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Acetylation of Cytidine in Messenger RNA Regulates Translation
Author(s) -
Oberdoerffer Shalini,
Arango Daniel,
Hosogane Masaki,
Sturgill David,
Yankova Ellie,
Kouzarides Tony,
Tzelepis Kostas
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00189
Subject(s) - untranslated region , biology , acetylation , messenger rna , translation (biology) , rna , translational efficiency , eukaryotic translation , coding region , translational regulation , pseudouridine , rna binding protein , genetics , gene , transfer rna
Modifications within RNA nucleobases have the potential to impact all aspects of post‐transcriptional mRNA metabolism. We recently identified N4‐acetylcytidine (ac4C) as a novel modification in mRNA that is catalyzed by the enzyme NAT10. The majority of ac4C sites were found to occur within coding sequences with a general 5′ localization bias. Comparative profiling of ac4C substrate mRNAs in the presence or absence of NAT10 demonstrated a direct role for acetylation in promoting mRNA stability through enhanced translation efficiency. However, transcriptome‐wide mapping of ac4C also revealed an increased occurrence within 5′ untranslated regions (UTRs), wherein a clear relationship to gene expression was not observed (Arango et al., Cell , 2018). Here, we directly examine the function of 5′UTR acetylation in mRNA expression and uncover a putative role in the regulation of translation initiation. Ribosomal footprinting analysis performed in the presence of the initiation inhibitor harringtonine demonstrated an increased prevalence of 80S ribosomes at annotated 5′UTRs marked by overlapping acetylation. Detailed analysis in cancer relevant cellular models supports a role for ac4C in alternative initiation at well‐established non‐AUG translation start sites of known oncogenes. Altogether, our results identify a location specific role for ac4C in mRNA translation wherein coding sequence acetylation promotes translation elongation, while 5′UTR acetylation regulates translation initiation to support pro‐proliferative protein isoforms. These findings illustrate the powerful and diverse impact of the epitranscriptome on mRNA regulation. Support or Funding Information This work is supported by the Intramural Research Program of the NIH, the National Cancer Institute and The Center for Cancer Research.