthetic strategies of noncanonical RNA capping and the elaborate decapping machinery reveal the regulation and turnover of metabolite‐capped RNAs. With noncanonical capping being a universal and ancient phenomenon, organisms have developed diverging strategies to adapt metabolite‐derived caps to their metabolic needs, but ultimately to establish noncanonical RNA caps as another intriguing layer of RNA regulation. This article is categorized under: RNA Processing > Capping and 5′ End Modifications RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability