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

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.

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    Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA.

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    Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA.

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    Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.

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    Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA. Department of Chemistry and Biochemistry, University of Denver, Denver, CO, 80208, USA.

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    Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands.

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    Laboratory of Virology, Wageningen University, Droevendaalsesteeg 1, 6708PB, Wageningen, The Netherlands. Laboratory of Nematology, Wageningen University, Droevendaalsesteeg 1, 6708PB, Wageningen, The Netherlands.

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    Laboratory of Virology, Wageningen University, Droevendaalsesteeg 1, 6708PB, Wageningen, The Netherlands.

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    Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.

    Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA. Jeffrey.Kieft@ucdenver.edu. RNA BioScience Initiative, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA. Jeffrey.Kieft@ucdenver.edu.

    Source

    Nature communications 9:1 2018 Jan 09 pg 119

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    29317714