3‐methyladenine DNA glycosylases: structure, function, and biological importance

Wyatt, Michael D.; Allan, James M.; Lau, Albert Y.; Ellenberger, Tom; Samson, Leona D.

doi:10.1002/(sici)1521-1878(199908)21:8<668::aid-bies6>3.3.co;2-4

Cited by 62 publications

(89 citation statements)

References 25 publications

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“…The bacterial enzyme AlkA has been shown to remove a wide variety of damaged purine and pyrimidine bases, including N 7-Me-Gua [219-221]. Mammalian cells do not possess a homologue of AlkA, but AAG, a member of the N -methylpurine DNA glycosylase family, removes a broad spectrum of modified purines from DNA including N 7-Me-Gua [222, 223]. Additional studies on knockout animals will be needed to demonstrate that DNA repair plays a significant role in removal of N 7-guanine adducts, compared to chemical depurination.…”

Section: Evidence For Mutations Resulting From N7-guanine Adductsmentioning

confidence: 99%

The formation and biological significance of N7-guanine adducts

Boysen

Pachkowski

Nakamura

et al. 2009

Mutation Research/Genetic Toxicology and Environmental Mutagene

186

182

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DNA alkylation or adduct formation occurs at nucleophilic sites in DNA, mainly the N7-position of guanine. Ever since identification of the first N7-guanine adduct, several hundred studies on DNA adducts have been reported. Major issues addressed include the relationships between N7-guanine adducts and exposure, mutagenesis, and other biological endpoints. It became quickly apparent that N7-guanine adducts are frequently formed, but may have minimal biological relevance, since they are chemically unstable and do not participate in Watson Crick base pairing. However, N7-guanine adducts have been shown to be excellent biomarkers for internal exposure to direct acting and metabolically activated carcinogens. Questions arise, however, regarding the biological significance for N7-guanine adducts that are readily formed, do not persist, and are not likely to be mutagenic. Thus, we set out to review the current literature to evaluate their formation and the mechanistic evidence for the involvement of N7-guanine adducts in mutagenesis or other biological processes. It was concluded that there is insufficient evidence that N7-guanine adducts can be used beyond confirmation of exposure to the target tissue and demonstration of the molecular dose. There is little to no evidence that N7-guanine adducts or their depurination product, apurinic sites, are the cause of mutations in cells and tissues, since increases in AP sites have not been shown unless toxicity is extant. However, more research is needed to define the extent of chemical depurination versus removal by DNA repair proteins. Interestingly, N7-guanine adducts are clearly present as endogenous background adducts and the endogenous background amounts appear to increase with age. Furthermore, the N7-guanine adducts have been shown to convert to ring opened lesions (FAPy), which are much more persistent and have higher mutagenic potency. Studies in humans are limited in sample size and differences between controls and study groups are small. Future investigations should involve human studies with larger numbers of individuals and analysis should include the corresponding ring opened FAPy derivatives.

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Section: Evidence For Mutations Resulting From N7-guanine Adductsmentioning

confidence: 99%

The formation and biological significance of N7-guanine adducts

Boysen

Pachkowski

Nakamura

et al. 2009

Mutation Research/Genetic Toxicology and Environmental Mutagene

186

182

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“…Deleting Mlh1 rescued the Rad51d -deficient hypersensitivity to MNNG by 5.2-fold, but did not fully rescue survival to that seen for Rad51d -proficient Mlh1 -deficient cells. MNNG and MMS both produce 7-methylguanine and lesser amounts of 3-methyladenine, which are substrates for AAG-mediated BER [3,35]. 3-Methyladenine is a replication blocking lesion.…”

Section: Discussionmentioning

confidence: 99%

RAD51D protects against MLH1-dependent cytotoxic responses to O6-methylguanine

Rajesh¹,

Rajesh²,

Wyatt³

et al. 2010

DNA Repair

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S N 1-type methylating agents generate O 6 -methyl guanine (O 6 -meG), which is a potently mutagenic, toxic, and recombinogenic DNA adduct. Recognition of O 6 -meG:T mismatches by mismatch repair (MMR) causes sister chromatid exchanges, which are representative of homologous recombination (HR) events. Although the MMR dependent mutagenicity and toxicity caused by O 6 -meG has been studied, the mechanisms of recombination induced by O 6 -meG are poorly understood. To explore the HR and MMR genetic interactions in mammals, we used the Rad51d and Mlh1 mouse models. Ablation of Mlh1 did not appreciably influence the developmental phenotypes conferred by the absence of Rad51d. Mouse embryonic fibroblasts (MEFs) deficient in Rad51d can only proliferate in p53-deficient background. Therefore, Rad51d −/− Mlh1 −/− Trp53 −/− MEFs with a combined deficiency of HR and MMR were generated and comparisons between MLH1 and RAD51D status were made. To our knowledge, these MEFs are the first mammalian model system for combined HR and MMR defects. Rad51d-deficient MEFs were 5.3 fold sensitive to N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) compared to the Rad51d-proficient MEFs. A pronounced G2/M arrest in Rad51d-deficient cells was accompanied by an accumulation of γ-H2AX and apoptosis. Mlh1-deficient MEFs were resistant to MNNG and showed no G2/M arrest or apoptosis at the doses used. Importantly, loss of Mlh1 alleviated sensitivity of Rad51d-deficient cells to MNNG, in addition to reducing γ-H2AX, G2/M arrest and apoptosis. Collectively, the data support the hypothesis that MMR-dependent sensitization of HRdeficient cells is specific for O 6 -meG and suggest that HR resolves DNA intermediates created by MMR recognition of O 6 -meG:T. This study provides insight into recombinogenic mechanisms of carcinogenesis and chemotherapy resulting from O 6 -meG adducts.

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“…These enzymes exhibit significant differences in their ability to excise lesions within polynucleotide repeats (Lingaraju et al, 2008; Wyatt and Samson, 2000) and can also excise normal, undamaged purines from DNA, albeit with very low efficiency (Berdal et al, 1998; Wyatt et al, 1999). The crystal structures of 3MeA DNA glycosylases from E. coli (AlkA and Tag) and from humans (hAAG, also called MPG or ANPG) reveal that these enzymes position the flipped out damaged base in the electron-rich, aromatic active site (Drohat et al, 2002; Hollis et al, 2000; Lau et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Frameshift Mutagenesis and Microsatellite Instability Induced by Human Alkyladenine DNA Glycosylase

et al. 2010

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Human alkyladenine DNA glycosylase (hAAG) excises alkylated purines, hypoxanthine and etheno bases from DNA to form abasic (AP) sites. Surprisingly, elevated expression of hAAG increases spontaneous frameshift mutagenesis. By random mutagenesis of eight active site residues, we isolated hAAG-Y127I/H136L double mutant that induces even higher rates of frameshift mutation than the wild-type hAAG; the Y127I mutation accounts for the majority of the hAAG-Y127I/H136L induced mutator phenotype. The hAAG-Y127I/H136L and hAAG-Y127I mutants increased the rate of spontaneous frameshifts by up to 120-fold in S. cerevisiae, and also induced high rates of microsatellite instability (MSI) in human cells. hAAG and its mutants bind DNA containing 1 and 2 base pair-loops with significant affinity, thus shielding them from mismatch repair; the strength of such binding correlates with their ability to induce the mutator phenotype. This study provides important insights into the mechanism of hAAG-induced genomic instability.

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3‐methyladenine DNA glycosylases: structure, function, and biological importance

Cited by 62 publications

References 25 publications

The formation and biological significance of N7-guanine adducts

The formation and biological significance of N7-guanine adducts

RAD51D protects against MLH1-dependent cytotoxic responses to O6-methylguanine

Frameshift Mutagenesis and Microsatellite Instability Induced by Human Alkyladenine DNA Glycosylase

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