Oxidative stress inactivates the human DNA mismatch repair system

In the human DNA mismatch repair(MMR) system, hMSH2 forms the hMutS and hMutS complexes withhMSH6 and hMSH3, respectively, whereas hMLH1 and hPMS2 form thehMutL heterodimer. These complexes, together with other componentsin the MMR system, correct single-base mismatches and smallinsertion/deletion loops that occur during DNA replication.Microsatellite instability (MSI) occurs when the loops in DNAmicrosatellites are not corrected because of a malfunctioning MMRsystem. Low-frequency MSI (MSI-L) is seen in some chronicallyinflamed tissues in the absence of genetic inactivation of the MMRsystem. We hypothesize that oxidative stress associated with chronicinflammation might damage protein components of the MMR system, leadingto its functional inactivation. In this study, we demonstrate thatnoncytotoxic levels of H₂O₂ inactivate bothsingle-base mismatch and loop repair activities of the MMR system in adose-dependent fashion. On the basis of in vitro complementation assaysusing recombinant MMR proteins, we show that this inactivation is mostlikely due to oxidative damage to hMutS, hMutS, and hMutLprotein complexes. We speculate that inactivation of the MMR functionin response to oxidative stress may be responsible for the MSI-L seenin nonneoplastic and cancer tissues associated with chronic inflammation.