Eukaryotic RNA 5′-End NAD⁺ Capping and DeNADding

A hallmark of eukaryotic mRNAs has long been the 5′-end m⁷G cap. This paradigm was recently amended by recent reports that Saccharomyces cerevisiae and mammalian cells also contain mRNAs carrying a novel nicotinamide adenine dinucleotide (NAD⁺) cap at their 5′-end. The presence of an NAD⁺ cap on mRNA uncovers a previously unknown mechanism for controlling gene expression through nucleotide metabolite-directed mRNA turnover. In contrast to the m⁷G cap that stabilizes mRNA, the NAD⁺ cap targets RNA for rapid decay in mammalian cells through the DXO non-canonical decapping enzyme which removes intact NAD⁺ from RNA in a process termed ‘deNADding’. This review highlights the identification of NAD⁺ caps, their mode of addition, and their functional significance in cells.