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The long-patch mismatch repair pathway contributes to the cytotoxic effect of methylating agents and loss of this pathway confers tolerance to DNA methylation damage. Two methylation-tolerant mouse cell lines were identified and were shown to be defective in the MSH2 protein by  in vitro  mismatch repair assay. A normal copy of the human  MSH2  gene, introduced by transfer of human chromosome 2, reversed the methylation tolerance. These mismatch repair defective mouse cells together with a fibroblast cell line derived from an  MSH2  –/–  mouse, were all as resistant to  N -methyl- N -nitrosourea as repair-defective human cells. Although long-patch mismatch repair-defective human cells were 50- to 100-fold more resistant to methylating agents than repair-proficient cells, loss of the same pathway from mouse cells conferred only a 3-fold increase. This discrepancy was accounted for by the intrinsic  N -methyl- N -nitrosourea resistance of normal or transformed mouse cells compared with human cells. The &gt;20-fold differential resistance between mouse and human cells could not be explained by the levels of either DNA methylation damage or the repair enzyme  O  6 -methylguanine–DNA methyltransferase. The resistance of mouse cells to  N -methyl- N -nitrosourea was selective and no cross-resistance to unrelated DNA damaging agents was observed. Pathways of apoptosis were apparently intact and functional after exposure to either  N -methyl- N -nitrosourea or ultraviolet light. Extracts of mouse cells were found to perform 2-fold less long-patch mismatch repair. The reduced level of mismatch repair may contribute to their lack of sensitivity to DNA methylation damage.

Mismatch repair and differential sensitivity of mouse and human cells to methylating agents