Role of DNA Glycosylase OGG1 in Oxidative Stress-Induced Innate Inflammation

$267,064P01FY2012AINIH

University Of Texas Med Br Galveston, Galveston TX

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Abstract

Oxidative DNA base damage is linked to inflammatory processes, but there are major shortcomings in understanding their disease etiology despite considerable efforts. The most abundant DNA base lesion, 8- oxoguanine (8-oxoG) is linked to inflammation, various age-associated diseases, and aging processes. It is excised from DNA by the 8-oxoG DNA glycosylase (0GG1) and the DNA base excision repair (BER) pathway. Unexpectedly, supraphysiological 8-oxoG levels in Oggi knockout mice do not show major pathologies; in fact, they have increased resistance to inflammation. An increase in 8-oxoG levels in DNA is the earliest event upon oxidative exposure of airways; however, its role in triggering inflammation is suspected but not understood. We have made unexpected discoveries showing that 1) OGGI depletion from the airway epithelium before oxidative exposure significantly decreased innate inflammatory responses; 2) 0GG1 binds its repair product, free 8-oxoG base; 3) the OGG1

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