Increased removal of 3-alkyladenine reduces the frequencies of<i>hprt</i>mutations induced by methyl- and ethylmethanesulfonate in Chinese hamster fibroblast cells

Klungland, Arne; Bjørås, Magnar; Hoff, E.; Seeberg, Erling

doi:10.1093/nar/22.9.1670

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…This implies that the highly mutagenic lesion O 6 -meG, which gives rise to GC3AT transitions (45), is not repaired and therefore dominated the induction of mutations. Furthermore, expression of the tag gene in these cells did reduce the mutagenicity of MMS by a factor of 2, implicating 3-meA as the likely mutagenic lesion (28). Furthermore, a role for 3-ethyladenine in the induction of mutations by ethylating agents has also been proposed by Op het Veld et al (40).…”

Section: Vol 18 1998 Mutation Induction In Apng Knockout Mice By MMmentioning

confidence: 80%

“…Although increased levels of DNA repair activities, including APNG, were observed in nitrogen mustard-resistant B lymphocytes (20) and N- (2-chloroethyl)-Nnitrosourea (CNU)-resistant gliomas (34), overexpression of human APNG in Chinese hamster ovary cells afforded no protection against the cytotoxic effects of CNU or nitrogen mustards (5). Similarly, while the overexpression of the Escherichia coli tag gene, which codes for a 3-meA-DNA glycosylase with a narrow substrate specificity (1), reduced the toxic and mutagenic effects of methylating agents in Chinese hamster V79 cells (27,28), no difference in the cytotoxicities of these or other alkylating agents was found in tag-transfected NIH 3T3 murine fibroblasts (23). Furthermore, while the expression of the Saccharomyces cerevisiae MAG gene in glycosylase-deficient S. cerevisiae cells or E. coli cells protected against methylating-agent and CNU cytotoxicity (9,35), overexpression of human APNG in Chinese hamster ovary cells resulted in greater sensitivity to cell killing by methyl methanesulfonate (MMS) and an increased frequency of chromosomal aberrations (13).…”

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confidence: 99%

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Alkylpurine–DNA–N-Glycosylase Knockout Mice Show Increased Susceptibility to Induction of Mutations by Methyl Methanesulfonate

Elder

Jansen

Weeks

et al. 1998

Molecular and Cellular Biology

108

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Alkylpurine-DNA-N-glycosylase (APNG) null mice have been generated by homologous recombination in embryonic stem cells. The null status of the animals was confirmed at the mRNA level by reverse transcription-PCR and by the inability of cell extracts of tissues from the knockout (ko) animals to release 3-methyladenine (3-meA) or 7-methylguanine (7-meG) from 3 H-methylated calf thymus DNA in vitro. Following treatment with DNA-methylating agents, increased persistence of 7-meG was found in liver sections of APNG ko mice in comparison with wild-type (wt) mice, demonstrating an in vivo phenotype for the APNG null animals. 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. Neither a difference in the number of leukocytes in peripheral blood nor a difference in the number of bone marrow polychromatic erythrocytes was found when ko and wt mice were exposed to methylating or chloroethylating agents. These agents also showed similar growth-inhibitory effects in primary embryonic fibroblasts isolated from ko and wt mice. 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. These mutations were predominantly singlebase-pair changes; in the ko mice, they consisted primarily of AT3TA and GC3TA transversions, which most likely are caused by 3-meA and 3-or 7-meG, respectively. These results clearly show an important role for APNG in attenuating the mutagenic effects of N-alkylpurines in vivo.Alkylpurine-DNA-N-glycosylase (APNG) is one of a growing list of enzymes responsible for the recognition and excision of altered bases in the first step of the base excision repair pathway (49, 56). In the simplest form of base excision repair, the resulting abasic site is then repaired by the sequential action of an apurinic-apyrimidinic (AP) endonuclease that generates a single-strand break, the removal of the 5Ј-terminal deoxyribose phosphate residue, insertion of a single nucleotide by DNA polymerase ␤, and finally ligation of the repaired patch by DNA ligase I or XRCC1-DNA ligase III (55, 56).Mammalian APNGs have been shown to be active against a wide range of modified bases in vitro, many structurally unrelated to 3-methyladenine (3-meA), the substrate after which the enzyme was first named (32). In particular, APNG appears to be the only glycosylase in mammalian cells that can release hypoxanthine from DNA, a promutagenic base resulting from the spontaneous deamination of adenine (22,47). Likewise, the highly mutagenic adduct 1,N 6 -ethenoadenine (41), which is produced by metabolic products of the environmental hepatocarcinogens vinyl chloride and ethyl carbamate, is released by APNG (22, 48); indeed, according to one report, the recombinant human enzyme reacted 10-to 20-fold more efficiently with this adduct than with 3-meA in an in vitro assay (14). These results, together ...

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Section: Vol 18 1998 Mutation Induction In Apng Knockout Mice By MMmentioning

confidence: 80%

mentioning

confidence: 99%

Alkylpurine–DNA–N-Glycosylase Knockout Mice Show Increased Susceptibility to Induction of Mutations by Methyl Methanesulfonate

Elder

Jansen

Weeks

et al. 1998

Molecular and Cellular Biology

108

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“…The substrate specificities of these enzymes are, however, usually much wider (Figure 2). 3-MeA has been demonstrated to be a major cytotoxic and mutagenic DNA lesion [107,108], although it is estimated to be some 40-fold less mutagenic than O'-methylguanine (O'-meG) [108], which is directly dealkylated by an alkyltransferase.…”

Section: Dna Glycosylases For Alkylated Basesmentioning

confidence: 99%

DNA glycosylases in the base excision repair of DNA

Krokan

Standal

Slupphaug

1997

Biochemical Journal

771

566

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A wide range of cytotoxic and mutagenic DNA bases are removed by different DNA glycosylases, which initiate the base excision repair pathway. DNA glycosylases cleave the Nglycosylic bond between the target base and deoxyribose, thus releasing a free base and leaving an apurinic\apyrimidinic (AP) site. In addition, several DNA glycosylases are bifunctional, since they also display a lyase activity that cleaves the phosphodiester backbone 3h to the AP site generated by the glycosylase activity. Structural data and sequence comparisons have identified common features among many of the DNA glycosylases. Their active sites have a structure that can only bind extrahelical target bases, as observed in the crystal structure of human uracil-DNA glycosylase in a complex with double-stranded DNA. Nucleotide flipping is apparently actively facilitated by the enzyme. With bacteriophage T4 endonuclease V, a pyrimidine-

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“…[149] have reported that overexpression of the TAG gene in mammalian cells may in fact increase resistance to the genotoxic effects of methylating agents such as MMS. TAG expression reduced the frequency of MMS‐ and EMS‐induced mutations at the HPRT locus to about half the normal rate [150]. Another group was, however, unable to obtain the same results with 3T3NIH murine fibroblasts [151].…”

Section: Overexpression Of Enzymes Involved In Repair Of Endogenous Dmentioning

confidence: 99%

Overexpression of enzymes that repair endogenous damage to DNA

Fròsina

2000

European Journal of Biochemistry

101

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A significant contribution to human mutagenesis and carcinogenesis may come from DNA damage of endogenous, rather than exogenous, origin. Efficient repair mechanisms have evolved to cope with this. The main repair pathway involved in repair of endogenous damage is DNA base excision repair. In addition, an important contribution is given by O 6 -alkylguanine DNA alkyltranferase, that repairs specifically the miscoding base O 6 -alkylguanine. In recent years, several attempts have been carried out to enhance the efficiency of repair of endogenous damage by overexpressing in mammalian cells single enzymatic activities. In some cases (e.g. O 6 -alkylguanine DNA alkyltransferase or yeast AP endonuclease) this approach has been successful in improving cellular protection from endogenous and exogenous mutagens, while overexpression of other enzymatic activities (e.g. alkyl N-purine glycosylase or DNA polymerase b) were detrimental and even produced a genome instability phenotype. The reasons for these different outcomes are analyzed and alternative enzymatic activities whose overexpression may improve the efficiency of repair of endogenous damage in human cells are proposed.Keywords: DNA repair; endogenous damage; O 6 -alkylguanine DNA alkyltransferase; oxidation; methylation; abasic sites; DNA base excision repair; rate-limiting step; transfection.A significant portion of carcinogenic events may be due to genetic damage of endogenous, rather than environmental, origin. Most endogenous damage originates from products of oxygen dismetabolism (so called reactive oxygen species), from the intrinsic lability of chemical bonds in DNA, from endogenous methylating agents or from DNA replication errors. Several mechanisms have evolved in humans to repair damage to DNA. We have known for several years that, should the repair of damage induced by sunlight be defective (as in the case of the hereditary disorder xeroderma pigmentosum), the probability of skin cancer is increased. [17,18] have appeared in recent years. The aim of this review is to survey and analyze the potential to increase the protective role of repair of endogenous damage against spontaneous mutagenesis and carcinogenesis. In those cases in which data are scant or unavailable, the survey will extend to protection from induced mutagenesis and carcinogenesis. E N D O G E N O U S D A M A G EEndogenous damage affects the primary, rather than the secondary, structure of the double helix. Four general classes of modifications can be envisaged. OxidationThis is due mainly to byproducts of oxygen metabolism and is the subject of current intensive investigation, as some oxidized bases have been shown to be miscoding and formed in huge amounts under physiological conditions [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG), thymine glycol and similar oxidized bases]. Perhaps the most abundant and dangerous of these lesions is 8-oxoG, which frequently mispairs with adenine [2,3]. It has been calculated that approximately 7500 8-oxoG lesions may form daily in a mammalian cell (< 5% ...

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Increased removal of 3-alkyladenine reduces the frequencies ofhprtmutations induced by methyl- and ethylmethanesulfonate in Chinese hamster fibroblast cells

Cited by 9 publications

References 29 publications

Alkylpurine–DNA–N-Glycosylase Knockout Mice Show Increased Susceptibility to Induction of Mutations by Methyl Methanesulfonate

Alkylpurine–DNA–N-Glycosylase Knockout Mice Show Increased Susceptibility to Induction of Mutations by Methyl Methanesulfonate

DNA glycosylases in the base excision repair of DNA

Overexpression of enzymes that repair endogenous damage to DNA

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