6RLW

Structure of the human 8-oxoguanine DNA Glycosylase hOGG1 in complex with inhibitor TH5487

This is a non-PDB format compatible entry.

Summary for 6RLW

• Entry DOI: 10.2210/pdb6rlw/pdb
• Descriptor: N-glycosylase/DNA lyase, 4-(4-bromanyl-2-oxidanylidene-3~{H}-benzimidazol-1-yl)-~{N}-(4-iodophenyl)piperidine-1-carboxamide (3 entities in total)
• Functional Keywords: dna repair, cancer, small molecule inhibitor, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 5
• Total formula weight: 192315.30

Authors

Masuyer, G.,Stenmark, P. (deposition date: 2019-05-03, release date: 2020-07-22, Last modification date: 2024-01-24)

Primary citation

Visnes, T.,Benitez-Buelga, C.,Cazares-Korner, A.,Sanjiv, K.,Hanna, B.M.F.,Mortusewicz, O.,Rajagopal, V.,Albers, J.J.,Hagey, D.W.,Bekkhus, T.,Eshtad, S.,Baquero, J.M.,Masuyer, G.,Wallner, O.,Muller, S.,Pham, T.,Gokturk, C.,Rasti, A.,Suman, S.,Torres-Ruiz, R.,Sarno, A.,Wiita, E.,Homan, E.J.,Karsten, S.,Marimuthu, K.,Michel, M.,Koolmeister, T.,Scobie, M.,Loseva, O.,Almlof, I.,Unterlass, J.E.,Pettke, A.,Bostrom, J.,Pandey, M.,Gad, H.,Herr, P.,Jemth, A.S.,El Andaloussi, S.,Kalderen, C.,Rodriguez-Perales, S.,Benitez, J.,Krokan, H.E.,Altun, M.,Stenmark, P.,Berglund, U.W.,Helleday, T.
Targeting OGG1 arrests cancer cell proliferation by inducing replication stress.
Nucleic Acids Res., 48:12234-12251, 2020

PubMed 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.

PubMed: 33211885
DOI: 10.1093/nar/gkaa1048

Experimental method

X-RAY DIFFRACTION (2 Å)