8-Oxo-2'-deoxyguanosine

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8-Oxo-2'-deoxyguanosine
8-Oxo-2'-deoxyguanosine.svg
Names
IUPAC name
2-amino-9-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3,7-dihydropurine-6,8-dione
Other names
7,8-Dihydro-8-oxo-2'-deoxyguanosine; 7,8-Dihydro-8-oxodeoxyguanosine; 8-Hydroxy-2'-deoxyguanosine; 8-Hydroxydeoxyguanosine; 8-Oxo-2'-deoxyguanosine; 8-Oxo-7,8-dihydro-2'-deoxyguanosine; 8-Oxo-7,8-dihydrodeoxyguanosine; 8-Oxo-dG; 8-OH-dG
Identifiers
88847-89-6
3D model (Jmol) Interactive image
Interactive image
ChEBI CHEBI:40304
ChemSpider 66049 YesY
PubChem 73318
Properties
C10H13N5O5
Molar mass 283.24 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

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.[1] Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress.

8-oxo-dG in DNA[edit]

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.

Steady-state levels of DNA damages represent the balance between formation and repair. Swenberg et al.[3] measured average frequencies of steady state endogenous DNA damages in mammalian cells. The most frequent oxidative DNA damage normally present in DNA is 8-oxo-dG, occurring at an average frequency of 2,400 per cell.

When 8-oxo-dG is induced by a DNA damaging agent it is rapidly repaired. 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. They also noted that increased levels of 8-oxo-dG are frequently found during carcinogenesis.

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[2]) 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,[6][7] and this leads 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).[2]

8-oxo-dG in aging[edit]

8-oxo-dG increases with age in DNA of mammalian tissues.[8] 8-oxo-dG increases in both mitochonndrial DNA and nuclear DNA with age.[9] Fraga et al.[10] estimated that in rat kidney, for every 54 residues of 8-oxo-dG repaired, one residue remaines unrepaired. (See also DNA damage theory of aging.)

8-oxo-dG in carcinogenesis[edit]

Valavanidis et al.[5] pointed out that oxidative DNA damage, such as 8-oxo-dG, likely contributes to carcinogenesis by two mechanisms. The first mechanism involves modulation of gene expression, whereas the second is through the induction of mutations.

Epigenetic alterations[edit]

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 general, epigenetic alteration can modulate gene expression. As reviewed by Bernstein and Bernstein,[11] 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).[12] Li et al.[13] 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.[14] 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[edit]

Yasui et al.[15] 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.

See also[edit]

References[edit]

  1. ^ Nadja C. de Souza-Pinto; Lars Eide; Barbara A. Hogue; Tanja Thybo; Tinna Stevnsner; Erling Seeberg; Arne Klungland & Vilhelm A. Bohr (July 2001). "Repair of 8-Oxodeoxyguanosine Lesions in Mitochondrial DNA Depends on the Oxoguanine DNA Glycosylase (OGG1) Gene and 8-Oxoguanine Accumulates in the Mitochondrial DNA of OGG1-defective Mice". Cancer Research. 61 (14): 5378–5381. PMID 11454679. 
  2. ^ a b c Prasad AR, Prasad S, Nguyen H, Facista A, Lewis C, Zaitlin B, Bernstein H, Bernstein C (2014). "Novel diet-related mouse model of colon cancer parallels human colon cancer". World J Gastrointest Oncol. 6 (7): 225–43. doi:10.4251/wjgo.v6.i7.225. PMC 4092339Freely accessible. PMID 25024814. 
  3. ^ Swenberg JA, Lu K, Moeller BC, Gao L, Upton PB, Nakamura J, Starr TB. (2011) Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment. Toxicol Sci. 120(Suppl 1):S130-45. doi:10.1093/toxsci/kfq371 PMID 21163908
  4. ^ Hamilton ML, Guo Z, Fuller CD, Van Remmen H, Ward WF, Austad SN, Troyer DA, Thompson I, Richardson A (2001). "A reliable assessment of 8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA". Nucleic Acids Res. 29 (10): 2117–26. doi:10.1093/nar/29.10.2117. PMC 55450Freely accessible. PMID 11353081. 
  5. ^ a b Valavanidis A, Vlachogianni T, Fiotakis K, Loridas S (2013). "Pulmonary oxidative stress, inflammation and cancer: respirable particulate matter, fibrous dusts and ozone as major causes of lung carcinogenesis through reactive oxygen species mechanisms". Int J Environ Res Public Health. 10 (9): 3886–907. doi:10.3390/ijerph10093886. PMC 3799517Freely accessible. PMID 23985773. 
  6. ^ Tsuei J, Chau T, Mills D, Wan YJ. Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer. Exp Biol Med (Maywood). 2014 Nov;239(11):1489-504. doi: 10.1177/1535370214538743. PMID 24951470
  7. ^ Ajouz H, Mukherji D, Shamseddine A. Secondary bile acids: an underrecognized cause of colon cancer. World J Surg Oncol. 2014 May 24;12:164. doi: 10.1186/1477-7819-12-164. Review. PMID 24884764
  8. ^ Nie B, Gan W, Shi F, Hu GX, Chen LG, Hayakawa H, Sekiguchi M, Cai JP (2013). "Age-dependent accumulation of 8-oxoguanine in the DNA and RNA in various rat tissues". Oxid Med Cell Longev. 2013: 303181. doi:10.1155/2013/303181. PMC 3657452Freely accessible. PMID 23738036. 
  9. ^ Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A (2001). "Does oxidative damage to DNA increase with age?". Proc. Natl. Acad. Sci. U.S.A. 98 (18): 10469–74. doi:10.1073/pnas.171202698. PMC 56984Freely accessible. PMID 11517304. 
  10. ^ Fraga CG, Shigenaga MK, Park JW, Degan P, Ames BN (1990). "Oxidative damage to DNA during aging: 8-hydroxy-2'-deoxyguanosine in rat organ DNA and urine". Proc. Natl. Acad. Sci. U.S.A. 87 (12): 4533–7. doi:10.1073/pnas.87.12.4533. PMC 54150Freely accessible. PMID 2352934. 
  11. ^ Bernstein C, Bernstein H (2015). "Epigenetic reduction of DNA repair in progression to gastrointestinal cancer". World J Gastrointest Oncol. 7 (5): 30–46. doi:10.4251/wjgo.v7.i5.30. PMC 4434036Freely accessible. PMID 25987950. 
  12. ^ Scott TL, Rangaswamy S, Wicker CA, Izumi T (2014). "Repair of oxidative DNA damage and cancer: recent progress in DNA base excision repair". Antioxid. Redox Signal. 20 (4): 708–26. doi:10.1089/ars.2013.5529. PMC 3960848Freely accessible. PMID 23901781. 
  13. ^ Li J, Braganza A, Sobol RW (2013). "Base excision repair facilitates a functional relationship between Guanine oxidation and histone demethylation". Antioxid. Redox Signal. 18 (18): 2429–43. doi:10.1089/ars.2012.5107. PMC 3671628Freely accessible. PMID 23311711. 
  14. ^ Nishida N, Arizumi T, Takita M, Kitai S, Yada N, Hagiwara S, Inoue T, Minami Y, Ueshima K, Sakurai T, Kudo M (2013). "Reactive oxygen species induce epigenetic instability through the formation of 8-hydroxydeoxyguanosine in human hepatocarcinogenesis". Dig Dis. 31 (5-6): 459–66. doi:10.1159/000355245. PMID 24281021. 
  15. ^ Yasui M, Kanemaru Y, Kamoshita N, Suzuki T, Arakawa T, Honma M (2014). "Tracing the fates of site-specifically introduced DNA adducts in the human genome". DNA Repair (Amst.). 15: 11–20. doi:10.1016/j.dnarep.2014.01.003. PMID 24559511. 
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