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A sequence-specific RNA acetylation catalyst

  1. Author:
    Thalalla Gamage,Supuni [ORCID]
    Howpay Manage,Shereen
    Sas-Chen, Aldema
    Nir, Ronit
    Burkhart, Brett W
    Jhulki, Isita
    Link, Courtney N
    Penikalapati,Manini
    Jones,Jane
    Iyer, Lakshminarayan M
    Aravind, L [ORCID]
    Santangelo, Thomas J [ORCID]
    Schwartz, Schraga [ORCID]
    Meier,Jordan [ORCID]

  2. Author Address

    1Chemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, United States. 2The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 6195001 Tel Aviv, Israel. 3Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7630031, Israel. 4Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, United States. 5Protein Expression Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, United States. 6Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, United States.
    1. Year: 2025
    2. Date: Mar 20
  2. Journal: Nucleic Acids Research
    1. 53
    2. 6
  4. Type of Article: Article
  5. Article Number: gkaf217
  1. Abstract:

    N4-acetylcytidine (ac4C) is a ubiquitous RNA modification incorporated by cytidine acetyltransferase enzymes. Here, we report the biochemical characterization of Thermococcus kodakarensis Nat10 (TkNat10), an RNA acetyltransferase involved in archaeal thermotolerance. We demonstrate that TkNat10's catalytic activity is critical for T. kodakarensis fitness at elevated temperatures. Unlike eukaryotic homologs, TkNat10 exhibits robust stand-alone activity, modifying diverse RNA substrates in a temperature, ATP, and acetyl-CoA-dependent manner. Transcriptome-wide analysis reveals TkNat10 preferentially modifies unstructured RNAs containing a 5'-CCG-3' consensus sequence. Using a high-throughput mutagenesis approach, we define sequence and structural determinants of TkNat10 substrate recognition. We find TkNat10 can be engineered to facilitate use of propionyl-CoA, providing insight into its cofactor specificity. Finally, we demonstrate TkNat10's utility for site-specific acetylation of RNA oligonucleotides, enabling analysis of ac4C-dependent RNA-protein interactions. Our findings establish a framework for understanding archaeal RNA acetylation and a new tool for studying the functional consequences of ac4C in diverse RNA contexts. © The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.

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External Sources

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  2. DOI: 10.1093/nar/gkaf217
  3. PMID: 40119730
  4. PMCID: PMC11928934
  5. PII : 8090310

Library Notes

  1. Fiscal Year: FY2024-2025
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