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Molecular clues to alkylating agent‐induced cell death and drug resistance

O6‐methyl‐guanine (O6‐meG) is the major carcinogenic lesion in DNA induced by methylating agents. This DNA adduct can be recognized and processed by both the mismatch repair (MMR) system and the repair protein, O6‐methylguanine methyltransferase (MGMT), also called alkylguanine alkyltransferase (AGT). While the processing of O6‐meG by AGT is to remove the methyl group from O6‐meG, the recognition by MMR recognition proteins, MutSα and MutSβ, initiates a signaling cascade to induce programmed cell death. Although both systems play important roles in maintaining genome stability, they appear to cause an opposite outcome in cancer chemoherapy, i.e., apoptosis mediated by the MMR system and drug‐resistance induced by AGT. However, little is known how these two systems partition O6meG adducts in vivo. Using gel‐shift analysis, we determined specific binding affinities of MutSα, MutSβ, and AGT for DNA duplexes containing an O6‐meG adduct. We demonstrate here that under the equal molar condition, the order of binding affinities for these proteins is: MutSβ > AGT > MutSα. These results were confirmed by competitive binding assays. Our data therefore provide useful molecular insights into the mechanism by which alkylating agents induce cell death or drug resistance.