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Endogenous Oxidize DNA Bases

Guanine (G) bases in potential G-quadruplex−forming sequences have the lowest redox potential and are susceptible to the formation of 8-oxoguanine (8-oxoG), a prevalent endogenous oxidized DNA base damage in the genome. 8-oxo-2'-deoxyguanosine or (8-oxo-dG) is an oxidized derivative of deoxyguanosine. and the major products of DNA oxidation. This is because guanine has a lower one-electron reduction potential than the other nucleotides bases in DNA. This means that the two of the most frequently oxidized bases in DNA, after ionizing radiation (causing oxidative stress) were the two oxidation products of guanine. One of the products being an enol form 8-OH-Gua, formed through a tautomeric shift from the original damage guanine, 8-oxo-Gua. A chemically changed base such as 8-OHdG, represents DNA damage and can cause changes in the structure of the genetic material and prevent the replication mechanism from functioning and performing properly. These endogenous oxidized DNA base damage plays an unique role in the spatiotemporal formation of G4 structures in the genome to regulate transcription and other biological processes. AP sites, a location in DNA that has neither a purine or a pyrimidine base due to DNA damage are the most prevalent type of endogenous DNA damage in cells. AP sites are generated spontaneously or even after cleavage of modified bases, including oxidation of guanine. With genome-wide ChIP-Seq analyses, cell-based assays, and in vitro biochemical analyses, a mechanistic framework has been provided linking oxidized DNA base-derived AP sites,  to G-quadruplex formation/stability, and the control of gene expression. Given guanine’s low oxidation potential, G bases of G4 sequences are more susceptible to oxidize and form 8-oxoG damage. However, excess DNA oxidation is linked to certain diseases and cancers that can affect the human genome.

DNA Oxidation effects on DNA

It is believed that increased levels of 8-oxo-dG in a tissue can serve as a biomarker to determine the level of oxidative stress produce. When produced, 8-oxo-dG in the promoter of a gene, may also inactivate OGG1, an enzyme that targets 8-oxo-dG and normally initiates repair of 8-oxo-dG damage. The inactivation allows for un-repaired DNA damages to accumulate in non-replicating cells, such as cells in the brains or muscles of adult mammals, and can cause aging. Moreover, the increased levels of 8-oxo-dG are frequently found associated with carcinogenesis and disease. This type of oxidative DNA damage, such as 8-oxo-dG, likely contributes to carcinogenesis. by two mechanisms. The first- modulation of gene expression, and the second-induction of mutations. Since AP sites are the most prevalent type of endogenous DNA damage in cells, a map of these AP sites (AP-seq) in the genome using a biotin-labeled aldehyde reactive probe that reacts explicitly with an AP site in DNA, can signal oxidative stress and the formation of 8-oxoG and AP sites.References