Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function 2022 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 376, no 6600, p. 1471-1476Article in journal (Refereed) Published

Abstract [en]

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. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Place, publisher, year, edition, pages

American Association for the Advancement of Science , 2022. Vol. 376, no 6600, p. 1471-1476

Keywords [en]

8 oxoguanine DNA glycosylase 1, DNA glycosyltransferase, glycine, phenylalanine, polynucleotide kinase phosphatase 1, small molecule transport agent, th 1078, unclassified drug, DNA (apurinic or apyrimidinic site) lyase, activation energy, amino acid, catalysis, catalyst, cell, DNA, enzyme activity, nitrogen, phosphatase, aging, Article, controlled study, DNA repair, drug structure, enzyme active site, human, in vitro study, DNA damage, enzyme specificity, metabolism, oxidative stress, DNA Glycosylases, DNA-(Apurinic or Apyrimidinic Site) Lyase, Substrate Specificity

National Category

Chemical Engineering

Identifiers

URN: urn:nbn:se:ri:diva-59834DOI: 10.1126/science.abf8980Scopus ID: 2-s2.0-85132689112OAI: oai:DiVA.org:ri-59834DiVA, id: diva2:1685494

Note

Correspondence Address: Michel, M.; Science for Life Laboratory, Sweden; email: maurice.grube@scilifelab.se; Correspondence Address: Helleday, T.; Science for Life Laboratory, Sweden; email: thomas.helleday@scilifelab.se; Chemicals/CAS: DNA glycosyltransferase, 70356-40-0; glycine, 56-40-6, 6000-43-7, 6000-44-8; phenylalanine, 3617-44-5, 63-91-2; DNA (apurinic or apyrimidinic site) lyase, 61811-29-8; DNA Glycosylases; DNA-(Apurinic or Apyrimidinic Site) Lyase; Funding details: 2020-02186; Funding details: European Molecular Biology Organization, EMBO; Funding details: Torsten Söderbergs Stiftelse, TSS, 2020-00306; Funding details: H2020 Marie Skłodowska-Curie Actions, MSCA, 722729; Funding details: Federation of European Biochemical Societies, FEBS; Funding details: European Research Council, ERC, TAROX-695376; Funding details: Deutsche Forschungsgemeinschaft, DFG, 239748522; Funding details: Cancerfonden, CAN 2017/716, CAN2018/0658; Funding details: Crafoordska Stiftelsen, 20190532; Funding details: Vetenskapsrådet, VR, 2015-00162, 2018-03406; Funding details: Instituto de Salud Carlos III, ISCIII, CP19/00063, PI20/00329; Funding details: Stiftelsen Lars Hiertas Minne; Funding details: Ministerio de Ciencia e Innovación, MICINN; Funding details: European Social Fund, ESF; Funding details: Alfred Österlunds Stiftelse; Funding details: Norges Forskningsråd, 303369; Funding details: Horizon 2020; Funding details: European Regional Development Fund, ERDF, PI19/00640; Funding details: Statens Serum Institut, SSI; Funding details: Innovative Medicines Initiative, IMI, 875510; Funding details: Agencia Estatal de Investigación, AEI, BFU2017-83900-P, Spain/10.13039/501.100011033; Funding text 1: 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.).

Available from: 2022-08-03 Created: 2022-08-03 Last updated: 2022-08-08Bibliographically approved

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