Genome-wide Profiling of 8-Oxoguanine Reveals Its Association with Spatial Positioning in Nucleus

Abstract

8-Oxoguanine (8-oxoG) is one of the most common DNA lesions generated by reactive oxygen species. In this study, we analysed the genome-wide distribution profile of 8-oxoG by combining immunoprecipitation by antibodies specific for the DNA fragments containing 8-oxoG with a microarray that covers rat genome. Genome-wide mapping of 8-oxoG in normal rat kidney revealed that 8-oxoG is preferentially located at gene deserts. We did not observe differences in 8-oxoG levels between groups of genes with high and low expression, possibly because of the generally low 8-oxoG levels in genic regions compared with gene deserts. The distribution of 8-oxoG and lamina-associated domains (LADs) were strongly correlated, suggesting that the spatial location of genomic DNA in the nucleus determines the susceptibility to oxidative modifications. One possible explanation for high 8-oxoG levels in LADs is that the nuclear periphery is more susceptible to the oxidative damage caused by the extra-nuclear factors. Moreover, LADs have a rather compact conformation, which may limit the recruitment of repair components to the modified bases.

8-Oxo-7,8-dihydroguanine, friend and foe: Epigenetic-like regulator versus initiator of mutagenesis

“…Thus, a major hurdle along the way to elucidating the role of OG in gene regulation will be the development and implementation of genome-level OG sequencing. Many laboratories have developed antibody-based OG sequencing that provides a low resolution sequence map of OG (~10–1000 kbp) [53, 54]. Recently, our laboratory developed an OG sequencing approach with single-nucleotide resolution implemented on plasmid DNA [55], in addition to an OG sequencing method with ~0.15-kbp resolution (i.e., OG-Seq) that was implemented on the mouse genome [56].…”

Malignant mesothelioma as an oxidative stress-induced cancer: An update

“…Moreover, it is still unknown why the p16 INK4a /p14 ARF locus is particularly sensitive to the effect of iron overload and oxidative stress. Elucidation of the mechanisms involved presumably via an oxygenomics approach [88][89][90] would certainly advance our understanding of oxidative stressassociated genotoxicity.…”

Sequencing the Mouse Genome for the Oxidatively Modified Base 8-Oxo-7,8-dihydroguanine by OG-Seq

“…If the genomic DNA is fragmented followed by OG antibody enrichment, microarray analysis allows OG sequencing at ∼10-kb resolution. 12 When in situ immunodetection of OG was used to construct a chromosome map of OG, the resulting map was obtained at ∼1000-kb resolution. 13 The OG antibody allowed ChIP-Seq analysis of OG in the rat genome at ∼0.1-kb resolution.…”

“…3-5 Lastly, one hypothesis for this non-random chromosome-level distribution of OG-enriched peaks may reside in the non-random spatial distribution of interphase chromosomes in the nucleus. 12 Interphase chromosomes bias regions for interacting with the nuclear envelope causing these regions to be preferentially exposed to more oxidants diffusing into the nucleus, while other regions are protected from oxidation because they are toward the interior of the nucleus. 12 The non-random spatial distribution of chromosomes in the nucleus would bias the observed regions of G oxidation.…”