Adaptation to alkylation resistance involves the induction of a DNA glycosylase

Abstract

Cells exposed to low doses of N-methyl-N′-nitro-N-nitroso-guanidine (MNNG) or methyl methanesulphonate (MMS) acquire resistance to both the mutagenic and lethal effects of a challenging dose of the same agents (ref. 1, and ref. 2 for a review). This response, termed adaptation, has been ascribed to the induced synthesis and accumulation of O-6-methyl-guanine (m⁶G) DNA methyltransferase^3,4 which rapidly demethylates the m⁶G residues induced by the challenging dose^3–5. Mutant studies, however, indicate that mutagenic adaptation and killing adaptation are at least partly under different genetic control and may therefore involve the induction of different repair enzymes^6,7. Whereas mutagenic adaptation correlates with the induction of the transferase, the data presented here show that killing adaptation can be ascribed to the induction of a DNA glycosylase. This inducible glycosylase releases the alkylation product 3-methyladenine (m³A) from DNA in vitro as does the constitutive m³A DNA glycosylase previously characterized by Riazuddin and Lindahl⁸. However, the enzymes are encoded by different genes and appear to have different roles in DNA repair in vivo.