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TitleDirect epitranscriptomic regulation of mammalian translation initiation through N4-acetylcytidine.
Journal, issue, pagesMol Cell, Vol. 82, Issue 15, Page 2797-2814.e11, Year 2022
Publish dateAug 4, 2022
AuthorsDaniel Arango / David Sturgill / Renbin Yang / Tapan Kanai / Paulina Bauer / Jyoti Roy / Ziqiu Wang / Masaki Hosogane / Sarah Schiffers / Shalini Oberdoerffer /
PubMed AbstractmRNA 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 ...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.
External linksMol Cell / PubMed:35679869 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.1 Å
Structure data

26444

7ucj

EMDB-26444, PDB-7ucj:
Mammalian 80S translation initiation complex with mRNA and Harringtonine
Method: EM (single particle) / Resolution: 3.1 Å

26445

7uck

EMDB-26445, PDB-7uck:
80S translation initiation complex with ac4c(-1) mRNA and Harringtonine
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-MQ6:
Harringtonine

ChemComp-ZN:
Unknown entry

Source
  • oryctolagus cuniculus (rabbit)
  • rabbit (rabbit)
KeywordsRIBOSOME/INHIBITOR / Mammalian / 80S / initiation / complex / mRNA modification / Harringtonine / RIBOSOME-INHIBITOR complex / mRNA acetylation

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