In molecular biology, the NAD+ five-prime cap (NAD+ 5’ cap) refers to a molecule of nicotinamide adenine dinucleotide (NAD+), a nucleoside-containing metabolite, covalently bonded the 5’ end of cellular mRNA. While the more common methylated guanosine (m7G) cap is added to RNA by a capping complex that associates with RNA polymerase II (RNAP II), the NAD cap is added during transcriptional initiation by the RNA polymerase itself, acting as a non-canonical initiating nucleotide (NCIN). As such, while m7G capping can only occur in organisms possessing specialized capping complexes, because NAD capping is performed by RNAP itself, it is hypothesized to occur in most, if not all, organisms.
The NAD+ 5’ cap has been observed in bacteria, contrary to the long-held belief that prokaryotes lacked 5’-capped RNA, as well as on the 5’ cap of eukaryotic mRNA, in place of the m7G cap. This modification also potentially allows for selective degradation of RNA]within prokaryotes as different pathways are involved in the degradation of NAD+-capped and uncapped 5′-triphosphate-RNAs.
In eukaryotic cells, while the more commonly observed m7G cap promotes the stability of the mRNA and supports translation, the NAD+ cap targets the RNA transcript for decay, facilitated by the non-canonical decapping enzyme, DXO. Considering the centrality of NAD in redox chemistry and post-translational protein modification, its attachment to RNA represents potentially undiscovered pathways in RNA metabolism and regulation.