Targeting OGG1 arrests cancer cell proliferation by inducing replication stress
Visnes, Torkild; Benitez-Buelga, Carlos; Cázares-Körner, Armando; Sanjiv, Kumar; Hanna, Bishoy M F; Mortusewicz, Oliver; Rajagopal, Varshni; Albers, Julian J.; Hagey, Daniel W.; Bekkhus, Tove; Eshtad, Saeed; Baquero, Juan Miguel; Masuyer, Geoffrey; Wallner, Olov; Müller, Sarah; Pham, Therese; Gokturk, Camilla; Rasti, Azita; Suman, Sharda; Torres-Ruiz, Raúl; Sarno, Antonio; Wiita, Elisée; Homan, Evert; Karsten, Stella; Marimuthu, Karthick; Michel, M; Koolmeister, Tobias; Scobie, Martin; Loseva, Olga; Almlöf, Ingrid; Unterlass, Judith Edda; Pettke, Aleksandra; Boström, Johan; Pandey, Monica; Gad, Helge; Herr, Patrick; Jemth, Ann-Sofie; El Andaloussi, Samir; Kalderén, Christina; Rodriguez-Perales, Sandra; Benítez, Javier; Krokan, Hans Einar; Altun, Mikael; Stenmark, Pål; Berglund, Ulrika Warpman; Helleday, Thomas
Peer reviewed, Journal article
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OriginalversjonNucleic Acids Research. 2020, 48 (21), 12234-12251. 10.1093/nar/gkaa1048
Abstract Altered 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.