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

Maurice Michel, Carlos Benítez-Buelga, Patricia A. Calvo, Bishoy M.F. Hanna, Oliver Mortusewicz, Geoffrey Masuyer, Jonathan Davies, Olov Wallner, Kumar Sanjiv, Julian J. Albers, Sergio Castañeda-Zegarra, Ann Sofie Jemth, Torkild Visnes, Ana Sastre-Perona, Akhilesh N. Danda, Evert J. Homan, Karthick Marimuthu, Zhao Zhenjun, Celestine N. Chi, Antonio SarnoElisée Wiita, Catharina von Nicolai, Anna J. Komor, Varshni Rajagopal, Sarah Müller, Emily C. Hank, Marek Varga, Emma R. Scaletti, Monica Pandey, Stella Karsten, Hanne Haslene-Hox, Simon Loevenich, Petra Marttila, Azita Rasti, Kirill Mamonov, Florian Ortis, Fritz Schömberg, Olga Loseva, Josephine Stewart, Nicholas D'Arcy-Evans, Tobias Koolmeister, Martin Henriksson, Dana Michel, Ana de Ory, Lucia Acero, Oriol Calvete, Martin Scobie, Christian Hertweck, Ivan Vilotijevic, Christina Kalderén, Ana Osorio, Rosario Perona, Alexandra Stolz, Pål Stenmark, Ulrika Warpman Berglund, Miguel de Vega, Thomas Helleday

Research output: Contribution to journalArticlepeer-review

20 Citations (SciVal)

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 b,d-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.

Original languageEnglish
Pages (from-to)1471-1476
Number of pages6
JournalScience
Volume376
Issue number6600
Early online date24 Jun 2022
DOIs
Publication statusPublished - 24 Jun 2022

Bibliographical note

Funding Information:
We thank J. E. Unterlass, M. Kullman Magnusson, L. Sjöholm, T. Pham, S. Demir, A. Pliakou, T. Sandvall, K. Edfeldt, and M. Sundström for support and discussions. We thank the scientists at stations I04 and I04-1 of the Diamond Light Source, Didcot, Oxfordshire (UK), for their support during data collection (allocations MX15806 and MX21625). This work was supported by European Research Council grant TAROX-695376 (T.H.); Swedish Research Council grant 2015-00162 (T.H.); Swedish Research Council grant 2018-03406 (P.S.); Ministry of Science and Innovation, Spain/State Research Agency, Spain/10.13039/501.100011033 and “ERDF A way to make Europe” grant BFU2017-83900-P (M.d.V.); Crafoord Foundation grant 20190532 (P.S.); an Alfred Österlund Foundation grant (P.S.); a Swedish Pain Relief Foundation grant (T.H.); Swedish Cancer Society grant CAN2018/0658 (T.H.); Swedish Cancer Society grant CAN 2017/716 (P.S.); a Torsten and Ragnar Söderberg foundation grant (T.H.); Dr. Åke-Olsson Foundation for Hematological Research grant 2020-00306 (M.M.); the Thomas Helleday Foundation for medical research postdoctoral stipends (M.M. and C.B.-B.); the NTNU Enabling Technology Programme on Biotechnology to Valentyn Oksenych (S.C.-Z.); EMBO Short-Term Fellowship 9005 (S.C.-Z.); a FEBS Short-Term Fellowship (S.C.-Z.); SSI Grants for Scandinavian Exchange (S.C.-Z.); German Research Foundation (DFG) 239748522 (A.J.K. and C.H.); Sonderforschungsbereich (SFB) 1127 (A.J.K. and C.H.); The Leibniz Award (C.H.); Norwegian Research Council grant 303369 (T.V.); Karolinska Institutet Research Foundation grant 2020-02186 (M.M.); a Lars Hiertas Minne Stiftelse grant (M.M.); and Asociacion Española Contra Cancer grant Postdoctoral AECC 2020, NºPOSTD20042BENI (C.B.-B.). This study was funded by “Instituto de Salud Carlos III CP19/00063 and PI20/00329” and cofunded by European Social Fund “Investigating in your future” and “European Regional Development Fund” (A.S.-P.). CNIO studies are partially funded by Instituto de Salud Carlos III, project reference PI19/00640, and cofounded by the European Regional Development Fund (ERDF), “A way to make Europe” (A.O.). This project received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 875510 (M.M., E.J.H., E.W., and A.St.). This work received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 722729 (T.H. and B.M.F.H.).

ASJC Scopus subject areas

  • General

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