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Proc Natl Acad Sci U S A. 2018 Jun 19;115(25):6404-6409. doi: 10.1073/pnas.1802429115. Epub 2018 Jun 4.

A folded viral noncoding RNA blocks host cell exoribonucleases through a conformationally dynamic RNA structure.

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Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado, Aurora, CO 80045.
Department of Entomology and Plant Pathology, North Carolina State University, Raleigh, NC 27606.
Molecular Biology Consortium, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado, Aurora, CO 80045;
RNA BioScience Initiative, School of Medicine, University of Colorado, Aurora, CO 80045.


Folded RNA elements that block processive 5' → 3' cellular exoribonucleases (xrRNAs) to produce biologically active viral noncoding RNAs have been discovered in flaviviruses, potentially revealing a new mode of RNA maturation. However, whether this RNA structure-dependent mechanism exists elsewhere and, if so, whether a singular RNA fold is required, have been unclear. Here we demonstrate the existence of authentic RNA structure-dependent xrRNAs in dianthoviruses, plant-infecting viruses unrelated to animal-infecting flaviviruses. These xrRNAs have no sequence similarity to known xrRNAs; thus, we used a combination of biochemistry and virology to characterize their sequence requirements and mechanism of stopping exoribonucleases. By solving the structure of a dianthovirus xrRNA by X-ray crystallography, we reveal a complex fold that is very different from that of the flavivirus xrRNAs. However, both versions of xrRNAs contain a unique topological feature, a pseudoknot that creates a protective ring around the 5' end of the RNA structure; this may be a defining structural feature of xrRNAs. Single-molecule FRET experiments reveal that the dianthovirus xrRNAs undergo conformational changes and can use "codegradational remodeling," exploiting the exoribonucleases' degradation-linked helicase activity to help form their resistant structure; such a mechanism has not previously been reported. Convergent evolution has created RNA structure-dependent exoribonuclease resistance in different contexts, which establishes it as a general RNA maturation mechanism and defines xrRNAs as an authentic functional class of RNAs.


RNA dynamics; RNA structure; exoribonuclease resistance; noncoding RNA maturation; single-molecule FRET

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