DNA oxidation
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DNA oxidation is the process of oxidative damage of
Excess DNA oxidation is linked to certain diseases and cancers,[3] while normal levels of oxidized nucleotides, due to normal levels of ROS, may be necessary for memory and learning.[4][5]
Oxidized bases in DNA
More than 20 oxidatively damaged DNA base lesions were identified in 2003 by Cooke et al.[6] and these overlap the 12 oxidized bases reported in 1992 by Dizdaroglu.[7] Two of the most frequently oxidized bases found by Dizdaroglu after ionizing radiation (causing oxidative stress) were the two oxidation products of guanine shown in the figure. One of these products was 8-OH-Gua (8-hydroxyguanine). (The article 8-oxo-2'-deoxyguanosine refers to the same damaged base since the keto form 8-oxo-Gua described there may undergo a tautomeric shift to the enol form 8-OH-Gua shown here.) The other product was FapyGua (2,6-diamino-4-hydroxy-5-formamidopyrimidine). Another frequent oxidation product was 5-OH-Hyd (5-hydroxyhydantoin) derived from cytosine.
Removal of oxidized bases
Most oxidized bases are removed from DNA by enzymes operating within the base excision repair pathway.[6] Removal of oxidized bases in DNA is fairly rapid. 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 removed with a half-life of 11 minutes.[8]
Steady-state levels of DNA damage
Steady-state levels of endogenous DNA damages represent the balance between formation and repair. Swenberg et al.[9] measured average amounts of steady state endogenous DNA damages in mammalian cells. The seven most common damages they found are shown in Table 1. Only one directly oxidized base, 8-hydroxyguanine, at about 2,400 8-OH-G per cell, was among the most frequent DNA damages present in the steady-state.
Endogenous lesions | Number per cell |
---|---|
Abasic sites | 30,000 |
N7-(2-hydroxethyl)guanine (7HEG) | 3,000 |
8-hydroxyguanine | 2,400 |
7-(2-oxoethyl)guanine | 1,500 |
Formaldehyde adducts | 960 |
Acrolein-deoxyguanine | 120 |
Malondialdehyde-deoxyguanine | 60 |
Increased 8-oxo-dG in carcinogenesis and disease
As reviewed by Valavanidis et al.[11] increased levels of 8-oxo-dG in a tissue can serve as a biomarker of oxidative stress. They also noted that increased levels of 8-oxo-dG are frequently found associated with carcinogenesis and disease.
In the figure shown in this section, the colonic epithelium from a mouse on a normal diet has a low level of 8-oxo-dG in its colonic crypts (panel A). However, a mouse likely undergoing colonic tumorigenesis (due to deoxycholate added to its diet[10]) has a high level of 8-oxo-dG in its colonic epithelium (panel B). Deoxycholate increases intracellular production of reactive oxygen resulting in increased oxidative stress,[12][13] and this may contribute to tumorigenesis and carcinogenesis. Of 22 mice fed the diet supplemented with deoxycholate, 20 (91%) developed colonic tumors after 10 months on the diet, and the tumors in 10 of these mice (45% of mice) included an adenocarcinoma (cancer).[10] Cooke et al.[6] point out that a number of diseases, such as Alzheimer's disease and systemic lupus erythematosus, have elevated 8-oxo-dG but no increased carcinogenesis.
Indirect role of oxidative damage in carcinogenesis
Valavanidis et al.[11] pointed out that oxidative DNA damage, such as 8-oxo-dG, may contribute to carcinogenesis by two mechanisms. The first mechanism involves modulation of gene expression, whereas the second is through the induction of mutations.
Epigenetic alterations
Epigenetic alteration, for instance by methylation of CpG islands in a promoter region of a gene, can repress expression of the gene (see DNA methylation in cancer). In general, epigenetic alteration can modulate gene expression. As reviewed by Bernstein and Bernstein,[14] the repair of various types of DNA damages can, with low frequency, leave remnants of the different repair processes and thereby cause epigenetic alterations. 8-oxo-dG is primarily repaired by base excision repair (BER).[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. These biopsies were taken from patients with chronic hepatitis C, a condition causing oxidative damages in the liver. Among 5 factors evaluated, only increased levels of 8-oxo-dG was highly correlated with promoter methylation of TSGs (p<0.0001). This promoter methylation could have reduced expression of these tumor suppressor genes and contributed to carcinogenesis.
Mutagenesis
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. They inserted 8-oxo-dG into about 800 cells, and could detect the products that occurred after the insertion of this altered base, as determined from the clones produced after growth of the cells. 8-oxo-dG was restored to G in 86% of the clones, probably reflecting accurate base excision repair or translesion synthesis without mutation. G:C to T:A transversions occurred in 5.9% of the clones, single base deletions in 2.1% and G:C to C:G transversions in 1.2%. Together, these more common mutations totaled 9.2% of the 14% of mutations generated at the site of the 8-oxo-dG insertion. Among the other mutations in the 800 clones analyzed, there were also 3 larger deletions, of sizes 6, 33 and 135 base pairs. Thus 8-oxo-dG, if not repaired, can directly cause frequent mutations, some of which may contribute to carcinogenesis.
Role of DNA oxidation in gene regulation
As reviewed by Wang et al.,[19] oxidized guanine appears to have multiple regulatory roles in gene expression. As noted by Wang et al.,[19] genes prone to be actively transcribed are densely distributed in high GC-content regions of the genome. They then described three modes of gene regulation by DNA oxidation at guanine. In one mode, it appears that oxidative stress may produce 8-oxo-dG in a promoter of a gene. The oxidative stress may also inactivate OGG1. The inactive OGG1, which no longer excises 8-oxo-dG, nevertheless targets and complexes with 8-oxo-dG, and causes a sharp (~70o) bend in the DNA. This allows the assembly of a transcriptional initiation complex, up-regulating transcription of the associated gene. The experimental basis establishing this mode was also reviewed by Seifermann and Epe[20]
A second mode of gene regulation by DNA oxidation at a guanine,[19][21] occurs when an 8-oxo-dG is formed in a guanine rich, potential G-quadruplex-forming sequence (PQS) in the coding strand of a promoter, after which active OGG1 excises the 8-oxo-dG and generates an apurinic/apyrimidinic site (AP site). The AP site enables melting of the duplex to unmask the PQS, adopting a G-quadruplex fold (G4 structure/motif) that has a regulatory role in transcription activation.
A third mode of gene regulation by DNA oxidation at a guanine,[19] occurs when 8-oxo-dG is complexed with OGG1 and then recruits chromatin remodelers to modulate gene expression. Chromodomain helicase DNA-binding protein 4 (CHD4), a component of the (NuRD) complex, is recruited by OGG1 to oxidative DNA damage sites. CHD4 then attracts DNA and histone methylating enzymes that repress transcription of associated genes.
Seifermann and Epe[20] noted that the highly selective induction of 8-oxo-dG in the promoter sequences observed in transcription induction may be difficult to explain as a consequence of general oxidative stress. However, there appears to be a mechanism for site-directed generation of oxidized bases in promoter regions. Perillo et al.,[22][23] showed that the lysine-specific histone demethylase LSD1 generates a local burst of reactive oxygen species (ROS) that induces oxidation of nearby nucleotides when carrying out its function. As a specific example, after treatment of cells with an estrogen, LSD1 produced H2O2 as a by-product of its enzymatic activity. The oxidation of DNA by LSD1 in the course of the demethylation of histone H3 at lysine 9 was shown to be required for the recruitment of OGG1 and also topoisomerase IIβ to the promoter region of bcl-2, an estrogen-responsive gene, and subsequent transcription initiation.
8-oxo-dG does not occur randomly in the genome. In mouse embryonic fibroblasts, a 2 to 5-fold enrichment of 8-oxo-dG was found in genetic control regions, including promoters, 5'-untranslated regions and 3'-untranslated regions compared to 8-oxo-dG levels found in gene bodies and in intergenic regions.[24] In rat pulmonary artery endothelial cells, when 22,414 protein-coding genes were examined for locations of 8-oxo-dG, the majority of 8-oxo-dGs (when present) were found in promoter regions rather than within gene bodies.[25] Among hundreds of genes whose expression levels were affected by hypoxia, those with newly acquired promoter 8-oxo-dGs were upregulated, and those genes whose promoters lost 8-oxo-dGs were almost all downregulated.[25]
Positive role of 8-oxo-dG in memory
Oxidation of guanine, particularly within CpG sites, may be especially important in learning and memory. Methylation of cytosines occurs at 60–90% of CpG sites depending on the tissue type.[26] In the mammalian brain, ~62% of CpGs are methylated.[26] Methylation of CpG sites tends to stably silence genes.[27] More than 500 of these CpG sites are de-methylated in neuron DNA during memory formation and memory consolidation in the hippocampus[28][29] and cingulate cortex[29] regions of the brain. As indicated below, the first step in de-methylation of methylated cytosine at a CpG site is oxidation of the guanine to form 8-oxo-dG.
Role of oxidized guanine in DNA de-methylation
The first figure in this section shows a CpG site where the cytosine is methylated to form
Altered protein expression in neurons, due to changes in methylation of DNA, (likely controlled by 8-oxo-dG-dependent de-methylation of CpG sites in gene promoters within neuron DNA) has been established as central to memory formation.[32]
Neurological conditions
Bipolar disorder
Evidence that oxidative stress induced DNA damage plays a role in bipolar disorder has been reviewed by Raza et al.[33] Bipolar patients have elevated levels of oxidatively induced DNA base damages even during periods of stable mental state.[34] The level of the base excision repair enzyme OGG1 that removes certain oxidized bases from DNA is also reduced compared to healthy individuals.[34]
Depressive disorder
Major depressive disorder is associated with an increase in oxidative DNA damage.[33] Increases in oxidative modifications of purines and pyrimidines in depressive patients may be due to impaired repair of oxidative DNA damages.[35]
Schizophrenia
Postmortem studies of elderly patients with chronic schizophrenia showed that oxidative DNA damage is increased in the hippocampus region of the brain.[36] The mean proportion of neurons with the oxidized DNA base 8-oxo-dG was 10-fold higher in patients with schizophrenia than in comparison individuals. Evidence indicating a role of oxidative DNA damage in schizophrenia has been reviewed by Raza et al.[33] and Markkanen et al.[37]
RNA Oxidation
Potential factors for RNA quality control
There have been furious debates on whether the issue of RNA quality control does exist. However, with the concern of various lengths of half lives of diverse RNA species ranging from several minutes to hours, degradation of defective RNA can not easily be attributed to its transient character anymore. Indeed, reaction with ROS takes only few minutes, which is even shorter than the average
References
- PMID 11848927.
- PMID 28057600.
- PMID 20840865.
- PMID 20649473.
- PMID 27625575.
- ^ S2CID 1132537.
- PMID 1383774.
- PMID 11353081.
- PMID 21163908.
- ^ PMID 25024814.
- ^ PMID 23985773.
- PMID 24951470.
- PMID 24884764.
- PMID 25987950.
- PMID 23901781.
- PMID 23311711.
- PMID 24281021.
- PMID 24559511.
- ^ PMID 30043138.
- ^ PMID 27871818.
- PMID 28629775.
- PMID 25482200.
- S2CID 52330096.
- PMID 28150947.
- ^ PMID 26432868.
- ^ PMID 28505093.
- PMID 11782440.
- PMID 28620075.
- ^ PMID 26656643.
- ^ PMID 27251462.
- PMID 29875631.
- PMID 20975755.
- ^ PMID 27126805.
- ^ PMID 29626765.
- PMID 25656523.
- PMID 15010346.
- PMID 27258260.
- Free radicalsand oxygen toxicity.Pharm Res. 5:253-60.
- ^ Wardman, P. and Candeias, L.P. (1996). Fenton chemistry: an introduction. Radiat. Res. 145, 523–531.
- S2CID 1132537.
- ^ S2CID 30141613.
- S2CID 13613547.
- PMID 10811907.
- PMID 2261442.
- PMID 1944345.
- S2CID 4268788.
- PMID 9311918.
- PMID 11788733.
- PMID 1565629.
- PMID 10820020.
- PMID 16467516.