title: Oxidative stress inactivates the human DNA mismatch repair system.
abstract: In the human DNA mismatch repair (MMR) system, hMSH2 forms the hMutSalpha and hMutSbeta complexes with hMSH6 and hMSH3, respectively, whereas hMLH1 and hPMS2 form the hMutLalpha 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 H2O2 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 hMutSalpha, hMutSbeta, and hMutLalpha 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.
authors.affiliation: Department of Medicine and Cancer Center; University of California at San Diego, La Jolla, California 92093 - 0688, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Chang
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
authors.forename: Dharam P
authors.initials: DP
authors.lastname: Chauhan
authors.forename: Hannah T
authors.initials: HT
authors.lastname: Ha
authors.forename: Dong K
authors.initials: DK
authors.lastname: Chang
authors.forename: Luigi
authors.initials: L
authors.lastname: Ricciardiello
authors.forename: Ann
authors.initials: A
authors.lastname: Randolph
authors.forename: John M
authors.initials: JM
authors.lastname: Carethers
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D000818:Animals; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D045643:DNA Repair Enzymes; D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017353:Gene Deletion; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007313:Insecta; D000070976:Mismatch Repair Endonuclease PMS2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins / Q000187:drug effects / Q000502:physiology; D009687:Nuclear Proteins; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D002352:Carrier Proteins; D045643:DNA Repair Enzymes; D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D006861:Hydrogen Peroxide; D000070976:Mismatch Repair Endonuclease PMS2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016877:Oxidants; D011518:Proto-Oncogene Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C078444:MSH3 protein, human; C094934:PMS2 protein, human; C497172:MSH2 protein, human; C421109:multidrug resistance-associated protein 1