Acetylation of cytidine in messenger RNA promotes translation efficiency

Authors

• D Arango
• DM Sturgill
• N Alhusaini
• AA Dillman
• TJ Sweet
• G Hanson
• WR Sincalir
• M Hosogane
• KK Nanan
• SD Fox
• TT Zengeya
• T Andresson
• JL Meier
• J Coller
• S Oberdoerffer

Abstract

Ribonucleoside modifications expand the metabolic and regulatory functions of RNA. Mainly studied in non-coding RNAs, ribonucleoside modifications have more recently been described in messenger RNAs (mRNAs), where they form the basis of the epitranscriptome. These epitranscriptome modifications have the capacity to regulate all steps of posttranscriptional mRNA metabolism including processing, structure, stability and translation. While most ribonucleoside modifications are methylation events, only a single acetylated ribonucleoside has been described in eukaryotes, occurring at the N4-position of cytidine (N4-acetylcytidine or ac4C). Initially discovered in transfer RNA (tRNA) and ribosomal RNA (rRNA), ac4C prevalence and locations transcriptome-wide has not been studied. Using a combination of chemical biology, RNA biology and antibody-based approaches, we identified N4-acetylcytidine as a novel mRNA modification that is catalyzed by the N-acetyltransferase enzyme NAT10. Transcriptome-wide mapping of ac4C identified discretely acetylated regions that were enriched within coding regions, with a 5’ localization bias. Depletion of ac4C through NAT10 ablation revealed a relationship to mRNA levels, wherein a reduction in ac4C was globally correlated with transcript down-regulation. Acetylated targets displayed elevated stability and enhanced translation as compared to non-acetylated mRNAs, and NAT10 depletion resulted in a decrease in both parameters specifically for acetylated targets. Ac4C was further demonstrated to directly enhance translation in vitro and in vivo. These findings expand the repertoire of mRNA modifications to include an acetylated residue and highlight a potential role for cytidine acetylation in regulating mRNA translation and stability.

Scientific Focus Area: Molecular Biology and Biochemistry

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