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Engineered transfer RNAs for suppression of premature termination codons

Author

Listed:
  • John D. Lueck

    (University of Rochester School of Medicine and Dentistry)

  • Jae Seok Yoon

    (CFFT Lab, Cystic Fibrosis Foundation Therapeutics)

  • Alfredo Perales-Puchalt

    (The Wistar Institute)

  • Adam L. Mackey

    (University of Iowa)

  • Daniel T. Infield

    (University of Iowa)

  • Mark A. Behlke

    (Integrated DNA Technologies Inc.)

  • Marshall R. Pope

    (University of Iowa)

  • David B. Weiner

    (The Wistar Institute)

  • William R. Skach

    (CFFT Lab, Cystic Fibrosis Foundation Therapeutics
    Cystic Fibrosis Foundation)

  • Paul B. McCray

    (University of Iowa)

  • Christopher A. Ahern

    (University of Iowa)

Abstract

Premature termination codons (PTCs) are responsible for 10–15% of all inherited disease. PTC suppression during translation offers a promising approach to treat a variety of genetic disorders, yet small molecules that promote PTC read-through have yielded mixed performance in clinical trials. Here we present a high-throughput, cell-based assay to identify anticodon engineered transfer RNAs (ACE-tRNA) which can effectively suppress in-frame PTCs and faithfully encode their cognate amino acid. In total, we identify ACE-tRNA with a high degree of suppression activity targeting the most common human disease-causing nonsense codons. Genome-wide transcriptome ribosome profiling of cells expressing ACE-tRNA at levels which repair PTC indicate that there are limited interactions with translation termination codons. These ACE-tRNAs display high suppression potency in mammalian cells, Xenopus oocytes and mice in vivo, producing PTC repair in multiple genes, including disease causing mutations within cystic fibrosis transmembrane conductance regulator (CFTR).

Suggested Citation

  • John D. Lueck & Jae Seok Yoon & Alfredo Perales-Puchalt & Adam L. Mackey & Daniel T. Infield & Mark A. Behlke & Marshall R. Pope & David B. Weiner & William R. Skach & Paul B. McCray & Christopher A. , 2019. "Engineered transfer RNAs for suppression of premature termination codons," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08329-4
    DOI: 10.1038/s41467-019-08329-4
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    Cited by:

    1. Nikhil Bharti & Leonardo Santos & Marcos Davyt & Stine Behrmann & Marie Eichholtz & Alejandro Jimenez-Sanchez & Jeong S. Hong & Andras Rab & Eric J. Sorscher & Suki Albers & Zoya Ignatova, 2024. "Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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