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Mechanism and structural diversity of exoribonuclease-resistant RNA structures in flaviviral RNAs

Author

Listed:
  • Andrea MacFadden

    (University of Colorado Denver School of Medicine)

  • Zoe O’Donoghue

    (University of Colorado Denver School of Medicine)

  • Patricia A. G. C. Silva

    (Leiden University Medical Center)

  • Erich G. Chapman

    (University of Colorado Denver School of Medicine
    University of Denver)

  • René C. Olsthoorn

    (Leiden University)

  • Mark G. Sterken

    (Wageningen University
    Wageningen University)

  • Gorben P. Pijlman

    (Wageningen University)

  • Peter J. Bredenbeek

    (Leiden University Medical Center)

  • Jeffrey S. Kieft

    (University of Colorado Denver School of Medicine
    University of Colorado Denver School of Medicine)

Abstract

Flaviviruses such as Yellow fever, Dengue, West Nile, and Zika generate disease-linked viral noncoding RNAs called subgenomic flavivirus RNAs. Subgenomic flavivirus RNAs result when the 5′–3′ progression of cellular exoribonuclease Xrn1 is blocked by RNA elements called Xrn1-resistant RNAs located within the viral genome’s 3′-untranslated region that operate without protein co-factors. Here, we show that Xrn1-resistant RNAs can halt diverse exoribonucleases, revealing a mechanism in which they act as general mechanical blocks that ‘brace’ against an enzyme’s surface, presenting an unfolding problem that confounds further enzyme progression. Further, we directly demonstrate that Xrn1-resistant RNAs exist in a diverse set of flaviviruses, including some specific to insects or with no known arthropod vector. These Xrn1-resistant RNAs comprise two secondary structural classes that mirror previously reported phylogenic analysis. Our discoveries have implications for the evolution of exoribonuclease resistance, the use of Xrn1-resistant RNAs in synthetic biology, and the development of new therapies.

Suggested Citation

  • Andrea MacFadden & Zoe O’Donoghue & Patricia A. G. C. Silva & Erich G. Chapman & René C. Olsthoorn & Mark G. Sterken & Gorben P. Pijlman & Peter J. Bredenbeek & Jeffrey S. Kieft, 2018. "Mechanism and structural diversity of exoribonuclease-resistant RNA structures in flaviviral RNAs," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02604-y
    DOI: 10.1038/s41467-017-02604-y
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    Cited by:

    1. Guiquan Zhang & Yao Liu & Shisheng Huang & Shiyuan Qu & Daolin Cheng & Yuan Yao & Quanjiang Ji & Xiaolong Wang & Xingxu Huang & Jianghuai Liu, 2022. "Enhancement of prime editing via xrRNA motif-joined pegRNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Andrii Slonchak & Rhys Parry & Brody Pullinger & Julian D. J. Sng & Xiaohui Wang & Teresa F. Buck & Francisco J. Torres & Jessica J. Harrison & Agathe M. G. Colmant & Jody Hobson-Peters & Roy A. Hall , 2022. "Structural analysis of 3’UTRs in insect flaviviruses reveals novel determinants of sfRNA biogenesis and provides new insights into flavivirus evolution," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Xiaolin Niu & Ruirui Sun & Zhifeng Chen & Yirong Yao & Xiaobing Zuo & Chunlai Chen & Xianyang Fang, 2021. "Pseudoknot length modulates the folding, conformational dynamics, and robustness of Xrn1 resistance of flaviviral xrRNAs," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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