Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
Author: Michel, Maurice; Benitez-Buelga, Carlos; Calvo, Patricia A; Hanna, Bishoy M F; Mortusewicz, Oliver; Masuyer, Geoffrey; Davies, Jonathan; Wallner, Olov; Sanjiv, Kumar; Albers, Julian J; Castaneda-Zegarra, Sergio; Jemth, Ann-Sofie; Visnes, Torkild; Saste-Perona, Ana; Danda, Akhilesh N; Homan, Evert J; Marimuthu, Kartrick; Zhenjun, Zhao; Chi, Celestine N; Sarno, Antonio; Wiita, Elisee; von Nicolai, Catharina; Komor, Anna J; Rajagopal, Varshni; Müller, Sarah; Hank, Emily C; Varga, Marek; Scaletti, Emma R; Pandey, Monica; Karsten, Stella; Haslene-Hox, Hanne; Loevenich, Simon; Marttila, Petra; Rasti, Azita; Mamonov, Kirill; Ortis, Florian; Schömberg, Fritz; Loseva, Olga; Stewart, Josephine; D'Arcy-Evans, Nicholas; Koolmeister, Tobias; Henriksson, Martin; Michel, Dana; de Ory, Ana; Acero, Lucia; Calvete, Oriol; Scobie, Martin; Hertweck, Christian; Vilotijevic, Ivan; Kalderén, Christina; Osorio, Ana; Perona, Rosario; Stolz, Alexandra; Stenmark, Pal; Warpman Berglund, Ulrika; de Vega, Miguel; Helleday, Thomas
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
Abstract
Oxidative DNA damage is recognised by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1), initiating repair. Here, we describe a small molecule (TH10785) that interacts with the Phe319 and Gly42 amino acids of OGG1, increases the enzyme activity 10-fold and generates a novel β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and ageing.
Institution:
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
- Department of Pharmacy and Pharmacology, Centre for Therapeutic Innovation, University of Bath, Bath, UK
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
- Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, Norway
- Department of Biotechnology and Nanomedicine, SINTEF Industry, Trondheim, Norway
- Experimental Therapies and Novel Biomarkers in Cancer, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
- Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- Department of Environment and New Resources, SINTEF Ocean, Trondheim, Norway
- Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Department of Biomolecular Chemistry, Jena, Germany
- Department of Experimental Medical Science, Lund University, Lund, Sweden
- Sheffield Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
- Institute of Organic and Macromolecular Chemistry, Friedrich Schiller University Jena, Jena, Germany
- Chemical Processes and Pharmaceutical Development, Unit Process Chemistry I, Research Institutes of Sweden - RISE, Södertälje, Sweden
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
- Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Institute of Microbiology, Friedrich-Schiller-University Jena, Jena, Germany
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
- Institute of Biochemistry II and Buchmann Institute for Molecular Life Science, Goethe University Frankfurt, Frankfurt, Germany
Citation: Science. 2022 Jun 24;376(6600):1471-1476.
Citation DOI: 10.1126/science.abf8980
Citation PMID: 35737787
Citation ISI: 000819288900045
Publishing journal: Science
Eprint status: Peer Reviewed
Version: Accepted
Issue date: 2022-08-19
Sponsorship:
- European Research Council, TAROX-695376
- Swedish Research Council, 2015-00162, 2018-03406
- Ministry of Science and Innovation, Spain/10.13039/501.100011033
- European Regional Development Fund, BFU2017-83900-P
- Crafoord Foundation, 20190532
- Alfred Osterlund Foundation
- Swedish Pain Relief Foundation
- Swedish Cancer Society, CAN 2018/0658, CAN 2017/716
- Torsten and Ragnar Soderberg Foundation
- Dr. Ake Olsson Foundation for Hematological Research, 2020-00306
- Thomas Helleday Foundation
- NTNU Enabling Technology Programme on Biotechnology
- EMBO Short-Term Fellowship 9005
- FEBS Short-Term Fellowship
- Scandinavian Exchange
- German Research Foundation, 239748522
- Sonderforschungsbereich, 1127
- Leibniz Award
- Norwegian Research Council, 303369
- Karolinska Institutet Research Foundation, 2020-02186
- Lars Hiertas Minne Stiftelse
- Asociacion Espanola Contra Cancer, POSTD20042BENI
- Instituto de Salud Carlos III CP19/00063, PI20/00329, PI19/00640
- European Social Fund
- Innovative Medicines Initiative, 875510
- EU's Horizon 2020 research and innovation program, Marie Sklodowska-Curie, 722729
Rights:
Article is made available in accordance with the publisher's policy and may be subject to copyright law. Please refer to the publisher's site for terms of use.
Publication year: 2022
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