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Direct epitranscriptomic regulation of mammalian translation initiation through N4-acetylcytidine

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

  2. Author Address

    Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA., Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Center for Molecular Microscopy, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21701, USA., Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: shalini.oberdoerffer@nih.gov.,
    1. Year: 2022
    2. Date: Jun 07
    3. Epub Date: 2022 06 07
  2. Journal: Molecular Cell
  4. Type of Article: Article
  1. 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. Published by Elsevier Inc.

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External Sources

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  2. DOI: 10.1016/j.molcel.2022.05.016
  3. PMID: 35679869
  4. PII : S1097-2765(22)00483-X

Library Notes

  1. Fiscal Year: FY2021-2022
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