Activation of Ras Signaling Pathway by 8-Oxoguanine DNA Glycosylase Bound to Its Excision Product, 8-Oxoguanine

8-Oxo-7,8-dihydroguanine (8-oxoG), arguably the most abundant base lesion induced in mammalian genomes by reactive oxygen species, is repaired via the base excision repair pathway that is initiated with the excision of 8-oxoG by OGG1. Here we show that OGG1 binds the 8-oxoG base with high affinity and that the complex then interacts with canonical Ras family GTPases to catalyze replacement of GDP with GTP, thus serving as a guanine nuclear exchange factor. OGG1-mediated activation of Ras leads to phosphorylation of the mitogen-activated kinases MEK1,2/ERK1,2 and increasing downstream gene expression. These studies document for the first time that in addition to its role in repairing oxidized purines, OGG1 has an independent guanine nuclear exchange factor activity when bound to 8-oxoG. 8-Oxo-7,8-dihydroguanine (8-oxoG) is an abundant DNA base lesion repaired by 8-oxoguanine glycosylase (OGG1) via the base excision repair pathway. OGG1 binds to its repair product 8-oxoG and activates canonical Ras family GTPases, causing gene activation via MAPK signaling. OGG1 complexed with 8-oxoG has guanine nucleotide exchange factor activity. OGG1 modulates cellular signaling via its DNA repair-independent function.