Disease relevance of O6-Methylguanine

• Mismatch correction at O6-methylguanine residues in E. coli DNA [1].
• Removal of O6-methylguanine from DNA of normal and xeroderma pigmentosum-derived lymphoblastoid lines [2].
• PURPOSE: This study was designed to determine whether resistance to the activity of nitrosourea (the drug BCNU) in BCNU-resistant human medulloblastoma (D341 Med) and human glioblastoma multiforme (D-456 MG) can be reversed by the methylating agent streptozocin and the O6-substituted guanines O6-methylguanine and O6-benzylguanine [3].
• Deficient repair of DNA lesion O6-methylguanine in cirrhosis [4].
• Using site-specific mutagenesis, we have examined the mutagenic activity in vivo of O6-methylguanine or O6-n-butylguanine located at a preselected site in gene G of bacteriophage phi X174 [5].

Psychiatry related information on O6-Methylguanine

• O6-Methylguanine methyltransferase (O6-MT) was measured and compared in extracts of 7 human fetal tissues obtained from 21 different fetal specimens as a function of fetal age and race and of maternal smoking and drug usage [6].

High impact information on O6-Methylguanine

• Mechanism of mutagenesis by O6-methylguanine [7].
• Time course of O6-methylguanine removal from DNA of N-methyl-N-nitrosourea-treated human fibroblasts [8].
• Day and his coworkers (see refs 7, 8 and previous paper) found that some human tumour cell strains (designated Mer- phenotype) are deficient in the ability to repair O6-methylguanine lesions in DNA [9].
• Exhaustion and recovery of repair excision of O6-methylguanine from rat liver DNA [10].
• RESULTS: Pretreatment with O6-benzylguanine, O6-methylguanine, or streptozocin reduced AGAT activity to 4%, 25%, and 95% of control values, respectively, in D341 Med and 0%, 0%, and 25% of control values, respectively, in D-456 MG 1 hour after injection [3].

Chemical compound and disease context of O6-Methylguanine

• The O6-methylguanine-DNA methyltransferase of Escherichia coli acts rapidly and stoichiometrically to convert a mutagenic O6-methylguanine residue in DNA to unsubstituted guanine [11].
• During exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), Escherichia coli cells induced for the adaptive response accumulate substantially less O6-methylguanine in their DNA than control cells [12].
• The concentration of 7-methylguanine and O6-methylguanine were similar in mammary epithelial DNA 0.25, 0.50, and 1.0 h after i.v. injection of 50 mg/kg body weight NMU on different days of the rat estrous cycle [13].
• Other alkylpurines, such as O6-methylguanosine, S6-methylthioguanine, O6-ethylguanine, and 3-methyladenine, did not have this effect on extracts of human tumor cells, while O6-methylguanosine and O6-methylguanine inactivated purified methyltransferase from Escherichia coli [14].
• We examined the protective role of the alkyltransferase in the nitrosourea resistance observed in this myeloid leukemia cell line to determine whether inactivation of the alkyltransferase with the modified base, O6-methylguanine (O6mGua), could sensitize these cells to nitrosoureas [15].

Biological context of O6-Methylguanine

• Evidence was obtained to support the hypothesis that these results were due to an enzymatic removal of O6-methylguanine from liver DNA, which occurred much more efficiently at lower initial levels of alkylation [16].
• After continuous DMN exposure, the O6-methylguanine:7-methylguanine ratio was lower in the S-phase and G2+M-phase livers than in the G0-phase and G1-phase livers, indicating an increased O6-methylguanine repair during DNA synthesis and the G2+M-phase [17].
• This finding suggests a mechanism for cirrhosis being a risk factor for cancer of the liver: increased cellular proliferation together with persistence of O6-methylguanine might lead to malignant transformation of liver cells through mutation and oncogene activation [4].
• A plasmid was constructed in which a single guanine residue was replaced with either O6-methylguanine or O6-ethylguanine, two of the DNA adducts formed by carcinogenic alkylating agents [18].
• Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct [19].

Anatomical context of O6-Methylguanine

• Extracts of peripheral lymphocytes from six individuals with chronic lymphocytic leukemia (CLL) were assayed for the ability to remove O6-methylguanine (O6MeGua) from exogenous DNA [20].
• Hybrid cells had an O6-methylguanine removal capacity per mole of guanine about one third to one half that of the Mex+ parents, i.e., about the same per cell [21].
• Two cell lines, one proficient (Mex+) and one deficient (Mex-) in the ability to remove O6-methylguanine, have been isolated by Epstein-Barr virus-mediated transformation of a single blood sample obtained from a normal human male [22].
• Accumulation of O6-methylguanine in human blood leukocyte DNA during exposure to procarbazine and its relationships with dose and repair [23].
• The alkyltransferase activity of HT29 cells was reduced by 60-80% by treatment for 24 h with 0.05-0.4 mM O6-methylguanine or O6-n-butylguanine [24].

Associations of O6-Methylguanine with other chemical compounds

• Alkylation of rat liver DNA by dimethylnitrosamine: effect of dosage on O6-methylguanine levels [16].
• HPLC analysis of DNA hydrolysates showed that ellagic acid caused a dose-dependent 36-84% decrease in O6-methylguanine but only a 20% decrease in the 7-methylguanine adduct [25].
• These results suggest that O6-methylguanine and its bulkier analogue O6-benzylguanine may induce mutagenesis by different mechanisms [26].
• Protonated base pairs explain the ambiguous pairing properties of O6-methylguanine [27].
• TMZ produces O6-methylguanine in DNA, which mispairs with thymine during the next cycle of DNA replication [28].

Gene context of O6-Methylguanine

• In cells not expressing the repair protein MGMT or expressing it at a low level, O6-methylguanine is the major genotoxic, recombinogenic, and apoptotic lesion [29].
• One of the MAG URS elements matches a decamer consensus sequence present in the promoters of 11 other S. cerevisiae DNA repair and metabolism genes, including the MGT1 gene, which encodes an O6-methylguanine DNA repair methyltransferase [30].
• O6-methylguanine methyltransferase, Mgmt, constitutes the first line of defense against O6-alkylguanine, which can result in G : C to A : T transitions upon DNA replication [31].
• Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1 [32].
• Possible involvement of O6-methylguanine formation and p53 dysfunction in mouse urinary bladder carcinogenesis [33].

Analytical, diagnostic and therapeutic context of O6-Methylguanine

• After treatment with O6-methylguanine, clonogenic leukemic cells from ten different donors became much more sensitive to BCNU, with a decrease in the dose needed to reduce colony survival by 50% (LD50) of 6.3 +/- 1.4-fold [34].
• Quantitation of 7-methylguanine and O6-methylguanine (O6MG) was achieved by highly sensitive optical methods following separation of DNA bases by high-performance liquid chromatography [35].
• Highly sensitive, specific detection of O6-methylguanine, O4-methylthymine, and O4-ethylthymine by the combination of high-performance liquid chromatography prefractionation, 32P postlabeling, and immunoprecipitation [36].
• The DNA of the stomach, liver, and intestines (large and small pooled together) was isolated 6 hr after cessation of treatment and analyzed for the presence of O6-methylguanine using a sensitive and specific radioimmunoassay [37].
• The radioimmunoassay also detected O6-methylguanine in DNA alkylated by agents known to produce O6-methylguanine, such as N'-methyl-N-nitrosourea [38].

References