Mechanism and structural diversity of exoribonuclease-resistant RNA structures in flaviviral RNAs
Macfadden, Andrea ; O’Donoghue, Zoe ; Silva, Patricia A.G.C. ; Chapman, Erich G. ; Olsthoorn, René C. ; Sterken, Mark G. ; Pijlman, Gorben P. ; Bredenbeek, Peter J. ; Kieft, Jeffrey S. - \ 2018
Nature Communications 9 (2018)1. - ISSN 2041-1723
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.