Alternative titles; symbols
HGNC Approved Gene Symbol: MPG
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:77,007-85,846 (from NCBI)
The bacterial enzyme 3-methyladenine (3MeA) DNA glycosylase repairs the lethal lesion 3MeA that blocks DNA replication in Escherichia coli. The removal of 3MeA is mediated by two 3MeA DNA glycosylases in E. coli, encoded by the alkA and tag genes. Using a human cDNA library cloned into a bacterial expression vector, Boosalis et al. (1991) cloned a 1.15-kb cDNA that rescued alkA(-) tag(-) glycosylase-deficient E. coli from alkylation-induced killing, and produced a 5-fold increase in 3MeA DNA glycosylase activity in the E. coli strain. The cDNA hybridized to human genomic DNA but did not hybridize to E. coli or yeast DNA. DNA sequence analysis defined an open reading frame coding for a 33-kD protein that showed extensive amino acid homology with rat 3MeA DNA glycosylase. The gene was designated N-methylpurine DNA glycosylase (MPG).
Samson et al. (1991) suggested that because of the 85% identity of 1 part of the human glycosylase with the middle of the rat glycosylase polypeptide and, hence, the likely common origin of the rat and human glycosylases, the human gene should be called AAG for 3-alkyladenine DNA glycosylase.
Vickers et al. (1993) also isolated a cDNA corresponding to the human MPG gene. The MPG gene was expressed in all cell lines and tissues examined, but was found at particularly high levels in a colon adenocarcinoma cell line (HT29).
The human enzyme 3-methyladenine DNA glycosylase removes a diverse group of damaged bases from DNA, including cytotoxic and mutagenic alkylation adducts of purines. Lau et al. (1998) reported the crystal structure of human 3-methyladenine DNA glycosylase complexed to a mechanism-based pyrrolidine inhibitor. The enzyme had intercalated into the minor groove of DNA, causing the abasic pyrrolidine nucleotide to flip into the enzyme active site, where a bound water was poised for nucleophilic attack.
Vickers et al. (1993) found that the completely characterized MPG gene spans 7 to 8 kb of genomic DNA.
Kielman et al. (1995) described the genomic organization of the mouse Mpg gene.
Boosalis et al. (1991) mapped the MPG gene to chromosome 16 by analysis of a panel of DNAs from mouse/human and hamster/human hybrid cell lines.
Vickers et al. (1993) mapped the MPG gene within a group of closely spaced genes in the terminal region of chromosome 16p, 75 kb upstream of the embryonic zeta-globin gene (HBZ; 142310).
Preliminary analyses by Kielman et al. (1993) and Kielman et al. (1994) indicated that the mouse Mpg gene is upstream of the alpha-globin gene cluster on chromosome 11.
By targeted homologous recombination, Engelward et al. (1997) generated mice deficient in the 3MeA DNA glycosylase encoded by the Aag gene. In several mouse tissues, the Aag gene product appears to be the only DNA glycosylase that is active against 3MeA, hypoxanthine, and 1,N6-ethenoadenine. Although the Aag protein has the capacity to remove 8-oxoguanine DNA lesions, it does not appear to be the major glycosylase for 8-oxoguanine repair.
To assess the contribution of Apng to the repair of several mutagenic lesions in vivo, Hang et al. (1997) biochemically analyzed cell-free extracts of tissues from mice with a targeted deletion of the Apng gene. They found that both 1,N6-ethenoadenine and hypoxanthine are substrates for Apng, but 3,N4-ethenocytosine and 8-oxoguanine are not.
Elder et al. (1998) developed mice deficient in alkylpurine-DNA-N-glycosylase by targeted disruption. Following treatment with DNA-methylating agents, increased persistence of 7-methylguanine (meG) was found in liver sections of APNG knockout mice in comparison with wildtype mice, demonstrating an in vivo phenotype for the APNG-null animals. Unlike other null mutants of the basic excision repair pathway, the APNG knockout mice exhibited a very mild phenotype, showed no outward abnormalities, were fertile, and had 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 knockout and wildtype mice were exposed to methylating or chloroethylating agents. Treatment with methyl methanesulfonate resulted in 3- to 4-fold more HPRT (308000) mutations in splenic T lymphocytes from APNG knockout mice than in those from wildtype mice. These mutations were predominantly single-basepair changes that most likely were caused by 3-meA and 3- or 7-meG, respectively.
Boosalis, M., Derfler, B., Call, K., Samson, L. Cloning of a human 3-methyladenine DNA glycosylase cDNA whose gene maps to human chromosome 16. (Abstract) Am. J. Hum. Genet. 49 (suppl.): 399 only, 1991.
Elder, R. H., Jansen, J. G., Weeks, R. J., Willington, M. A., Deans, B., Watson, A. J., Mynett, K. J., Bailey, J. A., Cooper, D. P., Rafferty, J. A., Heeran, M. C, Wijnhoven, S. W. P., van Zeeland, A. A., Margison, G. P. Alkylpurine-DNA-N-glycosylase knockout mice show increased susceptibility to induction of mutations by methyl methanesulfonate. Molec. Cell. Biol. 18: 5828-5837, 1998. [PubMed: 9742100] [Full Text: https://doi.org/10.1128/MCB.18.10.5828]
Engelward, B. P., Weeda, G., Wyatt, M. D., Broekhof, J. L. M., de Wit, J., Donker, I., Allan, J. M., Gold, B., Hoeijmakers, J. H. J., Samson, L. D. Base excision repair deficient mice lacking the Aag alkyladenine DNA glycosylase. Proc. Nat. Acad. Sci. 94: 13087-13092, 1997. [PubMed: 9371804] [Full Text: https://doi.org/10.1073/pnas.94.24.13087]
Hang, B., Singer, B., Margison, G. P., Elder, R. H. 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. Proc. Nat. Acad. Sci. 94: 12869-12874, 1997. [PubMed: 9371767] [Full Text: https://doi.org/10.1073/pnas.94.24.12869]
Kielman, M. F., Smits, R., Bernini, L. F. Structure of the mouse 3-methyladenine DNA glycosylase gene and exact localization upstream of the alpha-globin gene cluster on chromosome 11. Mammalian Genome 6: 499-504, 1995. [PubMed: 8589517] [Full Text: https://doi.org/10.1007/BF00356165]
Kielman, M. F., Smits, R., Bernini, L. F. Localization and characterization of the mouse alpha-globin locus control region. Genomics 21: 431-433, 1994. [PubMed: 8088839] [Full Text: https://doi.org/10.1006/geno.1994.1289]
Kielman, M. F., Smits, R., Devi, T. S., Fodde, R., Bernini, L. F. Homology of a 130-kb region enclosing the alpha-globin gene cluster, the alpha-locus controlling region, and two non-globin genes in human and mouse. Mammalian Genome 4: 314-323, 1993. [PubMed: 8318735] [Full Text: https://doi.org/10.1007/BF00357090]
Lau, A. Y., Scharer, O. D., Samson, L., Verdine, G. L., Ellenberger, T. Crystal structure of a human alkylbase-DNA repair enzyme complexed to DNA: mechanisms for nucleotide flipping and base excision. Cell 95: 249-258, 1998. [PubMed: 9790531] [Full Text: https://doi.org/10.1016/s0092-8674(00)81755-9]
Samson, L., Derfler, B., Boosalis, M., Call, K. Cloning and characterization of a 3-methyladenine DNA glycosylase cDNA from human cells whose gene maps to chromosome 16. Proc. Nat. Acad. Sci. 88: 9127-9131, 1991. [PubMed: 1924375] [Full Text: https://doi.org/10.1073/pnas.88.20.9127]
Vickers, M. A., Vyas, P., Harris, P. C., Simmons, D. L., Higgs, D. R. Structure of the human 3-methyladenine DNA glycosylase gene and localization close to the 16p telomere. Proc. Nat. Acad. Sci. 90: 3437-3441, 1993. [PubMed: 8475094] [Full Text: https://doi.org/10.1073/pnas.90.8.3437]