Open AccessTargeting OGG1 arrests cancer cell proliferation by inducing replication stress
Author(s) -
Torkild Visnes,
Carlos BenitézBuelga,
Armando CázaresKörner,
Kumar Sanjiv,
Bishoy Hanna,
Oliver Mortusewicz,
Varshni Rajagopal,
Julian J Albers,
Daniel W. Hagey,
Tove Bekkhus,
Saeed Eshtad,
Juan Miguel Baquero,
Geoffrey Masuyer,
Olov Wallner,
Sarah Müller,
T. M. Pham,
Camilla Göktürk,
Azita Rasti,
Sharda Suman,
Raúl Torres-Ruíz,
Antonio Sarno,
Elisée Wiita,
Evert Homan,
Stella Karsten,
Karthick Marimuthu,
Maurice Michel,
Tobias Koolmeister,
Martin Scobie,
Olga Loseva,
Ingrid Almlöf,
J.E. Unterlass,
Aleksandra Pettke,
Johan Boström,
Monica Pandey,
Helge Gad,
Patrick Herr,
AnnSofie Jemth,
Samir El Andaloussi,
Christina Kaldéren,
Sandra Rodríguez-Perales,
Javier Benı́tez,
Hans E. Krokan,
Mikael Altun,
Pål Stenmark,
Ulrika Warpman Berglund,
Thomas Helleday
Publication year - 2020
Publication title -
nucleic acids research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.008
H-Index - 537
eISSN - 1362-4954
pISSN - 0305-1048
DOI - 10.1093/nar/gkaa1048
Subject(s) - biology , dna glycosylase , dna damage , parp1 , cancer , base excision repair , cancer cell , dna repair , cell growth , cancer research , oncogene , oxidative stress , cell cycle , microbiology and biotechnology , dna , poly adp ribose polymerase , genetics , biochemistry , polymerase
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.