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The non-canonical adenine nucleotide-adding RNA polymerase refers to the activity of multi-subunit, single-subunit RNA polymerases, and primases that initiate transcription by incorporating adenine nucleotide-containing metabolites, such as NAD+, NADH, FAD, CoA, and UDP-GlcNAc, as 5′ caps on RNA transcripts instead of standard NTPs. This template-dependent process occurs at the transcription start site, where the nucleotide portion of these cofactors pairs with template DNA, producing non-canonical capped RNAs (NC-RNAs) that diversify 5′ end structures in both prokaryotes and eukaryotes. These NC caps influence RNA fate by modulating stability, nuclease susceptibility, and potentially protein recruitment, expanding the epitranscriptomic regulation of gene expression beyond canonical m7G caps. While primarily studied in bacteria, NC capping has been detected in human cells, suggesting conserved mechanisms that challenge traditional views of RNA metabolism. No direct therapeutic targeting or disease associations are established, as research focuses on fundamental biology rather than drug development.
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