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.

Details

Title
Mechanism and structural diversity of exoribonuclease-resistant RNA structures in flaviviral RNAs
Author
MacFadden, Andrea 1 ; Zoe O’Donoghue 1 ; Patricia A G C Silva 2 ; Chapman, Erich G 3 ; Olsthoorn, René C 4 ; Sterken, Mark G 5 ; Pijlman, Gorben P 6 ; Bredenbeek, Peter J 2 ; Kieft, Jeffrey S 7   VIAFID ORCID Logo 

1  Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, CO, USA 
2  Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands 
3  Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, CO, USA; Department of Chemistry and Biochemistry, University of Denver, Denver, CO, USA 
4  Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands 
5  Laboratory of Virology, Wageningen University, Wageningen, The Netherlands; Laboratory of Nematology, Wageningen University, Wageningen, The Netherlands 
6  Laboratory of Virology, Wageningen University, Wageningen, The Netherlands 
7  Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, CO, USA; RNA BioScience Initiative, University of Colorado Denver School of Medicine, CO, USA 
First page
1
Publication year
2018
Publication date
Jan 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-02604-y
ProQuest document ID
1986193898
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.