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Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
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Number of Authors: 402018 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 362, no 6416, p. 834-+Article in journal (Refereed) Published
Abstract [en]

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor-alpha-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor kappa B and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.

Place, publisher, year, edition, pages
2018. Vol. 362, no 6416, p. 834-+
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Biological Sciences
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URN: urn:nbn:se:su:diva-162778DOI: 10.1126/science.aar8048ISI: 000450488500054PubMedID: 30442810OAI: oai:DiVA.org:su-162778DiVA, id: diva2:1274127
Available from: 2018-12-28 Created: 2018-12-28 Last updated: 2018-12-28Bibliographically approved

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Masuyer, GeoffreyStenmark, Pål
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