title: Mapping structurally defined guanine oxidation products along DNA duplexes: influence of local sequence context and endogenous cytosine methylation.
abstract: DNA oxidation by reactive oxygen species is nonrandom, potentially leading to accumulation of nucleobase damage and mutations at specific sites within the genome. We now present the first quantitative data for sequence-dependent formation of structurally defined oxidative nucleobase adducts along p53 gene-derived DNA duplexes using a novel isotope labeling-based approach. Our results reveal that local nucleobase sequence context differentially alters the yields of 2,2,4-triamino-2H-oxal-5-one (Z) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (OG) in double stranded DNA. While both lesions are overproduced within endogenously methylated (Me)CG dinucleotides and at 5' Gs in runs of several guanines, the formation of Z (but not OG) is strongly preferred at solvent-exposed guanine nucleobases at duplex ends. Targeted oxidation of (Me)CG sequences may be caused by a lowered ionization potential of guanine bases paired with (Me)C and the preferential intercalation of riboflavin photosensitizer adjacent to (Me)C:G base pairs. Importantly, some of the most frequently oxidized positions coincide with the known p53 lung cancer mutational "hotspots" at codons 245 (GGC), 248 (CGG), and 158 (CGC) respectively, supporting a possible role of oxidative degradation of DNA in the initiation of lung cancer.
authors.affiliation: Department of Medicinal Chemistry and the Masonic Cancer Center and §Biostatistics and Bioinformatics Core at the Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Xun
authors.initials: X
authors.lastname: Ming
authors.forename: Brock
authors.initials: B
authors.lastname: Matter
authors.forename: Matthew
authors.initials: M
authors.lastname: Song
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Veliath
authors.forename: Ryan
authors.initials: R
authors.lastname: Shanley
authors.forename: Roger
authors.initials: R
authors.lastname: Jones
authors.forename: Natalia
authors.initials: N
authors.lastname: Tretyakova
mesh_terms: D000595:Amino Acid Sequence; D003596:Cytosine / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006147:Guanine / Q000737:chemistry* / Q000378:metabolism; D008745:Methylation; D009690:Nucleic Acid Conformation; D010084:Oxidation-Reduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D006147:Guanine; D003596:Cytosine; D004247:DNA