Discovery, Processing, and Potential Role of Noncanonical Caps in RNA

Abstract

AbstractThe modification of RNA species has been well documented for decades. In mRNA, both internal and 5′ end modifications can occur. Specifically, modification of the 5′ end is known as capping. The 5′-5′ triphosphate linked N7-methyl guanosine (m7G) structure is involved in a myriad of RNA processes and was long presumed to be the only functional cap. In recent years, this view was overturned by reports that nicotinamide adenine dinucleotide (NAD+), a critical redox cofactor, can serve as an RNA cap in bacteria. Subsequently, yeast, mammalian, and plant RNA species were also found to harbor the NAD+cap. Apart from NAD+, other noncanonical nucleotide analogs, including NADH, FAD, dpCoA, UDP-Glucose, and UDP-N-acetylglucosamine, were found to be caps in endogenous RNA, suggesting that a wide repertoire of RNA caps may be present. However, the functions of noncanonical capping remain mostly unknown. This chapter describes the detection methods for noncanonical RNA caps, their mode of capping and decapping, and their potential molecular and biological functions. The discovery of noncanonical caps represents a revolution in research on RNA modifications and prompts future efforts to delve into novel epitranscriptomic processes, which may link cellular metabolism with gene expression.KeywordsNoncanonical capsLC-MS analysisNAD+ captureSeqNAD+ tagSeqCapping mechanismDecapping enzymesNudixDXORNA stabilityTranslation initiation