Messenger RNA 5' NAD⁺ Capping Is a Dynamic Regulatory Epitranscriptome Mark That Is Required for Proper Response to...

Although eukaryotic messenger RNAs (mRNAs) normally possess a 5' end N⁷-methyl guanosine (m⁷G) cap, a non-canonical 5' nicotinamide adenine dinucleotide (NAD⁺) cap can tag certain transcripts for degradation mediated by the NAD⁺ decapping enzyme DXO1. Despite this importance, whether NAD⁺ capping dynamically responds to specific stimuli to regulate eukaryotic transcriptomes remains unknown. Here, we reveal a link between NAD⁺ capping and tissue- and hormone response-specific mRNA stability. In the absence of DXO1 function, transcripts displaying a high proportion of NAD⁺ capping are instead processed into RNA-dependent RNA polymerase 6-dependent small RNAs, resulting in their continued turnover likely to free the NAD⁺ molecules. Additionally, the NAD⁺-capped transcriptome is significantly remodeled in response to the essential plant hormone abscisic acid in a mechanism that is primarily independent of DXO1. Overall, our findings reveal a previously uncharacterized and essential role of NAD⁺ capping in dynamically regulating transcript stability during specific physiological responses.