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Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

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Science  16 Nov 2018:
Vol. 362, Issue 6416, pp. 834-839
DOI: 10.1126/science.aar8048

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DNA binding as an anti-inflammatory

Mice that lack the gene encoding 8-oxoguanine DNA glycosylase 1 (OGG1) show resistance to inflammation. This enzyme binds to sites of oxidative DNA damage and initiates DNA base excision repair. Visnes et al. developed a small-molecule drug that acts as a potent and selective active-site inhibitor that stops OGG1 from recognizing its DNA substrate (see the Perspective by Samson). The drug inhibited DNA repair and modified OGG1 chromatin dynamics, which resulted in the inhibition of proinflammatory pathway genes. The drug was well tolerated by mice and suppressed lipopolysaccharide- and tumor necrosis factor–α–mediated neutrophilic inflammation in the lungs.

Science, this issue p. 834; see also p. 748