© 1993 Oxford University Press
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Cloning and characterization of a mouse 3-methyladenine/7-methl-guanine/-methylguanine DNA glycosylase cDNA whose gene maps to chromosme 11
Department of Molecular and Cellular Toxiclogy,Havarad Scholl of Public Health, 665 Huntington Avenue, Boston, MA 02115
1Department of Molecular Genetics University fo Texas M.D.Anderson Cancer Center, Houston, TX 77030, USA
2To whom correspondence should be addressed
In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions by DNA glycosylases prevents alkylation induced cell death. We described previously the isolation of a human 3MeA DNA glycosylase (AAG) cDNA that maps to chromosome 16 and hybridizes to specific genomic DNA fragments from a number of mammals, including mouse. As first stemp in the generation of a 3MeA DNA glycosylase deficient mouse by homlogous replacement in embryonic stem cells, we have cloned the mouse 3MeA DNA glycosylase cDNA. The cloned 1095 base pair cDNA contains a complete 333 amino acid open reading frame that predicts a 36.5 KDa protein and hybridizes to a 1.5 kb mRNA transcript. Mouse 3MeA DNA glycoslase (Aag) transcript levels vary by up to 21 fold among tissues, being highest in the testes and lowest in the heart. The Aag cDNA encodes a glycosylase able to release 3MeA, 7-methlguanine (7MeG) and 3-methlgunanine (3MeG) form alkylated DNA. The expression fo Aag in E.coli provides substantial resistance against killing by methylating agents,but, unlike it E.coli counterparts, the Aag glycoslase fails to protect against killing by ethylating and prpylating agents. A 232 amino acid stretch of the predicted mouse prtein shares extensive amino acid identity with rat (93%) and human (83%) 3MeA DNA glycosylases and we observe that all three mammalian glycosylases have a bipartite nuclear localization signal. The Aag gene maps to mouse chromosome 11, suggesting a segment of conserved syntenty between mouse chromosome 11 and human chromosome 16, which bears the human 3MeA DNA glcosylase gene. Cloning the mouse 3MeA DNA glcsylase cDNA is a step toward understanding the role of this DNA repair enzyme in mammals.
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