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Extensive breaking of genetic code degeneracy with non-canonical amino acids

Author

Listed:
  • Clinton A. L. McFeely

    (Virginia Commonwealth University
    Virginia Commonwealth University)

  • Bipasana Shakya

    (Virginia Commonwealth University
    Virginia Commonwealth University)

  • Chelsea A. Makovsky

    (Virginia Commonwealth University
    Virginia Commonwealth University)

  • Aidan K. Haney

    (Virginia Commonwealth University)

  • T. Ashton Cropp

    (Virginia Commonwealth University)

  • Matthew C. T. Hartman

    (Virginia Commonwealth University
    Virginia Commonwealth University)

Abstract

Genetic code expansion (GCE) offers many exciting opportunities for the creation of synthetic organisms and for drug discovery methods that utilize in vitro translation. One type of GCE, sense codon reassignment (SCR), focuses on breaking the degeneracy of the 61 sense codons which encode for only 20 amino acids. SCR has great potential for genetic code expansion, but extensive SCR is limited by the post-transcriptional modifications on tRNAs and wobble reading of these tRNAs by the ribosome. To better understand codon-tRNA pairing, here we develop an assay to evaluate the ability of aminoacyl-tRNAs to compete with each other for a given codon. We then show that hyperaccurate ribosome mutants demonstrate reduced wobble reading, and when paired with unmodified tRNAs lead to extensive and predictable SCR. Together, we encode seven distinct amino acids across nine codons spanning just two codon boxes, thereby demonstrating that the genetic code hosts far more re-assignable space than previously expected, opening the door to extensive genetic code engineering.

Suggested Citation

  • Clinton A. L. McFeely & Bipasana Shakya & Chelsea A. Makovsky & Aidan K. Haney & T. Ashton Cropp & Matthew C. T. Hartman, 2023. "Extensive breaking of genetic code degeneracy with non-canonical amino acids," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40529-x
    DOI: 10.1038/s41467-023-40529-x
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    References listed on IDEAS

    as
    1. Heinz Neumann & Kaihang Wang & Lloyd Davis & Maria Garcia-Alai & Jason W. Chin, 2010. "Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome," Nature, Nature, vol. 464(7287), pages 441-444, March.
    2. Erika A. DeBenedictis & Gavriela D. Carver & Christina Z. Chung & Dieter Söll & Ahmed H. Badran, 2021. "Multiplex suppression of four quadruplet codons via tRNA directed evolution," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Jeffrey K. Noel & Paul C. Whitford, 2016. "How EF-Tu can contribute to efficient proofreading of aa-tRNA by the ribosome," Nature Communications, Nature, vol. 7(1), pages 1-10, December.
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