title: Nucleobase but not Sugar Fidelity is Maintained in the Sabin I RNA-Dependent RNA Polymerase.
abstract: The Sabin I poliovirus live, attenuated vaccine strain encodes for four amino acid changes (i.e., D53N, Y73H, K250E, and T362I) in the RNA-dependent RNA polymerase (RdRp). We have previously shown that the T362I substitution leads to a lower fidelity RdRp, and viruses encoding this variant are attenuated in a mouse model of poliovirus. Given these results, it was surprising that the nucleotide incorporation rate and nucleobase fidelity of the Sabin I RdRp is similar to that of wild-type enzyme, although the Sabin I RdRp is less selective against nucleotides with modified sugar groups. We suggest that the other Sabin amino acid changes (i.e., D53N, Y73H, K250E) help to re-establish nucleotide incorporation rates and nucleotide discrimination near wild-type levels, which may be a requirement for the propagation of the virus and its efficacy as a vaccine strain. These results also suggest that the nucleobase fidelity of the Sabin I RdRp likely does not contribute to viral attenuation.
authors.affiliation: Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA. xil5090@psu.edu.
authors.forename: Xinran
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA. derekmusser43@gmail.com.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Musser
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA. cherilee1125@gmail.com.
authors.forename: Cheri A
authors.initials: CA
authors.lastname: Lee
authors.affiliation: Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA. birxyang@scut.edu.cn.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA. jja5@psu.edu.
authors.forename: Jamie J
authors.initials: JJ
authors.lastname: Arnold
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA. cec9@psu.edu.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Cameron
authors.affiliation: Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA. ddb12@psu.edu.
authors.forename: David D
authors.initials: DD
authors.lastname: Boehr
mesh_terms: D009711:Nucleotides / Q000378:metabolism*; D017955:Poliovirus / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D011055:Poliovirus Vaccine, Oral / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity; D014779:Virus Replication
chemical_list: D009711:Nucleotides; D011055:Poliovirus Vaccine, Oral; D012324:RNA-Dependent RNA Polymerase
keywords: RNA-dependent RNA polymerase; Sabin; enterovirus; oral poliovirus vaccine; poliovirus; polymerase fidelity; vaccine-associated paralytic poliovirus; vaccine-derived poliovirus