title: Conserved RNA secondary structures and long-range interactions in hepatitis C viruses.
abstract: Hepatitis C virus (HCV) is a hepatotropic virus with a plus-strand RNA genome of ∼9.600 nt. Due to error-prone replication by its RNA-dependent RNA polymerase (RdRp) residing in nonstructural protein 5B (NS5B), HCV isolates are grouped into seven genotypes with several subtypes. By using whole-genome sequences of 106 HCV isolates and secondary structure alignments of the plus-strand genome and its minus-strand replication intermediate, we established refined secondary structures of the 5' untranslated region (UTR), the cis-acting replication element (CRE) in NS5B, and the 3' UTR. We propose an alternative structure in the 5' UTR, conserved secondary structures of 5B stem-loop (SL)1 and 5BSL2, and four possible structures of the X-tail at the very 3' end of the HCV genome. We predict several previously unknown long-range interactions, most importantly a possible circularization interaction between distinct elements in the 5' and 3' UTR, reminiscent of the cyclization elements of the related flaviviruses. Based on analogy to these viruses, we propose that the 5'-3' UTR base-pairing in the HCV genome might play an important role in viral RNA replication. These results may have important implications for our understanding of the nature of the cis-acting RNA elements in the HCV genome and their possible role in regulating the mutually exclusive processes of viral RNA translation and replication.
authors.affiliation: Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, 07743 Jena, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Fricke
authors.affiliation: Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, 35392 Giessen, Germany.
authors.forename: Nadia
authors.initials: N
authors.lastname: Dünnes
authors.affiliation: Department of Infectious Diseases, Molecular Virology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Margarita
authors.initials: M
authors.lastname: Zayas
authors.affiliation: Department of Infectious Diseases, Molecular Virology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, 35392 Giessen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Niepmann
authors.affiliation: Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, 07743 Jena, Germany FLI Leibniz Institute for Age Research, 07745 Jena, Germany manja@uni-jena.de.
authors.forename: Manja
authors.initials: M
authors.lastname: Marz
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D001483:Base Sequence; D016174:Hepacivirus / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry*; D014779:Virus Replication
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D012367:RNA, Viral
keywords: HCV; RNA long-range interaction prediction; RNA secondary structure prediction; bioinformatics; circularization