title: Replacing uridine with 2-thiouridine enhances the rate and fidelity of nonenzymatic RNA primer extension.
abstract: The nonenzymatic replication of RNA oligonucleotides is thought to have played a key role in the origin of life prior to the evolution of ribozyme-catalyzed RNA replication. Although the copying of oligo-C templates by 2-methylimidazole-activated G monomers can be quite efficient, the copying of mixed sequence templates, especially those containing A and U, is particularly slow and error-prone. The greater thermodynamic stability of the 2-thio-U(s(2)U):A base pair, relative to the canonical U:A base pair, suggests that replacing U with s(2)U might enhance the rate and fidelity of the nonenzymatic copying of RNA templates. Here we report that this single atom substitution in the activated monomer improves both the kinetics and the fidelity of nonenzymatic primer extension on mixed-sequence RNA templates. In addition, the mean lengths of primer extension products obtained with s(2)U is greater than those obtained with U, augmenting the potential for nonenzymatic replication of heritable function-rich sequences. We suggest that noncanonical nucleotides such as s(2)U may have played a role during the infancy of the RNA world by facilitating the nonenzymatic replication of genomic RNA oligonucleotides.
authors: Howard Hughes Medical Institute, Center for Computational and Integrative Biology, and Department of Molecular Biology, Simches Research Center, Massachusetts General Hospital , Boston, Massachusetts 02114, United States.
authors: Benjamin D
authors: BD
authors: Heuberger
authors: Ayan
authors: A
authors: Pal
authors: Francesca
authors: F
authors: Del Frate
authors: Ved V
authors: VV
authors: Topkar
authors: Jack W
authors: JW
authors: Szostak
mesh_terms: D007700:Kinetics; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D012313:RNA / Q000096:biosynthesis* / Q000737:chemistry*; D013891:Thiouridine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C105273:2-thiouridine; C034477:RNA primers; D013891:Thiouridine; D012313:RNA
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