Structural and biochemical impact of C8-aryl-guanine adducts within the Narl recognition DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicity

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dc.contributor.authorSproviero, Michael
dc.contributor.authorVerwey, Anne M. R.
dc.contributor.authorRankin, Katherine M.
dc.contributor.authorWitham, Aaron A.
dc.contributor.authorSoldatov, Dmitriy V.
dc.contributor.authorManderville, Richard A.
dc.contributor.authorFekry, Mostafa I.
dc.contributor.authorSturla, Shana J.
dc.contributor.authorSharma, Purshotam
dc.contributor.authorWetmore, Stacey D.
dc.date.accessioned2016-08-16T23:27:43Z
dc.date.available2016-08-16T23:27:43Z
dc.date.issued2014
dc.descriptionSherpa Romeo green journal, open accessen_US
dc.description.abstractChemical mutagens with an aromatic ring system may be enzymatically transformed to afford aryl radical species that preferentially react at the C8-site of 2 -deoxyguanosine (dG). The resulting carbonlinked C8-aryl-dG adduct possesses altered biophysical and genetic coding properties compared to the precursor nucleoside. Described herein are structural and in vitro mutagenicity studies of a series of fluorescent C8-aryl-dG analogues that differ in aryl ring size and are representative of authentic DNA adducts. These structural mimics have been inserted into a hotspot sequence for frameshift mutations, namely, the reiterated G3-position of the NarI sequence within 12mer (NarI(12)) and 22mer (NarI(22)) oligonucleotides. In the NarI(12) duplexes, the C8- aryl-dG adducts display a preference for adopting an anti-conformation opposite C, despite the strong syn preference of the free nucleoside. Using the NarI(22) sequence as a template for DNA synthesis in vitro, mutagenicity of the C8-aryl-dG adducts was assayed with representative high-fidelity replicative versus lesion bypass Y-family DNA polymerases, namely, Escherichia coli pol I Klenow fragment exo− (Kf−) and Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4). Our experiments provide a basis for a model involving a two-base slippage and subsequent realignment process to relate the miscoding properties of C-linked C8-aryl-dG adducts with their chemical structures.en_US
dc.description.peer-reviewYesen_US
dc.identifier.citationSproviero, M., Verwey, A. M. R., Rankin, K. M., Witham, A. A., Soldatov, D. V., Manderville, R. A. ... & Wetmore, S. D. (2014). Structural and biochemical impact of C8-aryl-guanine adducts within the NarI recognition of DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicity. Nucleic Acids Research, 42(21), 13405-13421. doi:10.1093/nar/gku1093en_US
dc.identifier.urihttps://hdl.handle.net/10133/4585
dc.language.isoen_CAen_US
dc.publisherOxford University Pressen_US
dc.publisher.departmentDepartment of Chemistry and Biochemistryen_US
dc.publisher.facultyArts and Scienceen_US
dc.publisher.institutionUniversity of Guelphen_US
dc.publisher.institutionInstitute of Food, Nutrition and Health (Switzerland)en_US
dc.publisher.institutionCairo Universityen_US
dc.publisher.institutionUniversity of Lethbridgeen_US
dc.subjectDNAen_US
dc.subjectC8-aryl-dG adductsen_US
dc.subjectNarIen_US
dc.subjectMutagenicityen_US
dc.titleStructural and biochemical impact of C8-aryl-guanine adducts within the Narl recognition DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicityen_US
dc.typeArticleen_US
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