2. Academic Validation
  3. Acetylation of Cytidine in mRNA Promotes Translation Efficiency

Acetylation of Cytidine in mRNA Promotes Translation Efficiency

  • Cell. 2018 Dec 13;175(7):1872-1886.e24. doi: 10.1016/j.cell.2018.10.030.
Daniel Arango 1,  David Sturgill 1,  Najwa Alhusaini 2,  Allissa A Dillman 1,  Thomas J Sweet 2,  Gavin Hanson 2,  Masaki Hosogane 1,  Wilson R Sinclair 3,  Kyster K Nanan 1,  Mariana D Mandler 1,  Stephen D Fox 4,  Thomas T Zengeya 3,  Thorkell Andresson 4,  Jordan L Meier 3,  Jeffery Coller 2,  Shalini Oberdoerffer 5
Affiliations

Affiliations

  • 1 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 2 Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH 44106, USA.
  • 3 Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21702, USA.
  • 4 Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA.
  • 5 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
PMID: 30449621 DOI: 10.1016/j.cell.2018.10.030
Abstract

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.

Keywords

N4-acetylcytidine; NAT10; epitranscriptome; mRNA stability; mRNA translation.

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