2. Academic Validation
  3. Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

  • Science. 2022 Jun 24;376(6600):1471-1476. doi: 10.1126/science.abf8980.
Maurice Michel  # 1,  Carlos Benítez-Buelga  # 1 2,  Patricia A Calvo  # 3,  Bishoy M F Hanna  # 1,  Oliver Mortusewicz  # 1,  Geoffrey Masuyer  # 4 5,  Jonathan Davies  # 5,  Olov Wallner  # 1,  Kumar Sanjiv  # 1,  Julian J Albers 1,  Sergio Castañeda-Zegarra 1 6,  Ann-Sofie Jemth 1,  Torkild Visnes 7,  Ana Sastre-Perona 8,  Akhilesh N Danda 1,  Evert J Homan 1,  Karthick Marimuthu 1,  Zhao Zhenjun 1,  Celestine N Chi 9,  Antonio Sarno 10,  Elisée Wiita 1,  Catharina von Nicolai 1,  Anna J Komor 11,  Varshni Rajagopal 1,  Sarah Müller 1,  Emily C Hank 1,  Marek Varga 1,  Emma R Scaletti 5 12,  Monica Pandey 1 13,  Stella Karsten 1,  Hanne Haslene-Hox 7,  Simon Loevenich 7,  Petra Marttila 1,  Azita Rasti 1,  Kirill Mamonov 1,  Florian Ortis 1,  Fritz Schömberg 14,  Olga Loseva 1,  Josephine Stewart 1,  Nicholas D'Arcy-Evans 1,  Tobias Koolmeister 1,  Martin Henriksson 1,  Dana Michel 15,  Ana de Ory 16,  Lucia Acero 8,  Oriol Calvete 17,  Martin Scobie 1,  Christian Hertweck 11 18,  Ivan Vilotijevic 14,  Christina Kalderén 1,  Ana Osorio 17 19,  Rosario Perona 2 19,  Alexandra Stolz 20,  Pål Stenmark 5 12,  Ulrika Warpman Berglund 1,  Miguel de Vega 3,  Thomas Helleday 1 13
Affiliations

Affiliations

  • 1 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
  • 2 Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), 28029 Madrid, Spain.
  • 3 Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28049 Madrid, Spain.
  • 4 Department of Pharmacy and Pharmacology, Centre for Therapeutic Innovation, University of Bath, Bath BA2 7AY, UK.
  • 5 Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden.
  • 6 Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway.
  • 7 Department of Biotechnology and Nanomedicine, SINTEF Industry, N-7465 Trondheim, Norway.
  • 8 Experimental Therapies and Novel Biomarkers in Cancer, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
  • 9 Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
  • 10 Department of Environment and New Resources, SINTEF Ocean, N-7496 Trondheim, Norway.
  • 11 Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Department of Biomolecular Chemistry, 07745 Jena, Germany.
  • 12 Department of Experimental Medical Science, Lund University, Lund, Sweden.
  • 13 Sheffield Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK.
  • 14 Institute of Organic and Macromolecular Chemistry, Friedrich Schiller University Jena, 07743 Jena, Germany.
  • 15 Chemical Processes and Pharmaceutical Development, Unit Process Chemistry I, Research Institutes of Sweden - RISE, 151 36 Södertälje, Sweden.
  • 16 Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden.
  • 17 Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
  • 18 Institute of Microbiology, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
  • 19 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • 20 Institute of Biochemistry II and Buchmann Institute for Molecular Life Science, Goethe University Frankfurt, 60590 Frankfurt, Germany.
  • # Contributed equally.
PMID: 35737787 DOI: 10.1126/science.abf8980
Abstract

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 Amino acids of OGG1, increases the Enzyme activity 10-fold, and generates a previously undescribed 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 aging.

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