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

DOI: 10.1126/science.abf8980 DOI Help

Authors: Maurice Michel (Karolinska Institutet) , Carlos Benítez-Buelga (Karolinska Institutet; Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM) , Patricia A. Calvo (Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)) , Bishoy M. F. Hanna (Karolinska Institutet) , Oliver Mortusewicz (Karolinska Institutet) , Geoffrey Masuyer (University of Bath; Stockholm University) , Jonathan Davies (Stockholm University) , Olov Wallner (Karolinska Institutet) , Sanjiv Kumar (KTH Royal Institute of Technology) , Julian J. Albers (Karolinska Institutet) , Sergio Castañeda-Zegarra (Karolinska Institutet; Norwegian University of Science and Technology) , Ann-Sofie Jemth (Karolinska Institutet) , Torkild Visnes (SINTEF Industry) , Ana Sastre-Perona (Hospital La Paz Institute for Health Research (IdiPAZ)) , Akhilesh N. Danda (Karolinska Institutet) , Evert J. Homan (Karolinska Institutet) , Karthick Marimuthu (Karolinska Institutet) , Zhao Zhenjun (Karolinska Institutet) , Celestine N. Chi (Uppsala University) , Antonio Sarno (SINTEF Ocean) , Elisée Wiita (Karolinska Institutet) , Catharina Von Nicolai (Karolinska Institutet) , Anna J. Komor (Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute) , Varshni Rajagopal (Karolinska Institutet) , Sarah Müller (Karolinska Institutet) , Emily C. Hank (Karolinska Institutet) , Marek Varga (Karolinska Institutet) , Emma R. Scaletti (Stockholm University; Lund University) , Monica Pandey (Karolinska Institutet; University of Sheffield) , Stella Karsten (Karolinska Institutet) , Hanne Haslene-Hox (SINTEF Industry) , Simon Loevenich (SINTEF Industry) , Petra Marttila (Karolinska Institutet) , Azita Rasti (Karolinska Institutet) , Kirill Mamonov (Karolinska Institutet) , Florian Ortis (Karolinska Institutet) , Fritz Schömberg (Friedrich Schiller University Jena) , Olga Loseva (Karolinska Institutet) , Josephine Stewart (Karolinska Institutet) , Nicholas D’arcy-Evans (Karolinska Institutet) , Tobias Koolmeister (Karolinska Institutet) , Martin Henriksson (Karolinska Institutet) , Dana Michel (Research Institutes of Sweden – RISE) , Ana De Ory (Stockholm University) , Lucia Acero (Hospital La Paz Institute for Health Research (IdiPAZ)) , Oriol Calvete , Martin Scobie (Karolinska Institutet) , Christian Hertweck (Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute; Friedrich-Schiller-University Jena) , Ivan Vilotijevic (Friedrich Schiller University Jena) , Christina Kalderén (Karolinska Institutet) , Ana Osorio (Spanish National Cancer Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)Research Centre (CNIO);) , Rosario Perona (Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM); Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)) , Alexandra Stolz (Goethe University Frankfurt) , Pal Stenmark (Stockholm University; Lund University) , Ulrika Warpman Berglund (Karolinska Institutet) , Miguel De Vega (Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)) , Thomas Helleday (Karolinska Institutet; University of Sheffield)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 376 , PAGES 1471 - 1476

State: Published (Approved)
Published: June 2022
Diamond Proposal Number(s): 15806 , 21625

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.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 29/06/2022 08:47

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Biochemistry Catalysis Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)