Mapping three guanine oxidation products along DNA following exposure to three types of reactive oxygen species

Brock Matter, Christopher L. Seiler, Kristopher Murphy, Xun Ming, Jianwei Zhao, Bruce Lindgren, Roger Jones, Natalia Tretyakova

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Reactive oxygen and nitrogen species generated during respiration, inflammation, and immune response can damage cellular DNA, contributing to aging, cancer, and neurodegeneration. The ability of oxidized DNA bases to interfere with DNA replication and transcription is strongly influenced by their chemical structures and locations within the genome. In the present work, we examined the influence of local DNA sequence context, DNA secondary structure, and oxidant identity on the efficiency and the chemistry of guanine oxidation in the context of the Kras protooncogene. A novel isotope labeling strategy developed in our laboratory was used to accurately map the formation of 2,2-diamino-4-[(2-deoxy-β-D-erythropentofuranosyl)amino]− 5(2 H)-oxazolone (Z), 8-oxo-7,8-dihydro-2’-deoxyguanosine (OG), and 8-nitroguanine (8-NO 2 -G) lesions along DNA duplexes following photooxidation in the presence of riboflavin, treatment with nitrosoperoxycarbonate, and oxidation in the presence of hydroxyl radicals. Riboflavin-mediated photooxidation preferentially induced OG lesions at 5’ guanines within GG repeats, while treatment with nitrosoperoxycarbonate targeted 3’-guanines within GG and AG dinucleotides. Little sequence selectivity was observed following hydroxyl radical-mediated oxidation. However, Z and 8-NO 2 -G adducts were overproduced at duplex ends, irrespective of oxidant identity. Overall, our results indicate that the patterns of Z, OG, and 8-NO 2 -G adduct formation in the genome are distinct and are influenced by oxidant identity and the secondary structure of DNA.

Original languageEnglish (US)
Pages (from-to)180-189
Number of pages10
JournalFree Radical Biology and Medicine
Volume121
DOIs
StatePublished - Jun 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Keywords

  • 8-oxo-guanine
  • DNA damage
  • Isotope labeling of DNA-mass spectrometry
  • Kras protooncogene
  • Reactive oxygen species

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