Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-7156
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dc.contributor.authorKnizhnik, Anna V.-
dc.contributor.authorRoos, Wynand Paul-
dc.contributor.authorNikolova, Teodora-
dc.contributor.authorQuiros, Steve-
dc.contributor.authorTomaszowski, Karl-Heinz-
dc.contributor.authorChristmann, Markus-
dc.contributor.authorKaina, Bernd-
dc.date.accessioned2022-06-15T08:43:42Z-
dc.date.available2022-06-15T08:43:42Z-
dc.date.issued2013-
dc.identifier.urihttps://openscience.ub.uni-mainz.de/handle/20.500.12030/7170-
dc.description.abstractApoptosis, autophagy, necrosis and cellular senescence are key responses of cells that were exposed to genotoxicants. The types of DNA damage triggering these responses and their interrelationship are largely unknown. Here we studied these responses in glioma cells treated with the methylating agent temozolomide (TMZ), which is a first-line chemotherapeutic for this malignancy. We show that upon TMZ treatment cells undergo autophagy, senescence and apoptosis in a specific time-dependent manner. Necrosis was only marginally induced. All these effects were completely abrogated in isogenic glioma cells expressing O(6)-methylguanine-DNA methyltransferase (MGMT), indicating that a single type of DNA lesion, O(6)-methylguanine (O(6)MeG), is able to trigger all these responses. Studies with mismatch repair mutants and MSH6, Rad51 and ATM knockdowns revealed that autophagy induced by O(6)MeG requires mismatch repair and ATM, and is counteracted by homologous recombination. We further show that autophagy, which precedes apoptosis, is a survival mechanism as its inhibition greatly ameliorated the level of apoptosis following TMZ at therapeutically relevant doses (<100 microM). Cellular senescence increases with post-exposure time and, similar to autophagy, precedes apoptosis. If autophagy was abrogated, TMZ-induced senescence was reduced. Therefore, we propose that autophagy triggered by O(6)MeG adducts is a survival mechanism that stimulates cells to undergo senescence rather than apoptosis. Overall, the data revealed that a specific DNA adduct, O(6)MeG, has the capability of triggering autophagy, senescence and apoptosis and that the decision between survival and death is determined by the balance of players involved. The data also suggests that inhibition of autophagy may ameliorate the therapeutic outcome of TMZ-based cancer therapy.de_DE
dc.description.sponsorshipDFG, Open Access-Publizieren Universität Mainz / Universitätsmedizinde
dc.language.isoengde
dc.rightsCC BY*
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/*
dc.subject.ddc610 Medizinde_DE
dc.subject.ddc610 Medical sciencesen_GB
dc.titleSurvival and death strategies in glioma cells : autophagy, senescence and apoptosis triggered by a single type of temozolomide-induced DNA damagede_DE
dc.typeZeitschriftenaufsatzde
dc.identifier.doihttp://doi.org/10.25358/openscience-7156-
jgu.type.dinitypearticleen_GB
jgu.type.versionPublished versionde
jgu.type.resourceTextde
jgu.organisation.departmentFB 04 Medizinde
jgu.organisation.number2700-
jgu.organisation.nameJohannes Gutenberg-Universität Mainz-
jgu.rights.accessrightsopenAccess-
jgu.journal.titlePLoS onede
jgu.journal.volume8de
jgu.journal.issue1de
jgu.pages.alternativee55665de
jgu.publisher.year2013-
jgu.publisher.namePLoSde
jgu.publisher.placeLawrence, Kan.de
jgu.publisher.urihttp://dx.doi.org/10.1371/journal.pone.0055665de
jgu.publisher.issn1932-6203de
jgu.organisation.placeMainz-
jgu.identifier.pmid23383259-
jgu.subject.ddccode610de
opus.date.modified2018-07-31T09:57:26Z-
opus.subject.dfgcode00-000-
opus.organisation.stringFB 04: Medizin: Institut für Toxikologiede_DE
opus.identifier.opusid25280-
opus.importsourcepubmed-
opus.institute.number0414-
opus.metadataonlyfalse-
opus.type.contenttypeKeinede_DE
opus.type.contenttypeNoneen_EN
opus.affiliatedRoos, Wynand Paul-
opus.affiliatedNikolova, Teodora-
opus.affiliatedTomaszowski, Karl-Heinz-
opus.affiliatedChristmann, Markus-
opus.affiliatedKaina, Bernd-
jgu.publisher.doi10.1371/journal.pone.0055665de
jgu.organisation.rorhttps://ror.org/023b0x485
Appears in collections:DFG-OA-Publizieren (2012 - 2017)

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