Disease relevance of 8-OXOGUANINE

• Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH, and CSB and implications for Cockayne syndrome [1].
• Genetic analyses showed that, in E. coli, 8-oxoguanine is subject to transcription-coupled repair [2].
• Induction of cytochrome P4501A1 (CYP1A1) in the hepatoma Hepa1c1c7 cell line results in an elevation in the excretion rate of 8-oxoguanine (oxo8Gua), a biomarker of oxidative DNA damage and the major repair product of 8-oxo-2'-deoxyguanosine (oxo8dG) residues in DNA [3].
• Using a functional assay for the removal of the oxidative DNA lesion 8-oxoguanine by the DNA-repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1), we have previously shown that reduced OGG activity is a risk factor in lung cancer [4].
• Reduced repair of the oxidative 8-oxoguanine DNA damage and risk of head and neck cancer [4].

Psychiatry related information on 8-OXOGUANINE

• Effect of polyphenolic extract, Pycnogenol(R), on the level of 8-oxoguanine in children suffering from attention deficit/hyperactivity disorder [5].

High impact information on 8-OXOGUANINE

• Transcriptional mutagenesis induced by uracil and 8-oxoguanine in Escherichia coli [2].
• Sequence analyses of the transcript population revealed that RNA polymerase inserts adenine opposite to uracil, and adenine or cytosine opposite to 8-oxoguanine [2].
• In this issue of Molecular Cell, present genetic analysis of E. coli to indicate that the highly mutagenic purine modification, 8-oxoguanine, is subject to transcription-coupled repair despite transcriptional bypass and generation of mutant transcripts [6].
• In the present study, we investigated the impact of the oxidative lesions 8-oxoguanine, thymine glycol and 5-hydroxyuracil on RNA polymerase II (RNA pol II) transcription using a well-defined in vitro transcription system [7].
• The formamidopyrimidine-DNA glycosylase (Fpg, MutM) is a bifunctional base excision repair enzyme (DNA glycosylase/AP lyase) that removes a wide range of oxidized purines, such as 8-oxoguanine and imidazole ring-opened purines, from oxidatively damaged DNA [8].

Chemical compound and disease context of 8-OXOGUANINE

• Site-specific DNA transesterification by vaccinia topoisomerase: effects of benzo[alpha]pyrene-dA, 8-oxoguanine, 8-oxoadenine and 2-aminopurine modifications [9].
• MutT protein of Escherichia coli and related mammalian protein MTH1 specifically degrade 8-oxo-dGTP to 8-oxo-dGMP, thereby preventing misincorporation of 8-oxoguanine into DNA [10].
• Nevertheless, the DSBs in both As- and Cd-treated cells seem to come from the excision of oxidized bases such as formamidopyrimidine and 8-oxoguanine, as the Escherichia coli enzyme formamidopyrimidine-DNA glycosylase (Fpg) increased DSBs in cells treated with As, 3-morpholinosydnonimine (a peroxynitrite-generating agent), Cd, or H2O2 [11].
• The 8-oxoguanine (8-oxoG) DNA glycosylase from Archaeoglobus fulgidus (Afogg), which excises an oxidatively-damaged form of guanine, was overproduced in Escherichia coli, purified and characterized [12].
• During replication, Escherichia coli MutT prevents the misincorporation of mutagenic 8-oxoguanine into nascent DNA strands opposite adenine by hydrolyzing 8-oxo-dGTP in nucleotide pools to 8-oxo-dGMP [13].

Biological context of 8-OXOGUANINE

• A Drosophila ribosomal protein contains 8-oxoguanine and abasic site DNA repair activities [14].
• A major product of free radical DNA damage is the formation of 8-oxoguanine, which is a highly mutagenic base modification produced by oxidative stress [14].
• The significance of this DNA repair activity acting on 8-oxoguanine is shown by the ability of S3 to rescue the H2O2 sensitivity of an Escherichia coli mutM strain (defective for the repair of 8-oxoguanine) and to abolish completely the mutator phenotype of mutM caused by 8-oxoguanine-mediated G-->T transversions [14].
• Human oxoguanine DNA glycosylase 1 (hOgg1), for example, must search out rare 8-oxoguanine lesions to prevent transversion mutations arising from oxidative stress [15].
• 8-Oxoguanine rearranges the active site of human topoisomerase I [16].

Anatomical context of 8-OXOGUANINE

• To address the cause of growth cessation in senescent IMR-90 human fibroblast cells, we determined the level of oxidative DNA damage by using 8-oxoguanine excised from DNA and 8-oxo-2'-deoxyguanosine in DNA as markers [17].
• Repair of 8-oxoguanine and Ogg1-incised apurinic sites in a CHO cell line [18].
• We previously demonstrated that mammalian mitochondria from mice efficiently remove 8-oxodG from their genomes and isolated a protein from rat liver mitochondria with 8-oxoguanine (8-oxodG) DNA glycosylase/apurinic DNA lyase activity [19].
• To assess the extent of DNA damage associated with the response, 8-oxoguanine levels were quantified in DNA extracted from spleens of tumor-bearing mice [20].
• Repair of 8-oxoguanine in DNA is deficient in Cockayne syndrome group B cells [21].

Associations of 8-OXOGUANINE with other chemical compounds

• Targeted deletion of alkylpurine-DNA-N-glycosylase in mice eliminates repair of 1,N6-ethenoadenine and hypoxanthine but not of 3,N4-ethenocytosine or 8-oxoguanine [22].
• 8-Oxoguanine (8-oxoG), a common and mutagenic form of oxidized guanine in DNA, is eliminated mainly through base excision repair [23].
• Molecular modeling techniques employed to integrate the two domains of MutY with DNA suggest that MutY can wrap around the DNA and initiate catalysis by potentially flipping adenine and 8-oxoguanine out of the DNA helix [24].
• Mutation of this residue reduced excision of 8-oxoguanine from thermally unstable mispairs with guanine or thymine, while excision from the stable cytosine and adenine base pairs was less affected [25].
• NEIL1 also excises efficiently 5-hydroxyuracil, an oxidation product of cytosine, from the bubble and single-stranded DNA but does not have strong activity toward 8-oxoguanine in the bubble [26].

Gene context of 8-OXOGUANINE

• In view of the ubiquity of OGG2, we have proposed a model named "bipartite antimutagenic processing of 8-oxoguanine" and is an extension of the original "GO model." The GO model explains the presence of OGG1 (MutM) that excises 8-oxoG from nonreplicated DNA [27].
• Major substrates of these enzymes, a uracil opposite an adenine for UNG2 and an adenine opposite an 8-oxoguanine for MYH, are formed during DNA replication [28].
• 8-Oxoguanine formation induced by chronic UVB exposure makes Ogg1 knockout mice susceptible to skin carcinogenesis [29].
• These results represent the first demonstration of the essential contribution of BRCA1 and BRCA2 gene products in the repair of the 8-oxoguanine oxidative damage specifically located on the transcribed strand in human cells [30].
• We show that deficiency for either BRCA1 or BRCA2 in human cancer cells leads to a block of the RNA polymerase II transcription machinery at the 8-oxoguanine site and impairs the transcription-coupled repair of the lesion, leading to a high mutation rate [30].

Analytical, diagnostic and therapeutic context of 8-OXOGUANINE

• A novel HPLC procedure for the analysis of 8-oxoguanine in DNA [31].
• Fluorescence detection of 8-oxoguanine in nuclear and mitochondrial DNA of cultured cells using a recombinant Fab and confocal scanning laser microscopy [32].
• In short, we use the Escherichia coli repair enzyme formamidopyrimidine (Fapy) glycosylase to release the base 8-oxoguanine from full-length DNA, then separate 8-oxoguanine from high molecular weight molecules by ultrafiltration (10,000 Da exclusion) and analyze the base adduct by reverse-phase HPLC [33].
• Then we applied different protocols of the comet assay to quantify genomic DNA damage and conducted immunohistochemistry for 8-oxoguanine as a molecular marker for oxidative stress [34].
• Immunohistochemistry revealed high levels of 8-oxoguanine in thyroid epithelial cells [34].

References