BioProject

Oxidative DNA damage has been linked to cancer, aging, inflammation, and other pathological conditions. More...

Oxidative DNA damage has been linked to cancer, aging, inflammation, and other pathological conditions. Although the chemical nature of the damaged bases is well understood, the precise distribution of oxidatively damaged DNA bases in the human genome is not known. Here we have used the recently developed circle-damage-sequencing method to map two types of oxidative DNA damage, oxidized guanines produced by hydrogen peroxide and oxidized thymines created by treatment of cells with potassium permanganate, at single base resolution. We show that oxidized guanines, chiefly 8-oxo-G, occur strictly dependent on the G/C sequence context and show a pronounced peak at transcription start sites (TSS). We determined the trinucleotide sequence pattern of guanine oxidation. This pattern shows high similarity to the cancer-associated single base substitution signatures SBS18 and SBS36. SBS36 is found in colorectal cancers that carry mutations in MUTYH, encoding a DNA repair enzyme that operates on 8-oxo-G mispairs. SBS18 is common in inflammation-associated upper GI tract tumors including esophageal and gastric adenocarcinomas. Oxidized thymines induced by permanganate occur with a distinct dinucleotide specificity, 5’T-A/C, and are depleted at the TSS. Collectively, our data provides a comprehensive analysis of two types of oxidized DNA bases in the human genome and suggests that two cancer mutational signatures, SBS18 and SBS36, are caused by reactive oxygen species. Overall design: Oxidized DNA damages were mapped in genome-wide in HDF and U2OS cells treated with 10 mM of H2O2 and KMnO4, respectively. Less...