Mapping Structurally Defined Guanine Oxidation Products along DNA Duplexes: Influence of Local Sequence Context and Endogenous Cytosine Methylation

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• 作者：Xun Ming ; Brock Matter ; Matthew Song ; Elizabeth Veliath ; Ryan Shanley ; Roger Jones ; Natalia Tretyakova
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：March 19, 2014
• 年：2014
• 卷：136
• 期：11
• 页码：4223-4235
• 全文大小：802K
• 年卷期：v.136,no.11(March 19, 2014)
• ISSN：1520-5126

文摘

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鈥?deoxyguanosine (OG) in double stranded DNA. While both lesions are overproduced within endogenously methylated ^MeCG dinucleotides and at 5鈥?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 鈥渉otspots鈥?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.