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Oxidative DNA damage contributes to aging and the pathogenesis of numerous human diseases including cancer. 8-hydroxyguanine (8-oxoG) is the major product of oxidative DNA lesions. Although OGG1-mediated base excision repair is the primary mechanism for 8-oxoG removal, DNA mismatch repair has also been implicated in processing oxidative DNA damage. However, the mechanism of the latter is not fully understood. Here, we treated human cells defective in various 8-oxoG repair factors with H2O2 and performed biochemical, live cell imaging, and chromatin immunoprecipitation sequencing analyses to determine their response to the treatment. We show that the mismatch repair processing of oxidative DNA damage involves cohesive interactions between mismatch recognition protein MutSα, histone mark H3K36me3, and H3K36 trimethyltransferase SETD2, which activates the ATM DNA damage signaling pathway. We found that cells depleted of MutSα or SETD2 accumulate 8-oxoG adducts and fail to trigger H2O2-induced ATM activation. Furthermore, we show that SETD2 physically interacts with both MutSα and ATM, which suggests a role for SETD2 in transducing DNA damage signals from lesion-bound MutSα to ATM. Consistently, MutSα and SETD2 are highly coenriched at oxidative damage sites. The data presented here support a model wherein MutSα, SETD2, ATM, and H3K36me3 constitute a positive feedback loop to help cells cope with oxidative DNA damage. Oxidative DNA damage contributes to aging and the pathogenesis of numerous human diseases including cancer. 8-hydroxyguanine (8-oxoG) is the major product of oxidative DNA lesions. Although OGG1-mediated base excision repair is the primary mechanism for 8-oxoG removal, DNA mismatch repair has also been implicated in processing oxidative DNA damage. However, the mechanism of the latter is not fully understood. Here, we treated human cells defective in various 8-oxoG repair factors with H2O2 and performed biochemical, live cell imaging, and chromatin immunoprecipitation sequencing analyses to determine their response to the treatment. We show that the mismatch repair processing of oxidative DNA damage involves cohesive interactions between mismatch recognition protein MutSα, histone mark H3K36me3, and H3K36 trimethyltransferase SETD2, which activates the ATM DNA damage signaling pathway. We found that cells depleted of MutSα or SETD2 accumulate 8-oxoG adducts and fail to trigger H2O2-induced ATM activation. Furthermore, we show that SETD2 physically interacts with both MutSα and ATM, which suggests a role for SETD2 in transducing DNA damage signals from lesion-bound MutSα to ATM. Consistently, MutSα and SETD2 are highly coenriched at oxidative damage sites. The data presented here support a model wherein MutSα, SETD2, ATM, and H3K36me3 constitute a positive feedback loop to help cells cope with oxidative DNA damage. Exposure to ionizing radiation or reactive oxygen species (ROS) results in oxidative stress and the formation of large amounts of oxidative DNA lesion 7,8-dihydro-8-oxoguanine (8-oxoG) (1Aruoma O.I. Halliwell B. Dizdaroglu M. Iron ion-dependent modification of bases in DNA by the superoxide radical-generating system hypoxanthine/xanthine oxidase.J. Biol. Chem. 1989; 264: 13024-13028Abstract Full Text PDF PubMed Google Scholar, 2Friedberg E.C. Walker G.C. Siede W. Wood R.D. Schultz R.A. Ellenberger T. DNA Repair and Mutagenesis. ASM Press, Washington, DC2006Google Scholar), which contributes to aging and can lead to human diseases like cancer and neurological disorders (3Klaunig J.E. Kamendulis L.M. The role of oxidative stress in carcinogenesis.Annu. Rev. Pharmacol. 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The mismatch recognition protein MutSα, a key MMR factor consisting of the MSH2 and MSH6 subunits, identifies mismatches and recruits downstream factors to trigger mismatch-provoked incision and exonuclease 1-catalyzed mismatch removal, followed by DNA polymerase δ–conducted DNA repair synthesis (20Ortega J. Lee G.S. Gu L. Yang W. Li G.M. Mispair-bound human MutS-MutL complex triggers DNA incisions and activates mismatch repair.Cell Res. 2021; 31: 542-553Crossref PubMed Scopus (7) Google Scholar, 21Zhang Y. Yuan F. Presnell S.R. K. Y. et of human mismatch repair in a Full Text Full Text PDF PubMed Scopus Google Scholar). However, in MMR in human cells histone F. G. D. J. Gu L. Yang W. et al.The histone mark H3K36me3 human DNA mismatch repair with 2013; Full Text Full Text PDF PubMed Scopus Google Scholar), an histone mark that is highly in and Y. Gu L. Li G.M. mismatch repair from Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). 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ATM has been to as an of in human as a large of protein in response to oxidative stress Z. S. M.F. T.T. ATM by oxidative PubMed Scopus Google Scholar). We that ATM is of the signaling pathway in response to oxidative DNA damage. In we to H2O2 in cells with various MMR We show that cells depleted of MutSα, SETD2, or H3K36me3 accumulate 8-oxoG adducts and are to H2O2 than MutSα, SETD2, and ATM with other to oxidative DNA damage. SETD2 interacts with both MutSα and ATM H2O2 MutSα and SETD2 are highly coenriched in and both are for the ATM signaling pathway. data presented here support a model MutSα, SETD2, ATM, and H3K36me3 constitute a positive feedback loop to cope with oxidative DNA damage. determine MMR with oxidative DNA we treated cells with 1 of H2O2 for a that rate in We the MutSα in the chromatin of cells treated with or Although the protein of MutSα between and cells the the of MutSα higher in treated cells than in cells and We performed to MutSα to chromatin by The results show that H2O2 the of both H3K36me3 and MSH6 which the of H3K36me3 and MSH6 and results that H2O2 the of H3K36me3, which in recruits MutSα to as F. G. D. J. Gu L. Yang W. et al.The histone mark H3K36me3 human DNA mismatch repair with 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). an MSH2 as MSH6 and H3K36me3 in cells than in with the MSH2 in that oxidative DNA damage the of H3K36me3, MutSα to and ATM been implicated in DNA damage signaling in response to agents L. P. M. S. G. et by of agents the Dev. 2004; 18: PubMed Scopus Google Scholar, K. Y. P. by and in response to Cell. 2006; Full Text Full Text PDF PubMed Scopus Google and ionizing radiation A. R. et al.The mismatch repair system is required for Genet. PubMed Scopus Google Scholar), determine ATM or is in oxidative we the of at H2O2 treatment. We ATM H2O2 but of which suggests that ATM, but not in oxidative with ATM we the of a downstream of the ATM However, is not downstream is which is to the but with between the ATM and A. L. DNA damage by the ATM and Biol. 2013; PubMed Scopus Google or an protein Y. T. of in cell and cancer J. PubMed Scopus Google Scholar). that H2O2-induced is ATM but not we the of protein in cells treated with or ATM Y. et and of a and of the Res. 2004; 64: PubMed Scopus Google Scholar). We found that H2O2-induced ATM by but the of of H2O2 determine the role of MutSα in H2O2-induced ATM we or SETD2 in cells and the and for ATM signaling in response to H2O2 treatment. The results that of the cells of ATM than and the also for The in ATM and in cells significant MMR in cells also their H2O2-induced ATM MSH2 of the in cells higher of and results that H2O2-induced ATM signaling determine the between MutSα, SETD2, and ATM in the response to oxidative stress, we an to 8-oxoG in cells with or SETD2, or ATM H2O2 treatment. We the oxidative response the primary responsible for 8-oxoG removal (2Friedberg E.C. Walker G.C. Siede W. Wood R.D. Schultz R.A. Ellenberger T. DNA Repair and Mutagenesis. ASM Press, Washington, DC2006Google Scholar, 8David S.S. O'Shea V.L. Kundu S. Base-excision repair of oxidative DNA damage.Nature. 2007; 447: 941-950Crossref PubMed Scopus (855) Google Scholar). cells treated with an a higher 8-oxoG than cells and 1 and The performed in cells that are in but depleted of or ATM. The results that MSH2 cells higher of 8-oxoG adducts than cells and 1 and which is with the that MMR 8-oxoG in an C. Parlanti E. Degan P. Aquilina G. Barnes D. Macpherson P. et al.The mammalian mismatch repair pathway removes DNA 8-oxodGMP incorporated from the oxidized dNTP pool.Curr. Biol. 2002; 12: 912-918Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). The results also in cells and 1 and which that SETD2 is in 8-oxoG SETD2 is responsible for the of H3K36me3 to MutSα to chromatin F. G. D. J. Gu L. Yang W. et al.The histone mark H3K36me3 human DNA mismatch repair with 2013; Full Text Full Text PDF PubMed Scopus Google Scholar), role in processing 8-oxoG the MMR pathway. we 8-oxoG in cells in the of an for the ATM Y. et and of a and of the Res. 2004; 64: PubMed Scopus Google Scholar), and found like and cells treated with a higher 8-oxoG than cells 1 and we not a in 8-oxoG or cells treated with and with with suggests that MutSα, SETD2, and ATM oxidative DNA damage in the pathway. we also not an in 8-oxoG in or cells treated with the and and and is to that or cells of oxidative DNA damage not the and the data in and in is known in response to DNA is by the DNA repair to DNA DNA damage is the cell E.C. DNA damage and PubMed Scopus Google Scholar, J. between the and repair of DNA 2002; PubMed Scopus Google Scholar). the of MMR cell in response to oxidative stress in the of we treated or cells with H2O2 for and in for for cell to determine cell The results that of MMR or their However, H2O2 cell in and and cell to H2O2 results that MMR processing of oxidative DNA damage is for and cell is that or cells additional to H2O2 is as with cells the is known that cells are to as and agents than cells G.M. The role of mismatch repair in DNA damage-induced apoptosis.Oncol. Res. 1999; 11: 393-400PubMed Google Scholar, D. S. The role of DNA mismatch repair in Res. 4: Google Scholar). is the MMR system and the DNA lesions the repair the DNA adducts in the DNA trigger the MMR which the for mismatch repair G.M. The role of mismatch repair in DNA damage-induced apoptosis.Oncol. Res. 1999; 11: 393-400PubMed Google Scholar, D. The mismatch DNA damage and Repair. PubMed Scopus Google Scholar). However, cells fail to the repair to the DNA lesions. numerous chemical is that of the of cells during H2O2 treatment. The repair also there is in the cell rate between and cells treated with H2O2 in the of the as 8-oxoG adducts can in but not in the in cells their the cells is the The to that MutSα, SETD2, and ATM with other in response to oxidative DNA damage. we generated SETD2 including the which is the responsible for H3K36 We the SETD2 to ATM and MutSα in cell MSH6 and ATM with the of SETD2 In both a with that both MutSα and ATM physically with SETD2 the SETD2 We to interactions with MutSα and ATM. However, of a SETD2 we to and SETD2 in we the for the in the of SETD2 The cells by DNA sequencing and to determine interactions by The results that both MSH6 and ATM with SETD2 in cell from cells but not in from cells a for H2O2 in SETD2 interactions with MutSα and ATM determine the of the and interactions response to oxidative stress, we the in cells and the interactions and ATM by H2O2 treatment. MSH6 and ATM in cells the of H2O2 and which suggests that SETD2 interacts with MutSα and ATM with the that H2O2 activates ATM in a we ATM in and cells 1 and results that SETD2 a complex with MutSα and ATM, which a role in signaling in response to oxidative that H3K36me3 and MutSα are in chromatin F. G. D. J. Gu L. Yang W. et al.The histone mark H3K36me3 human DNA mismatch repair with 2013; Full Text Full Text PDF PubMed Scopus Google and are highly in Y. Gu L. Li G.M. mismatch repair from Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Li G.M. DNA mismatch repair Repair. PubMed Scopus Google Scholar). The between MutSα and SETD2 to that MutSα, H3K36me3, and SETD2 are coenriched in chromatin in response to oxidative DNA damage. We performed chromatin immunoprecipitation with DNA sequencing to determine the chromatin and in the of SETD2, and H3K36me3 in cells treated with We found that there MSH6 in cells than in cells which with the and results in The SETD2 a that H2O2 the of SETD2 in chromatin in treated cells with the physical between MutSα and SETD2, we between MSH6 and SETD2, for and of MSH6 and SETD2 in the In MSH6 and SETD2 to at H2O2 which suggests that and physically at H2O2 also the of H3K36me3 However, with MSH6 and SETD2, we found the H3K36me3 downstream of The for is in the of oxidative the MutSα from H3K36me3 and to a 8-oxoG at which the H3K36me3 mark to a of the MutSα interacts with SETD2, which not recruits ATM to activate DNA damage signaling but also downstream a both the MutSα and SETD2 at but the H3K36me3 downstream of the is also by the that MutSα is highly chromatin in response to H2O2 Although oxidative DNA lesions are by OGG1-mediated base excision MMR an role in processing oxidative DNA damage. However, the mechanism of the latter is not fully understood. In we show that processing of oxidative DNA lesions is a cohesive MutSα, SETD2, H3K36me3, and ATM, which a positive feedback loop during the response to oxidative the that the of H3K36me3, which recruits various DNA repair to SETD2 DNA repair including MMR F. G. D. J. Gu L. Yang W. et al.The histone mark H3K36me3 human DNA mismatch repair with 2013; Full Text Full Text PDF PubMed Scopus Google and repair S. et is required for DNA repair and of the PubMed Scopus Google Scholar, F. B. E. P. S. et chromatin recruits at DNA Biol. PubMed Scopus Google Scholar, S. S. F. et histone H3K36 is required for repair and Full Text Full Text PDF PubMed Scopus Google Scholar). In we show that the response to oxidative DNA damage with cells depleted of SETD2 accumulate 8-oxoG and are to H2O2 than cells also in cells and C. Parlanti E. Degan P. Aquilina G. Barnes D. Macpherson P. et al.The mammalian mismatch repair pathway removes DNA 8-oxodGMP incorporated from the oxidized dNTP pool.Curr. Biol. 2002; 12: 912-918Abstract Full Text Full Text PDF PubMed Scopus (185) Google like MutSα, SETD2 of by H2O2 MutSα and SETD2 are coenriched in SETD2 physically interacts with both MutSα and ATM that the processing of oxidative lesions involves cohesive interactions MutSα, SETD2, H3K36me3, and ATM. MutSα, SETD2, and H3K36me3, other for their MutSα H3K36me3 F. G. D. J. Gu L. Yang W. et al.The histone mark H3K36me3 human DNA mismatch repair with 2013; Full Text Full Text PDF PubMed Scopus Google Scholar), which is the product of SETD2 L.C. histone during H3K36 J. 2008; PubMed Scopus Google Scholar). is interactions occur and which factor The data presented in to an for We found in response to H2O2 MSH6 and SETD2 are coenriched in oxidative DNA but the H2O2-induced in H3K36me3 signals is downstream of results that H2O2-induced of MSH6 and SETD2 at the damage has to with the H2O2-induced MutSα 8-oxoG A. Berardini M. Fishel R. Activation of human MutS homologs by 8-oxo-guanine DNA damage.J. Biol. Chem. 2002; 277: 8260-8266Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 12Ni T.T. Marsischky G.T. Kolodner R.D. MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S. cerevisiae.Mol. Cell. 1999; 4: 439-444Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar), we that the oxidative response with the of 8-oxoG lesions by MutSα, which recruits SETD2 to the damage to activate the ATM signaling pathway. data and the results presented we a model for the oxidative response In the of oxidative DNA lesions as MutSα by H3K36me3 to 8-oxoG which the H3K36me3 to additional MutSα to which to of MutSα at damage sites. The MutSα interacts with SETD2, which in recruits ATM, the ATM signaling pathway to cope with oxidative DNA lesions. The SETD2 by MutSα the of downstream which the of H3K36me3 downstream of H3K36me3 can MutSα and other DNA factors to the oxidative stress response involves a positive feedback feedback loop with MutSα a followed by SETD2 to ATM and which MutSα chromatin for lesion recognition to feedback However, are required to cells in and cells in at with cells the and in The to and cell and in cells B. J. H. J. K. Li Z. et of Res. 2013; PubMed Scopus Google Scholar). with and and by DNA cells treated with H2O2 for and treated cells to in for or The human MutSα protein and as Y. Yuan F. Presnell S.R. K. Y. et of human mismatch repair in a Full Text Full Text PDF PubMed Scopus Google Scholar). The human SETD2 the in and as a as J. Y. G. Yang S. G. Gu L. et mutations H3K36 and S. A. PubMed Scopus Google Scholar). The to and ATM and treated with or H2O2 with and 1 for and by in for at cells with at with for for 1 at 8-oxoG cells for with and for with with cells with in and for 1 at followed by with and and for DNA in with in for and with and and for treated with for at to with for 1 at cells with an at a of in and at in a with with a and with by and with of chromatin performed as repair DNA 1 to of oxidative DNA damage.J. Biol. 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