Disease relevance of 8-Oxodeoxyguanosine triphosphate

• Expression of Fpg in bone marrow (BM) cells via a retrovirus vector was associated with demonstrable 8-oxodeoxyguanosine DNA glycosylase activity [1].
• Assessing the metabolic function of the MutT 8-oxodeoxyguanosine triphosphatase in Escherichia coli by nucleotide pool analysis [2].
• We have measured the efficiencies of utilization of 8-oxo-dGTP and 8-NH2-dGTP by human immunodeficiency virus type 1 and murine leukemia virus reverse transcriptases and compared them to those of DNA polymerases alpha and beta [3].
• We therefore tested this concept in human renal-cell carcinomas (RCCs) by evaluating the expression of hMTH1, an enzyme preventing the misincorporation into DNA of 8-oxo-dGTP (8-oxo-7,8-dihydrodeoxyguanosine triphosphate), an oxidized form of dGTP in the nucleotide pool [4].
• Relationship between urinary 15-F2t-isoprostane and 8-oxodeoxyguanosine levels and breast cancer risk [5].

High impact information on 8-Oxodeoxyguanosine triphosphate

• Microsequencing of DIPP revealed a 'MutT' domain, which in other contexts guards cellular integrity by dephosphorylating 8-oxo-dGTP, which causes AT to CG transversion mutations [6].
• The MTH1 gene encodes an enzyme that hydrolyzes 8-oxo-dGTP to monophosphate in the nucleotide pool, thereby preventing occurrence of transversion mutations [7].
• EpsilondA was more mutagenic than 8-oxodeoxyguanosine, which induced targeted G-->T transversions in HeLa cells [8].
• Using this assay, which involves reversed-phase high-performance liquid chromatography and electrochemical detection, we have been unable to detect 8-oxo-dGTP in extracts of three different mutT mutants of E. coli, even after growth of the bacteria in the presence of hydrogen peroxide [2].
• The bacterial MutT protein and its mammalian homolog have been shown to catalyze in vitro the hydrolysis of the oxidized deoxyguanosine nucleotide, 8-oxo-dGTP, to its corresponding monophosphate [2].

Chemical compound and disease context of 8-Oxodeoxyguanosine triphosphate

• Mammalian MTH1 proteins, homologs of Escherichia coli MutT, are enzymes decomposing 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) to 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-monophosphate and inorganic pyrophosphate [9].

Biological context of 8-Oxodeoxyguanosine triphosphate

• When 8-oxo-dGTP was added at 0.34 microm to an in vitro DNA replication system primed with a DNA template that permits scoring of replication errors and with the four normal dNTPs at their estimated intracellular concentrations, there was no detectable effect upon the frequency of replication errors [2].
• 3) Polymerase alpha exhibits a mixed kinetic phenotype, with a large discrimination against 8-oxo-dGTP but a comparatively higher preference for 8-NH2-dGTP [3].
• Oxidative damage of DNA results in the formation of many products, including 8-oxodeoxyguanosine, which has been used as a marker to quantify DNA damage [10].
• (1) 8-Oxo-dGTP can be generated not only by direct oxidation of dGTP but also by phosphorylation of 8-oxo-dGDP by nucleoside diphosphate kinase [11].
• 8-Oxodeoxyguanosine, the most abundant lesion generated by oxidative stress, is highly mutagenic [12].

Anatomical context of 8-Oxodeoxyguanosine triphosphate

• The 8-oxo-dGTPase activity of CHO cells depends on magnesium, has a pH optimum of 8.5, Km for 8-oxo-dGTP of 9.3 microM, and is inhibited by 8-oxo-dGDP, the product of interfering 8-oxo-dGTP phosphatases [13].
• Following this finding, in the present study we have tested the canonical ribo- and deoxyribonucleoside 5'-diphosphates (NDPs and dNDPs) for possible inhibition of 8-oxo-dGTP hydrolysis by hMTH1 extracted from CCRF-CEM cells (a human leukemia cell line) [14].
• Human MTH1 protein hydrolyzes oxidized purine nucleotides 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dGTP), 2-OH-dATP or their ribo-forms to their monophosphates, thus minimizing replicational and transcriptional errors both in the nuclei and mitochondria [15].
• Evaluation of 8-oxodeoxyguanosine, typical oxidative DNA damage, in lymphocytes of ozone-treated arteriosclerotic patients [16].
• Of all the polar adducts, the known mutagenic lesion, 8-oxodeoxyguanosine, predominated in all cervix conditions [17].

Associations of 8-Oxodeoxyguanosine triphosphate with other chemical compounds

• Human MTH1 hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-dATP, to monophosphates, thereby preventing the misincorporation of these oxidized nucleotides during replication [18].
• The chromatographic quantitation of 8-oxoguanine adducts in DNA is widespread in the literature, although results obtained by HPLC of 8-oxodeoxyguanosine do not always agree with levels determined by GC-MS [19].
• DNA replication fidelity with 8-oxodeoxyguanosine triphosphate [20].
• HPLC analysis also revealed significantly increased levels of 8-oxodeoxyguanosine after potassium bromate treatment but not after potassium superoxide treatment [21].
• In support of this hypothesis, immunocytochemistry indicated an elevation of 8-oxodeoxyguanosine in A549 cells treated with 10 and 500 microM sodium dichromate for 1 h [22].

Gene context of 8-Oxodeoxyguanosine triphosphate

• P2N also resulted in the formation of 8-aminodeoxyguanosine and increased the level of 8-oxodeoxyguanosine in V79-hP-PST cells, but not in the parental V79-MZ cells, which do not show any sulfotransferase activity [23].
• ytkD and mutT of Bacillus subtilis encode potential 8-oxo-dGTPases that can prevent the mutagenic effects of 8-oxo-dGTP [24].
• The mutT gene product specifically hydrolyzes 8-oxo-dGTP to the monophosphate form while the mutM and the mutY gene products function to correct mispairs caused by incorporation of 8-oxoguanine into DNA [25].
• Organisms possess 8-oxo-dGTPase, an enzyme that specifically degrades 8-oxo-dGTP to 8-oxo-dGMP [26].
• Thus, our findings address that the insertion of 8-oxo-dG into KG-1 DNA is not due to the direct incorporation of exogenous 8-oxo-dG, but rather to the inaccurate incorporation of endogenous 8-oxo-dGTP by DNA polymerase beta [27].

Analytical, diagnostic and therapeutic context of 8-Oxodeoxyguanosine triphosphate

• On the basis of sequence analyses, it has been recently suggested that the C-terminal domain is distantly related to MutT, a dNTPase which hydrolyzes 8-oxo-dGTP [Noll et al. (1999) Biochemistry 38, 6374-6379] [28].
• With both cell lines, we assessed single-strand DNA cleavage using the comet assay and the formation of oxidized DNA bases, such as 8-oxodeoxyguanosine, utilizing the Trevigen Fpg comet assay [29].
• Site-specific mutagenesis using a gapped duplex vector: a study of translesion synthesis past 8-oxodeoxyguanosine in E. coli [30].
• Controlled oxidation of calf thymus DNA to produce standard samples for 8-oxodeoxyguanosine analysis; effects of freeze-drying, storage and hydrolysis conditions [31].
• To examine associations between two different classes of DNA damage that can occur through endogenous processes or exogenous exposures such as smoking, N7-methyldeoxyguanosine (N7-MedG) and 8-oxodeoxyguanosine (8-oxodG) levels were measured in lymphocyte DNA from 22 bronchoscopy patients [32].

References