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Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden..
Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.;Inst Invest Biomed Alberto Sols CSIC UAM, Madrid 28029, Spain..
Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid 28049, Spain..
Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden..
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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 beta,delta-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.
Place, publisher, year, edition, pages
American Association for the Advancement of Science (AAAS) American Association for the Advancement of Science (AAAS), 2022. Vol. 376, no 6600, p. 1471-1476
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-481194DOI: 10.1126/science.abf8980ISI: 000819288900045PubMedID: 35737787OAI: oai:DiVA.org:uu-481194DiVA, id: diva2:1686036
Funder
EU, European Research Council, TAROX-695376Swedish Research Council, 2015-00162Swedish Research Council, 2018-03406Swedish Cancer Society, CAN2018/0658Swedish Cancer Society, CAN 2017/716EU, Horizon 2020, POSTD20042BENIAvailable from: 2022-08-08 Created: 2022-08-08 Last updated: 2024-01-15Bibliographically approved

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Chi, Celestine N.

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Mortusewicz, OliverMasuyer, GeoffreyAlbers, Julian J.Visnes, TorkildChi, Celestine N.de Vega, Miguel
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Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)Cell and Molecular Biology

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