Mapping structurally defined guanine oxidation products along DNA duplexes: Influence of local sequence context and endogenous cytosine methylation

Xun Ming, Brock Matter, Matthew Song, Elizabeth Veliath, Ryan Shanley, Roger Jones, Natalia Tretyakova

Research output: Contribution to journalArticle

27 Scopus citations

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 MeCG 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 MeCG sequences may be caused by a lowered ionization potential of guanine bases paired with MeC and the preferential intercalation of riboflavin photosensitizer adjacent to MeC: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.

Original languageEnglish (US)
Pages (from-to)4223-4235
Number of pages13
JournalJournal of the American Chemical Society
Volume136
Issue number11
DOIs
StatePublished - Mar 19 2014

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