In vitro Insight toward the Mutagenicity of Carbon- and Oxygen-Linked C8-Aryl-Deoxyguanosine Adducts

Date
2015-01-23
Authors
Verwey, Anne
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Volume Title
Publisher
University of Guelph
Abstract

Aryl radicals generated through metabolism of polyaromatic hydrocarbons and arylhydrazines can react directly at the C8-site of 2’-deoxyguanosine (dG) to form carbon (C)-linked C8-dG adducts. The ambident reactivity of phenolic radicals can yield either C- or oxygen (O)-linked C8-dG adducts. Studies on nitrogen (N)-linked C8-dG adducts show that conformation (syn versus anti) plays a critical role in mutagenic outcome, e.g. targeted (at the site) or semi-targeted (distal from the site of damage) mutations. N-Linked adducts can also block DNA replication by high-fidelity polymerases, and reduce bypass efficiency of specialized Y-family translesion polymerases. To determine the mutagenicity of C- and O-linked C8-dG adducts, modifications with increasing aryl size and shape were incorporated into the G3-site of the NarI sequence in a 22mer template. Primer extension assays were performed with two model polymerase enzymes. These biochemical results expand our understanding of the mutagenicity of C- and O-linked adducts.

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Keywords
DNA damage, DNA, DNA adducts, DNA replication, Mutagenicity, Deoxyguanosine, Klenow fragment, Translesion polymerase, C8-aryl-dG adducts
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