Oxidative stress inactivates the human DNA mismatch repair system

1 Department of Medicine and Cancer Center; University of California at San Diego, La Jolla, California 92093 - 0688; and 2 Institute of Medical Radiobiology, University of Zürich, 8008 Zürich, Switzerland In the human DNA mismatch repair (MMR) system, hMSH2 forms the hMutS and hMutS complexes with hMSH6 and hMSH3, respectively, whereas hMLH1 and hPMS2 form the hMutL heterodimer. These complexes, together with other components in the MMR system, correct single-base mismatches and small insertion/deletion loops that occur during DNA replication. Microsatellite instability (MSI) occurs when the loops in DNA microsatellites are not corrected because of a malfunctioning MMR system. Low-frequency MSI (MSI-L) is seen in some chronically inflamed tissues in the absence of genetic inactivation of the MMR system. We hypothesize that oxidative stress associated with chronic inflammation might damage protein components of the MMR system, leading to its functional inactivation. In this study, we demonstrate that noncytotoxic levels of H 2 O 2 inactivate both single-base mismatch and loop repair activities of the MMR system in a dose-dependent fashion. On the basis of in vitro complementation assays using recombinant MMR proteins, we show that this inactivation is most likely due to oxidative damage to hMutS , hMutS , and hMutL protein complexes. We speculate that inactivation of the MMR function in response to oxidative stress may be responsible for the MSI-L seen in nonneoplastic and cancer tissues associated with chronic inflammation. hMutS ; hMutS ; hMutL ; inflammation * C. L. Chang and G. Marra contributed equally to this work.