title: Copper generated reactive oxygen leads to formation of lysine-DNA adducts.
abstract: This work describes the addition of a lysine derivative to guanine base in a nucleoside, an oligonucleotide, and to a large DNA that occurs via oxidation by copper generated reactive oxygen species. Nucleophiles present during oxidation leads to the formation of adducts. In this work, 2'-deoxyguanosine is oxidized by copper generated reactive oxygen species in the presence of a lysine derivative, Nalpha-acetyl-lysine methyl ester. Under these conditions the guanidinohydantoin-lysine adduct is observed in a relative yield of 27% when compared to other guanine oxidation products. MS2 strongly supports that lysine is added to the 5-position during the formation of guanidinohydantoin-lysine. A fourteen-nucleotide DNA duplex was oxidized under similar conditions. Digestion showed formation of the same guanidinohydantoin-lysine nucleoside. The reaction was then examined on a 392-nucleotide DNA substrate. Oxidation in the presence of the lysine ester showed adduct formation as stops in a primer extension assay. Adducts predominately formed at a 5'-GGG at position 415. Six of the seven sites that showed reaction greater than 3-fold above background were guanine sites. We conclude from this study that copper can catalyze the formation of DNA-protein adducts and may form in cells with elevated copper and oxidative stress.
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, United States.
authors.forename: Morwena J
authors.initials: MJ
authors.lastname: Solivio
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Joy
authors.forename: Larry
authors.initials: L
authors.lastname: Sallans
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Merino
mesh_terms: D003300:Copper / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D003849:Deoxyguanosine / Q000737:chemistry; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000737:chemistry*
chemical_list: D018736:DNA Adducts; C093096:DNA-lysine adduct; D017382:Reactive Oxygen Species; D003300:Copper; D003849:Deoxyguanosine; D008239:Lysine