Abstract
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-α-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB 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.
Highlights
reactive oxygen species (ROS) generate a localized increase in oxoguanine DNA glycosylase 1 (OGG1) substrates in guanine-rich promoter regions [4, 6, 9,10], including proinflammatory genes [3,4,12]
Because TH5487 prevents OGG1 from binding 8-oxoG in DNA, we examined if TH5487 could suppress proinflammatory gene expression
Emerging evidence suggests that OGG1 binding to gene regulatory regions exerts an epigenetic role for 8-oxoG, causing OGG1 to act as a modulator of gene expression [3,4,6,7,8,9,10,11]
Summary
ROS generate a localized increase in OGG1 substrates in guanine-rich promoter regions [4, 6, 9,10], including proinflammatory genes [3,4,12]. TH5487mediated protein destabilization did not account for the observed decrease in enzyme activity, suggesting that TH5487 binds OGG1 to 8-oxoG extruded from DNA. TH5487 is a potent and selective active site inhibitor that prevents OGG1 from binding to its DNA substrate.
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