Nuclear Oxidation of a Major Peroxidation DNA Adduct, M1dG, in the Genome

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• 作者：Orrette R. Wauchope ; William N. Beavers ; James J. Galligan ; Michelle M. Mitchener ; Philip J. Kingsley ; Lawrence J. Marnett
• 刊名：Chemical Research in Toxicology
• 出版年：2015
• 出版时间：December 21, 2015
• 年：2015
• 卷：28
• 期：12
• 页码：2334-2342
• 全文大小：448K
• ISSN：1520-5010

文摘

Chronic inflammation results in increased production of reactive oxygen species (ROS), which can oxidize cellular molecules including lipids and DNA. Our laboratory has shown that 3-(2-deoxy-尾-d-erythro-pentofuranosyl)pyrimido[1,2-伪]purin-10(3H)-one (M₁dG) is the most abundant DNA adduct formed from the lipid peroxidation product, malondialdehyde, or the DNA peroxidation product, base propenal. M₁dG is mutagenic in bacterial and mammalian cells and is repaired via the nucleotide excision repair system. Here, we report that M₁dG levels in intact DNA were increased from basal levels of 1 adduct per 10⁸ nucleotides to 2 adducts per 10⁶ nucleotides following adenine propenal treatment of RKO, HEK293, or HepG2 cells. We also found that M₁dG in genomic DNA was oxidized in a time-dependent fashion to a single product, 6-oxo-M₁dG (to 鈭? adducts per 10⁷ nucleotides), and that this oxidation correlated with a decline in M₁dG levels. Investigations in RAW264.7 macrophages indicate the presence of high basal levels of M₁dG (1 adduct per 10⁶ nucleotides) and the endogenous formation of 6-oxo-M₁dG. This is the first report of the production of 6-oxo-M₁dG in genomic DNA in intact cells, and it has significant implications for understanding the role of inflammation in DNA damage, mutagenesis, and repair.