Direct epitranscriptomic regulation of mammalian translation initiation through N4-acetylcytidine

Daniel Arango, David Sturgill, Renbin Yang, Tapan Kanai, Paulina Bauer, Jyoti Roy, Ziqiu Wang, Masaki Hosogane, Sarah Schiffers, Shalini Oberdoerffer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

mRNA function is influenced by modifications that modulate canonical nucleobase behavior. We show that a single modification mediates distinct impacts on mRNA translation in a position-dependent manner. Although cytidine acetylation (ac4C) within protein-coding sequences stimulates translation, ac4C within 5′ UTRs impacts protein synthesis at the level of initiation. 5′ UTR acetylation promotes initiation at upstream sequences, competitively inhibiting annotated start codons. Acetylation further directly impedes initiation at optimal AUG contexts: ac4C within AUG-flanking Kozak sequences reduced initiation in base-resolved transcriptome-wide HeLa results and in vitro utilizing substrates with site-specific ac4C incorporation. Cryo-EM of mammalian 80S initiation complexes revealed that ac4C in the −1 position adjacent to an AUG start codon disrupts an interaction between C and hypermodified t6A at nucleotide 37 of the initiator tRNA. These findings demonstrate the impact of RNA modifications on nucleobase function at a molecular level and introduce mRNA acetylation as a factor regulating translation in a location-specific manner.

Original languageEnglish (US)
Pages (from-to)2797-2814.e11
JournalMolecular cell
Volume82
Issue number15
DOIs
StatePublished - Aug 4 2022

Keywords

  • 80S
  • Kozak
  • NAT10
  • ac4C
  • acetylcytidine
  • cryo-EM
  • epitranscriptome
  • initiation
  • t6A
  • translation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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