Visnes, TorkildBenítez-Buelga, CarlosCázares-Körner, ArmandoSanjiv, KumarHanna, Bishoy M FMortusewicz, OliverRajagopal, VarshniAlbers, Julian JHagey, Daniel WBekkhus, ToveEshtad, SaeedBaquero, Juan MiguelMasuyer, GeoffreyWallner, OlovMüller, SarahPham, ThereseGöktürk, CamillaRasti, AzitaSuman, ShardaRaul, Torres-RuizSarno, AntonioWiita, EliséeHoman, Evert JKarsten, StellaMarimuthu, KarthickMichel, MauriceKoolmeister, TobiasScobie, MartinLoseva, OlgaAlmlöf, IngridUnterlass, Judith EddaPettke, AleksandraBoström, JohanPandey, MonicaGad, HelgeHerr, PatrickJemth, Ann-SofieEl Andaloussi, SamirKalderén, ChristinaRodriguez-Perales, SandraBenítez, JavierKrokan, Hans EAltun, MikaelStenmark, PålBerglund, Ulrika WarpmanHelleday, ThomasRodriguez Perales, SandraEl Andaloussi, Samir2021-03-162021-03-162020Nucleic Acids Res . 2020 ;48(21):12234-12251.0305-1048http://hdl.handle.net/20.500.12105/12279Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/Gene Expression Regulation, NeoplasticAnimalsAntineoplastic AgentsCell Line, TumorCell ProliferationColonic NeoplasmsDNA DamageDNA GlycosylasesDNA RepairDNA ReplicationDNA, NeoplasmEnzyme InhibitorsGuanineHCT116 CellsHumansMiceMice, NudeMolecular Targeted TherapyOxidative StressPoly (ADP-Ribose) Polymerase-1RNA, Small InterferingReactive Oxygen SpeciesSignal TransductionSurvival AnalysisTumor BurdenXenograft Model Antitumor AssaysAtribución-NoComercial-CompartirIgual 4.0 Internacional33211885482112234-1225110.1093/nar/gkaa10481362-4962Nucleic acids researchopen access