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An unnatural enzyme with endonuclease activity towards small non-coding RNAs

Author

Listed:
  • Noreen Ahmed

    (University of Ottawa)

  • Nadine Ahmed

    (University of Ottawa)

  • Didier A. Bilodeau

    (University of Ottawa)

  • John Paul Pezacki

    (University of Ottawa)

Abstract

Endonucleases are enzymes that cleave internal phosphodiester bonds within double-stranded DNA or RNA and are essential for biological functions. Herein, we use genetic code expansion to create an unnatural endonuclease that cleaves non-coding RNAs including short interfering RNA (siRNA) and microRNAs (miRNAs), a function that does not exist in nature. We introduce a metal-chelating unnatural amino acid, (2,2′-bipyridin-5-yl)alanine (BpyAla) to impart endonuclease activity to the viral suppressor of RNA silencing protein p19. Upon binding of copper, the mutant p19-T111BpyAla displays catalytic site-specific cleavage of siRNA and human miRNAs. Catalysis is confirmed using fluorescence polarization and fluorescence turn-on. Global miRNA profiling reveals that the engineered enzyme cleaves miRNAs in a human cell line. The therapeutic potential is demonstrated by targeting miR-122, a critical host factor for the hepatitis C virus (HCV). Unnatural endonuclease function is shown to deplete miR-122 levels with similar effects to an antagomir that reduces HCV levels therapeutically.

Suggested Citation

  • Noreen Ahmed & Nadine Ahmed & Didier A. Bilodeau & John Paul Pezacki, 2023. "An unnatural enzyme with endonuclease activity towards small non-coding RNAs," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39105-0
    DOI: 10.1038/s41467-023-39105-0
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    References listed on IDEAS

    as
    1. Rajarshi Choudhury & Yihsuan S. Tsai & Daniel Dominguez & Yang Wang & Zefeng Wang, 2012. "Engineering RNA endonucleases with customized sequence specificities," Nature Communications, Nature, vol. 3(1), pages 1-8, January.
    2. Christopher S. Sullivan & Adam T. Grundhoff & Satvir Tevethia & James M. Pipas & Don Ganem, 2005. "SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells," Nature, Nature, vol. 435(7042), pages 682-686, June.
    3. A. Gupta & J. J. Gartner & P. Sethupathy & A. G. Hatzigeorgiou & N. W. Fraser, 2006. "Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript," Nature, Nature, vol. 442(7098), pages 82-85, July.
    4. Philipp Schult & Hanna Roth & Rebecca L. Adams & Caroline Mas & Lionel Imbert & Christian Orlik & Alessia Ruggieri & Anna M. Pyle & Volker Lohmann, 2018. "microRNA-122 amplifies hepatitis C virus translation by shaping the structure of the internal ribosomal entry site," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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