Acetylation of Cytidine in mRNA Promotes Translation Efficiency

Generation of the “epitranscriptome” through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here, we describe N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wi...

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Bibliographic Details
Published in:Cell 2018-12, Vol.175 (7), p.1872-1886.e24
Main Authors: Arango, Daniel, Sturgill, David, Alhusaini, Najwa, Dillman, Allissa A., Sweet, Thomas J., Hanson, Gavin, Hosogane, Masaki, Sinclair, Wilson R., Nanan, Kyster K., Mandler, Mariana D., Fox, Stephen D., Zengeya, Thomas T., Andresson, Thorkell, Meier, Jordan L., Coller, Jeffery, Oberdoerffer, Shalini
Format: Article
Language:English
Subjects:
Acetylation
Cytidine - analogs & derivatives
Cytidine - genetics
Cytidine - metabolism
epitranscriptome
HeLa Cells
Humans
mRNA stability
mRNA translation
N-Terminal Acetyltransferase E - genetics
N-Terminal Acetyltransferase E - metabolism
N4-acetylcytidine
NAT10
Protein Biosynthesis
RNA, Messenger - genetics
RNA, Messenger - metabolism
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Summary:Generation of the “epitranscriptome” through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here, we describe N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were enriched within coding sequences. Ablation of NAT10 reduced ac4C detection at the mapped mRNA sites and was globally associated with target mRNA downregulation. Analysis of mRNA half-lives revealed a NAT10-dependent increase in stability in the cohort of acetylated mRNAs. mRNA acetylation was further demonstrated to enhance substrate translation in vitro and in vivo. Codon content analysis within ac4C peaks uncovered a biased representation of cytidine within wobble sites that was empirically determined to influence mRNA decoding efficiency. These findings expand the repertoire of mRNA modifications to include an acetylated residue and establish a role for ac4C in the regulation of mRNA translation. [Display omitted] •NAT10 catalyzes N4-acetylcytidine (ac4C) modification of a broad range of mRNAs•mRNA acetylation within coding sequences promotes translation and mRNA stability•ac4C in wobble sites stimulates translation efficiency Post-transcriptional acetylation of cytidines in mammalian mRNAs enhances RNA stability and translation.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2018.10.030