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

ABSTRACT: 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-?-d-erythro-pentofuranosyl)pyrimido[1,2-?]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 10(8) nucleotides to 2 adducts per 10(6) 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 ? 5 adducts per 10(7) 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 10(6) 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.

SUBMITTER: Wauchope OR

PROVIDER: S-EPMC4993022 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Wauchope Orrette R OR Beavers William N WN Galligan James J JJ Mitchener Michelle M MM Kingsley Philip J PJ Marnett Lawrence J LJ

Chemical research in toxicology 20151111 12

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-β-d-erythro-pentofuranosyl)pyrimido[1,2-α]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 ...[more]

PMID: 26469224

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Project description:The dimensions and arrangements of aromatic rings (topology) in adducts derived from the reactions of polycyclic aromatic hydrocarbon (PAH) diol epoxide metabolites with DNA influence the distortions and stabilities of double-stranded DNA, and hence their recognition and processing by the human nucleotide excision repair (NER) system. Dibenzo[a,l]pyrene (DB[a,l]P) is a highly tumorigenic six-ring PAH, which contains a nonplanar and aromatic fjord region that is absent in the structurally related bay region five-ring PAH benzo[a]pyrene (B[a]P). The PAH diol epoxide-DNA adducts formed include the stereoisomeric 14S and 14R trans-anti-DB[a,l]P-N(2)-dG and the stereochemically analogous 10S- and 10R-B[a]P-N(2)-dG (B[a]P-dG) guanine adducts. However, nuclear magnetic resonance (NMR) solution studies of the 14S-DB[a,l]P-N(2)-dG adduct in DNA have not yet been presented. Here we have investigated the 14S-DB[a,l]P-N(2)-dG adduct in two different sequence contexts using NMR methods with distance-restrained molecular dynamics simulations. In duplexes with dC opposite the adduct deleted, a well-resolved base-displaced intercalative adduct conformation can be observed. In full duplexes, in contrast to the intercalated 14R stereoisomeric adduct, the bulky DB[a,l]P residue in the 14S adduct is positioned in a greatly widened and distorted minor groove, with significant disruptions and distortions of base pairing at the lesion site and two 5'-side adjacent base pairs. These unique structural features are significantly different from those of the stereochemically analogous but smaller B[a]P-dG adduct. The greater size and different topology of the DB[a,l]P aromatic ring system lead to greater structurally destabilizing DNA distortions that are partially compensated by stabilizing DB[a,l]P-DNA van der Waals interactions, whose combined effects impact the NER response to the adduct. These structural results broaden our understanding of the structure-function relationship in NER.

Dataset Information

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

Publications

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

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