DNA oxidation is the process of oxidative damage of
deoxyribonucleic acid. As described in detail by Burrows et al.,
8-oxo-2'-deoxyguanosine
8-Oxo-2'-deoxyguanosine (8-oxo-dG) is an oxidized derivative of deoxyguanosine. 8-Oxo-dG is one of the major products of DNA oxidation. Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress.
In DNA
Steady-state leve ...
(8-oxo-dG) is the most common oxidative lesion observed in duplex DNA because
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
has a lower one-electron
reduction potential
Redox potential (also known as oxidation / reduction potential, ''ORP'', ''pe'', ''E_'', or E_) is a measure of the tendency of a chemical species to acquire electrons from or lose electrons to an electrode and thereby be reduced or oxidised respe ...
than the other
nucleoside
Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...
s in DNA. The one electron reduction potentials of the nucleosides (in volts versus
NHE
The standard hydrogen electrode (abbreviated SHE), is a redox electrode which forms the basis of the thermodynamic scale of oxidation-reduction potentials. Its absolute electrode potential is estimated to be at 25 °C, but to form a basis ...
) are
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
1.29,
adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivati ...
1.42,
cytosine
Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an am ...
1.6 and
thymine
Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nu ...
1.7. About 1 in 40,000 guanines in the genome are present as 8-oxo-dG under normal conditions. This means that >30,000 8-oxo-dGs may exist at any given time in the genome of a human cell. Another product of DNA oxidation is 8-oxo-dA. 8-oxo-dA occurs at about 1/10 the frequency of 8-oxo-dG. The reduction potential of guanine may be reduced by as much as 50%, depending on the particular neighboring nucleosides stacked next to it within DNA.
Excess DNA oxidation is linked to certain diseases and cancers,
while normal levels of oxidized nucleotides, due to normal levels of
ROS, may be necessary for memory and learning.
Oxidized bases in DNA
![Guanine and 2 oxidative products](https://upload.wikimedia.org/wikipedia/commons/c/ce/Guanine_and_2_oxidative_products.svg)
More than 20 oxidatively damaged DNA base lesions were identified in 2003 by Cooke et al.
and these overlap the 12 oxidized bases reported in 1992 by Dizdaroglu.
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
8-Oxo-2'-deoxyguanosine (8-oxo-dG) is an oxidized derivative of deoxyguanosine. 8-Oxo-dG is one of the major products of DNA oxidation. Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress.
In DNA
Steady-state leve ...
refers to the same damaged base since the keto form 8-oxo-Gua described there may undergo a
tautomer
Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert.
The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hydr ...
ic 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.
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.
Steady-state levels of DNA damages
Steady-state levels of
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
DNA damages represent the balance between formation and repair. Swenberg et al. 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.
Increased 8-oxo-dG in carcinogenesis and disease
![Colonic epithelium mouse without tumorigenesis (A) and with tumorigenesis (B)](https://upload.wikimedia.org/wikipedia/commons/d/df/Colonic_epithelium_mouse_without_tumorigenesis_%28A%29_and_with_tumorigenesis_%28B%29._Brown_shows_8-oxo-dG.jpg)
As reviewed by Valavanidis et al.
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
Deoxycholic acid is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and chenodeoxycholic acid. Bacteria me ...
added to its diet
) 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, and this may contribute to tumorigenesis and carcinogenesis. Of 22 mice fed the diet supplemented with
deoxycholate
Deoxycholic acid is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and chenodeoxycholic acid. Bacteria me ...
, 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).
Cooke et al.
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.
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 DNA methylation in cancer plays a variety of roles, helping to change the healthy cells by regulation of gene expression to a cancer cells or a diseased cells disease pattern. One of the most widely studied DNA methylation dysregulation is the pro ...
). In general, epigenetic alteration can modulate gene expression. As reviewed by Bernstein and Bernstein,
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
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
(BER).
Li et al.
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.
examined 8-oxo-dG levels and also evaluated promoter methylation of 11
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
s (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 gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
s and contributed to
carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
.
Mutagenesis
Yasui et al.
examined the fate of 8-oxo-dG when this oxidized derivative of
deoxyguanosine
Deoxyguanosine is composed of the purine nucleobase guanine linked by its N9 nitrogen to the C1 carbon of deoxyribose. It is similar to guanosine, but with one hydroxyl group removed from the 2' position of the ribose sugar (making it deoxyribose ...
was inserted into the
thymidine kinase
Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Cert ...
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
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
or
translesion synthesis
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dama ...
without mutation. G:C to T:A
transversion
Transversion, in molecular biology, refers to a point mutation in DNA in which a single (two ring) purine ( A or G) is changed for a (one ring) pyrimidine ( T or C), or vice versa. A transversion can be spontaneous, or it can be caused by i ...
s 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
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
.
Role of DNA oxidation in gene regulation
As reviewed by Wang et al.,
oxidized guanine appears to have multiple regulatory roles in gene expression. As noted by Wang et al.,
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 (~70
o) 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
A second mode of gene regulation by DNA oxidation at a guanine,
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
In molecular biology, G-quadruplex Nucleic acid secondary structure, secondary structures (G4) are formed in nucleic acids by sequences that are rich in guanine. They are helical in shape and contain guanine tetrads that can form from one, two o ...
fold (G4 structure/motif) that has a regulatory role in transcription activation.
A third mode of gene regulation by DNA oxidation at a guanine,
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
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.,
showed that the lysine-specific histone demethylase
LSD1
Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein in humans that is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-me ...
generates a local burst of
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(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 H
2O
2 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
DNA topoisomerase 2-beta is an enzyme that in humans is encoded by the ''TOP2B'' gene.
Function
This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is i ...
to the promoter region of
bcl-2
Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. ...
, an estrogen-responsive gene, and subsequent transcription initiation.
8-oxo-dG does not occur randomly in the genome. In
mouse embryonic fibroblast
Mouse Embryonic Fibroblasts (MEFs) are a type of fibroblast prepared from mouse embryo. MEFs show a spindle shape when cultured ''in vitro'', a typical feature of fibroblasts.
The MEF is a limited cell line. After several transmission, MEFs will s ...
s, 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
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
bodies and in
intergenic region
An intergenic region is a stretch of DNA sequences located between genes. Intergenic regions may contain functional elements and junk DNA. ''Inter''genic regions should not be confused with ''intra''genic regions (or introns), which are non-cod ...
s.
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.
Among hundreds of genes whose expression levels were affected by hypoxia, those with newly acquired promoter 8-oxo-dGs were
upregulated
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pro ...
, and those genes whose promoters lost 8-oxo-dGs were almost all
downregulated
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...
.
Positive role of 8-oxo-dG in memory
Oxidation of guanine, particularly within
CpG site
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
s, may be especially important in learning and memory. Methylation of cytosines occurs at 60–90% of CpG sites depending on the tissue type.
In the mammalian brain, ~62% of CpGs are methylated.
Methylation of CpG sites tends to stably silence genes.
More than 500 of these CpG sites are de-methylated in neuron DNA during
memory formation
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...
and
memory consolidation
Memory consolidation is a category of processes that stabilize a memory trace after its initial acquisition. A memory trace is a change in the nervous system caused by memorizing something. Consolidation is distinguished into two specific processe ...
in the
hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
and
cingulate cortex
The cingulate cortex is a part of the brain situated in the medial aspect of the cerebral cortex. The cingulate cortex includes the entire cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the ci ...
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
![Initiation of DNA demethylation at a CpG site](https://upload.wikimedia.org/wikipedia/commons/0/07/Initiation_of_DNA_demethylation_at_a_CpG_site.svg)
The first figure in this section shows a CpG site where the cytosine is methylated to form
5-methylcytosine (5mC) and the guanine is oxidized to form
8-oxo-2'-deoxyguanosine
8-Oxo-2'-deoxyguanosine (8-oxo-dG) is an oxidized derivative of deoxyguanosine. 8-Oxo-dG is one of the major products of DNA oxidation. Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress.
In DNA
Steady-state leve ...
(in the figure this is shown in the tautomeric form 8-OHdG). When this structure is formed, the
base excision repair
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
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 de-methylation of 5mC.
TET1 is a key enzyme involved in de-methylating 5mCpG. However, TET1 is only able to act on 5mCpG if the guanine was first oxidized to form
8-hydroxy-2'-deoxyguanosine
8-Oxo-2'-deoxyguanosine (8-oxo-dG) is an oxidized derivative of deoxyguanosine. 8-Oxo-dG is one of the major products of DNA oxidation. Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress.
In DNA
Steady-state levels ...
(8-OHdG or its tautomer 8-oxo-dG), resulting in a 5mCp-8-OHdG dinucleotide (see first figure in this section).
This initiates the de-methylation pathway on the methylated cytosine, finally resulting in an unmethylated cytosine, shown in the second figure in this section.
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.
Neurological conditions
Bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
Evidence that
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
induced
DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
plays a role in
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
has been reviewed by Raza et al.
Bipolar patients have elevated levels of oxidatively induced DNA base damages even during periods of stable mental state.
The level of the
base excision repair
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
enzyme
OGG1 that removes certain oxidized bases from DNA is also reduced compared to healthy individuals.
Depressive disorder
Major depressive disorder
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
is associated with an increase in oxidative DNA damage.
Increases in oxidative modifications of
purine
Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...
s and
pyrimidine
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...
s in depressive patients may be due to impaired repair of oxidative DNA damages.
Schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
Postmortem studies of elderly patients with chronic
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
showed that oxidative DNA damage is increased in the
hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
region of the brain.
The mean proportion of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s 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.
and Markkanen et al.
RNA Oxidation
RNAs
The Royal Naval Air Service (RNAS) was the air arm of the Royal Navy, under the direction of the Admiralty's Air Department, and existed formally from 1 July 1914 to 1 April 1918, when it was merged with the British Army's Royal Flying Corps t ...
in native milieu are exposed to various insults. Among these threats,
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
is one of the major causes of damage to RNAs. The level of oxidative stress that a cell endures is reflected by the quantity of reactive oxygen species (ROS). ROS are generated from normal oxygen metabolism in cells and are recognized as a list of active molecules, such as
O2•−,
1O2,
H2O2 and,
•OH . A
nucleic acid
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
can be oxidized by ROS through a
Fenton reaction. To date, around 20 oxidative lesions have been discovered in DNA. RNAs are likely to be more sensitive to ROS for the following reasons: i) the basically single-stranded structure exposes more sites to ROS; ii) compared with nuclear DNA, RNAs are less compartmentalized; iii) RNAs distribute broadly in cells not only in the nucleus as DNAs do, but also in large portions in the cytoplasm.
This theory has been supported by a series of discoveries from rat livers, human
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
, etc. Actually, monitoring a system by applying the isotopical label
18O">sup>18OH
2O
2 shows greater oxidation in cellular RNA than in DNA.
Oxidation randomly damages RNAs, and each attack bring problems to the normal cellular metabolism. Although alteration of genetic information on mRNA is relatively rare, oxidation on mRNAs
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
and
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
results in low
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
efficiency and aberrant protein products.
Though the oxidation strikes the nucleic strands randomly, particular residues are more susceptible to ROS, such hotspot sites being hit by ROS at a high rate. Among all the lesions discovered thus far, one of the most abundant in DNA and RNA is the 8-hydroxyguanine. Moreover, 8-hydroxyguanine is the only one measurable among all the RNA lesions. Besides its abundance,
8-hydroxydeoxyguanosine (8-oxodG) and
8-hydroxyguanosine (8-oxoG) are identified as the most detrimental oxidation lesions for their mutagenic effect, in which this non-canonical counterpart can faultily pair with both adenine and cytosine at the same efficiency. This mis-pairing brings about the alteration of genetic information through the synthesis of DNA and RNA. In RNA, oxidation levels are mainly estimated through 8-oxoG-based assays. So far, approaches developed to directly measure 8-oxoG level include HPLC-based analysis and assays employing monoclonal anti-8-oxoG antibody. The HPLC-based method measures 8-oxoG with an electrochemical detector (ECD) and total G with a
UV detector. The ratio that results from comparing the two numbers provides the extent that the total G is oxidized. Monoclonal anti-8-oxoG mouse antibody is broadly applied to directly detect this residue on either tissue sections or membrane, offering a more visual way to study its distribution in tissues and in discrete subsets of DNA or RNA. The established indirect techniques are mainly grounded on this lesion’s mutagenic aftermath, such as the lacZ assay. This method was first set up and described by Taddei and was a potentially powerful tool to understand the oxidation situation at both the RNA sequence level and single nucleotide level.
Another source of oxidized RNAs is mis-incorporation of oxidized counterpart of single nucleotides. Indeed, the RNA precursor pool size is hundreds of sizes bigger than DNA’s.
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
life-span
Life expectancy is a statistical measure of the average time an organism is expected to live, based on the year of its birth, current age, and other demographic factors like sex. The most commonly used measure is life expectancy at birth ...
of the most unstable RNAs.
Adding the fact that stable RNA take the lion’s share of total RNA, RNA error deleting becomes hypercritical and should not be neglected anymore. This theory is upheld by the fact that level of oxidized RNA decreases after removal of the oxidative challenge.
Some potential factors include
ribonucleases
Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within t ...
, which are suspected to selectively degrade damaged RNAs under stresses. Also
enzymes
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
working at RNA precursor pool level, are known to control quality of RNA sequence by changing error precursor to the form that can't be included directly into nascent strand.
References
{{DEFAULTSORT:Dna Oxidation
Organic redox reactions