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Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

DOI: 10.1093/nar/gkaa1048 DOI Help

Authors: Torkild Visnes (Karolinska Institutet; SINTEF Industry) , Carlos Benítez-Buelga (Karolinska Institutet) , Armando Cázares-Körner (Karolinska Institutet) , Kumar Sanjiv (Karolinska Institutet) , Bishoy M. F. Hanna (Karolinska Institutet) , Oliver Mortusewicz (Karolinska Institutet) , Varshni Rajagopal (Karolinska Institutet) , Julian J. Albers (Karolinska Institutet) , Daniel W Hagey (Karolinska Institutet) , Tove Bekkhus (Karolinska Institutet) , Saeed Eshtad (Karolinska Institutet) , Juan Miguel Baquero (Spanish National Cancer Research Centre (CNIO)) , Geoffrey Masuyer (Stockholm University; University of Bath) , Olov Wallner (Karolinska Institutet) , Sarah Müller (Karolinska Institutet) , Therese Pham (Karolinska Institutet) , Camilla Göktürk (Karolinska Institutet) , Azita Rasti (Karolinska Institutet) , Sharda Suman (Karolinska Institutet) , Raúl Torres-Ruiz (Spanish National Cancer Research Centre (CNIO); University of Barcelona) , Antonio Sarno (Norwegian University of Science and Technology; Research and Innovation in Central Norway; SINTEF Ocean) , Elisée Wiita (Karolinska Institutet) , Evert J. Homan (Karolinska Institutet) , Stella Karsten (Karolinska Institutet) , Karthick Marimuthu (Karolinska Institutet) , Maurice Michel (Karolinska Institutet) , Tobias Koolmeister (Karolinska Institutet) , Martin Scobie (Karolinska Institutet) , Olga Loseva (Karolinska Institutet) , Ingrid Almlöf (Karolinska Institutet) , Judith Edda Unterlass (Karolinska Institutet) , Aleksandra Pettke (Karolinska Institutet) , Johan Boström (Karolinska Institutet) , Monica Pandey (University of Sheffield) , Helge Gad (University of Sheffield) , Patrick Herr (University of Sheffield) , Ann-Sofie Jemth (Karolinska Institutet) , Samir El andaloussi (Karolinska Institutet) , Christina Kalderén (Karolinska Institutet) , Sandra Rodriguez-Perales (Spanish National Cancer Research Centre (CNIO)) , Javier Benítez (Spanish National Cancer Research Centre (CNIO); Spanish Network on Rare Diseases (CIBERER)) , Hans E Krokan (Norwegian University of Science and Technology; Research and Innovation in Central Norway) , Mikael Altun (Karolinska Institutet) , Pal Stenmark (Stockholm University; Lund University) , Ulrika Warpman Berglund (Karolinska Institutet) , Thomas Helleday (Karolinska Institutet; University of Sheffield)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nucleic Acids Research , VOL 434

State: Published (Approved)
Published: November 2020
Diamond Proposal Number(s): 15806

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 25/11/2020 13:44


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)