5’ end RNA Caps in Gene Expression

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Project Summary The proposed studies are focused on our long-term effort to delineate the functional contribution of canonical and non-canonical nucleotide metabolite mRNA 5¢ end caps and their removal in the control of RNA stability and gene expression. Regulation of RNA turnover is a critical step in the modulation of gene expression and minor alterations in mRNA stability can have profound consequences and may manifest as clinical phenotypes. A key component controlling the fate of eukaryotic mRNA is the 5¢-end cap. Eukaryotic caps are generally thought to possess a canonical N7 methyl guanosine (m7G) cap at their 5¢-end to promote their stability and translation. Removal of the m7G cap (decapping) is exquisitely regulated and renders the RNA translationally silent and subject to rapid decay and gene silencing. Moreover, a recent exciting paradigm shift emerged with the demonstration that eukaryotic RNAs can also carry noncanonical 5´end nucleotide metabolite caps, initially of nicotinamide adenine diphosphate (NAD) and subsequently flavin adenine dinucleotide (FAD) and Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). Such caps provide a potential link between RNA metabolism and cellular metabolism. However, there is a major gap in our understanding of these novel caps and their physiological function as well as their unambiguous identification. Thus, a detailed mechanistic understanding of the individual novel nucleotide metabolite capped RNAs and their functional consequence on cellular energetics and gene expression will have broad implications for cells in both normal and disease states.