Nuclear translocation of mismatch repair proteins MSH2 and MSH6 as a response of cells to alkylating agents

Mammalian:mismatch repair has been implicated in mismatch correction, the p revention of mutagenesis and cancer, and the induction of genotoxicity and apoptosis.:sere, we show that treatment of cells specifically with agents i nducing O-6-methylguanine in DNA, such as N-methyl-N'-nitro-N-nitrosoguanid ine and N-methyl-N-nitrosourea, elevates the level of MSH2 and MSH6 and inc reases GT mismatch binding activity in the nucleus. This inducible response occurs immediately after alkylation, is long-lasting and dose-dependent, a nd results from translocation of the preformed MutS alpha complex (composed of MSHS and MSH6) from the cytoplasm into the nucleus. It is not caused by an increase in MSH2 gene activity. Cells expressing the DNA repair protein O-6-methylguanine-DNA methyltransferase (MG:MT), thus having the ability t o repair O-6-methylguanine, showed no translocation of MutSa, whereas inhib ition of MGMT by O-6-benzylguanine provoked the translocation. The results demonstrate that O-6-methylguanine lesions are,involved in triggering nucle ar accumulation of MSH2 and MSH6. The finding that treatment of cells with O-6-methylguanine-generating mutagens results in an increase of MutS alpha and GT binding activity in the nucleus:indicates a novel type of genotoxic stress response.