Disease relevance of Mpg

• The present study examines the role of the BER enzyme 3-alkyladenine DNA glycosylase (AAG) and the NER protein xeroderma pigmentosum group A (XPA) in protecting cerebellar neurons and astrocytes from chloroacetaldehyde (CAA) or the alkylating agent 3-methyllexitropsin (Me-Lex), which produce ethenobases or 3-methyladenine (3-MeA), respectively [1].
• Interestingly, STZ-treated APNG(-/-) mice succumbed to diabetes 8 months after treatment, in contrast to previous work with PARP inhibitors, where a high incidence of beta-cell tumors was observed [2].
• Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice [2].
• Pol-beta-deficient cells were significantly more susceptible to killing by temozolomide than wild-type or Aag-deficient cells, a hypersensitivity likely caused by accumulation of BER intermediates [3].
• After 1 year, only mice in the high-dose group developed hepatocellular carcinoma; however, the incidence was not higher in APNG-/- mice [4].

High impact information on Mpg

• Repair-deficient 3-methyladenine DNA glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation-induced chromosome damage and cell killing [5].
• Here we report the generation of mice deficient in the 3MeA DNA glycosylase encoded by the Aag (Mpg) gene [6].
• It has previously been reported that 1,N6-ethenoadenine (epsilonA), deaminated adenine (hypoxanthine, Hx), and 7,8-dihydro-8-oxoguanine (8-oxoG), but not 3,N4-ethenocytosine (epsilonC), are released from DNA in vitro by the DNA repair enzyme alkylpurine-DNA-N-glycosylase (APNG) [7].
• 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 [7].
• Fibroblasts derived from Aag -/- mice are alkylation sensitive, indicating that Aag -/- mice may be similarly sensitive [6].

Chemical compound and disease context of Mpg

• Mouse N-methylpurine-DNA glycosylase, responsible for the removal of N-alkylpurines in DNA that are induced by simple monofunctional alkylating agents, also releases 8-hydroxyguanine from DNA in vitro and in vivo in Escherichia coli [8].
• Activity of fotemustine in medulloblastoma and malignant glioma xenografts in relation to O6-alkylguanine-DNA alkyltransferase and alkylpurine-DNA N-glycosylase activity [9].

Biological context of Mpg

• Structure of the mouse 3-methyladenine DNA glycosylase gene and exact localization upstream of the alpha-globin gene cluster on chromosome 11 [10].
• Aag(-/-) neurons were more sensitive to the acute (>20 microM) and long-term (>5 microM) effects of CAA than comparably treated wild type neurons and this sensitivity correlated with the extent of DNA fragmentation and nuclear changes [1].
• Base excision repair deficient mice lacking the Aag alkyladenine DNA glycosylase [6].
• However, 48 h after STZ treatment, there was a peak of apoptosis in the beta cells of APNG(-/-) mice [2].
• Unlike other null mutants of the base excision repair pathway, the APNG ko mice exhibit a very mild phenotype, show no outward abnormalities, are fertile, and have an apparently normal life span [11].

Anatomical context of Mpg

• Astrocytes from the cerebellum of wild type, Aag(-/-) or Xpa(-/-) mice were essentially insensitive to CAA at the concentrations tested [1].
• Aag appears to be the only 3MeA and hypoxanthine DNA glycosylase in liver, testes, kidney, and lung, and the only epsilonA DNA glycosylase in liver, testes, and kidney; another epsilonA DNA glycosylase may be expressed in lung [6].
• Alkylpurine-DNA-N-glycosylase (APNG) null mice have been generated by homologous recombination in embryonic stem cells [11].
• Indeed, PARP activity was not induced in APNG(-/-) islet cells following treatment with STZ in vitro [2].
• However, treatment with methyl methanesulfonate resulted in three- to fourfold more hprt mutations in splenic T lymphocytes from APNG ko mice than in those from wt mice [11].

Associations of Mpg with chemical compounds

• The effect of dietary folic acid deficiency on the cytotoxic and mutagenic responses to methyl methanesulfonate in wild-type and in 3-methyladenine DNA glycosylase-deficient Aag null mice [12].
• Weanling wild-type or 3-methyladenine glycosylase (Aag) null mice were maintained on a FA- diet or the same diet supplemented with folic acid (FA+) for 4 weeks [12].
• Aag(-/-) neurons were also sensitive to Me-Lex at comparable concentrations of CAA [1].
• Neuronal and astrocyte cell cultures prepared from the cerebellum of wild type (C57BL/6) mice or Aag(-/-) or Xpa(-/-) mice were treated with 0.1-50 microM CAA for 24h to 7 days and examined for cell viability, DNA fragmentation (TUNEL labeling), nuclear changes, and glutathione levels [1].
• Overexpression of Aag (the initiating BER enzyme) triggered a further increase in temozolomide-induced cytotoxicity [3].

Other interactions of Mpg

• The cells exposed to amsacrine and treated with endonuclease III and 3-methyladenine-DNA glycosylase II, the enzymes recognizing oxidized and alkylated bases, respectively, displayed greater extent of DNA damage than those not treated with these enzymes [13].

Analytical, diagnostic and therapeutic context of Mpg

• Flow cytometry indicated that in vivo alkylation resistance in Aag null BM cells may be restricted to cells of the myeloid lineage [14].
• Quantitative reverse transcriptase polymerase chain reaction for measuring the N-methylpurine-DNA glycosylase mRNA level in rodent cells [15].

References