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

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 and Jeffrey S. Kieft ()
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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
René C. Olsthoorn: Leiden University
Mark G. Sterken: Wageningen University
Gorben P. Pijlman: Wageningen University
Peter J. Bredenbeek: Leiden University Medical Center
Jeffrey S. Kieft: University of Colorado Denver School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02604-y

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