8-Oxo-2'-deoxyguanosine

Swenberg et al.[3] measured average frequencies of steady state endogenous DNA damages in mammalian cells.

For example, 8-oxo-dG was increased 10-fold in the livers of mice subjected to ionizing radiation, but the excess 8-oxo-dG was rapidly removed with a half-life of 11 minutes.

[4] As reviewed by Valavanidis et al.[5] increased levels of 8-oxo-dG in a tissue can serve as a biomarker of oxidative stress.

Increased oxidant stress inactivates temporarily the enzyme OGG1 (Oxoguanine glycosylase) at sites with 8-oxo-dG, which recruits transcription factor NFkB to the promoter DNA sequences of inflammatory genes, and activates gene expression, inducing mechanisms of innate immunity that contribute to lung carcinogenesis.

In individuals with chronic hepatitis C virus infection, increased expression of 8-oxo-dG is a risk factor for the development of hepatocellular carcinoma.

[15] Li et al.[16] reviewed studies indicating that one or more BER proteins also participate(s) in epigenetic alterations involving DNA methylation, demethylation or reactions coupled to histone modification.

Nishida et al.[17] examined 8-oxo-dG levels and also evaluated promoter methylation of 11 tumor suppressor genes (TSGs) in 128 liver biopsy samples.

Yasui et al.[18] examined the fate of 8-oxo-dG when this oxidized derivative of deoxyguanosine was inserted into the thymidine kinase gene in a chromosome within human lymphoblastoid cells in culture.

8-Oxo-dG was restored to G in 86% of the clones, probably reflecting accurate base excision repair or translesion synthesis without mutation.

[29] As shown by Zhou et al.,[23] and illustrated below, oxidation of the guanine in the methylated CpG site, to form 5mCp-8-oxo-dG is the first step in demethylation.

As shown in 2016 by Halder et al.[30] using mice, and in 2017 by Duke et al.[27] using rats, when contextual fear conditioning is applied to the rodents, causing an especially strong long-term memory to form, within hours there are thousands of methylations and demethylations in the hippocampus brain region neurons.

There were 1,223 differentially methylated genes in the anterior cingulate cortex of mice four weeks after contextual fear conditioning.

Colonic epithelium from a mouse not undergoing colonic tumorigenesis (A), and a mouse that is undergoing colonic tumorigenesis (B). Cell nuclei are stained dark blue with hematoxylin (for nucleic acid) and immunostained brown for 8-oxo-dG. The level of 8-oxo-dG was graded in the nuclei of colonic crypt cells on a scale of 0-4. Mice not undergoing tumorigenesis had crypt 8-oxo-dG at levels 0 to 2 (panel A shows level 1) while mice progressing to colonic tumors had 8-oxo-dG in colonic crypts at levels 3 to 4 (panel B shows level 4) Tumorigenesis was induced by adding deoxycholate to the mouse diet to give a level of deoxycholate in the mouse colon similar to the level in the colon of humans on a high fat diet. [ 2 ] The images were made from original photomicrographs.
Initiation of DNA demethylation at a CpG site . In adult somatic cells DNA methylation typically occurs in the context of CpG dinucleotides ( CpG sites ), forming 5-methylcytosine -pG, or 5mCpG. Reactive oxygen species (ROS) may attack guanine at the dinucleotide site, forming 8-hydroxy-2'-deoxyguanosine (8-OHdG), and resulting in a 5mCp-8-OHdG dinucleotide site. The base excision repair enzyme OGG1 targets 8-OHdG and binds to the lesion without immediate excision. OGG1, present at a 5mCp-8-OHdG site recruits TET1 and TET1 oxidizes the 5mC adjacent to the 8-OHdG. This initiates demethylation of 5mC. [ 23 ]
Demethylation of 5-Methylcytosine (5mC) in neuron DNA. As reviewed in 2018, [ 31 ] in brain neurons, 5mC is oxidized by the ten-eleven translocation (TET) family of dioxygenases ( TET1 , TET2 , TET3 ) to generate 5-hydroxymethylcytosine (5hmC). In successive steps TET enzymes further hydroxylate 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine-DNA glycosylase (TDG) recognizes the intermediate bases 5fC and 5caC and excises the glycosidic bond resulting in an apyrimidinic site ( AP site ). In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex (AID/APOBEC) deaminases to form 5-hydroxymethyluracil (5hmU) or 5mC can be converted to thymine (Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 ( SMUG1 ), Nei-Like DNA Glycosylase 1 ( NEIL1 ), or methyl-CpG binding protein 4 ( MBD4 ). AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield cytosine (Cyt).