8-Oxoguanine DNA glycosylase-1 links DNA repair to cellular signaling via the activation of the small GTPase Rac1

Abstract

8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the most abundant DNA base lesions induced by reactive oxygen species (ROS). Accumulation of 8-oxoG in the mammalian genome is considered a marker of oxidative stress, to be causally linked to inflammation, and is thought to contribute to aging processes and various aging-related diseases. Unexpectedly, mice that lack 8-oxoguanine DNA glycosylase-1 (OGG1) activity and accumulate 8-oxoG in their genome have a normal phenotype and longevity; in fact, they show increased resistance to both inflammation and oxidative stress. OGG1 excises and generates free 8-oxoG base during DNA base-excision repair (BER) processes. In the present study, we report that in the presence of the 8-oxoG base, OGG1 physically interacts with guanine nucleotide-free and GDP-bound Rac1 protein. This interaction results in rapid GDP→GTP, but not GTP→GDP, exchange in vitro. Importantly, a rise in the intracellular 8-oxoG base levels increases the proportion of GTP-bound Rac1. In turn Rac1-GTP mediates an increase in ROS levels via nuclear membrane-associated NADPH oxidase type 4. These results show a novel mechanism by which OGG1 in complex with 8-oxoG is linked to redox signaling and cellular responses.

NADPH Oxidase-generated Hydrogen Peroxide Induces DNA Damage in Mutant FLT3-expressing Leukemia Cells

“…6B). Similarly, NOX4 was proposed to localize to the nuclear membrane in alveolar epithelial cell A549 (47). We have also shown that p22 phox localizes to the nuclear membrane (Fig.…”

Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial Cells

“…As compared with wild-type neuronal stem cells, loss of plasticity toward a terminally differentiated astrocytic lineage occurs in Ogg1-deficient neuronal stem cells that accumulate mtDNA damage (58). Ogg1 also has an emerging important role in linking DNA repair to Rac1 and Ras cellular signaling pathways (59,60). These findings support the notion that defects in Ogg1 and 8-oxoG DNA repair play an important role in enhancing mtDNA damage.…”

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

“…In mammals, the intra-helical 8-oxoG is recognized and excised by the E. coli Fpg homolog 8-oxoguanine DNA glycosylase 1 (OGG1) from nuclear and mitochondrial genome during base excision repair processes [19,20]. The resulting free 8-oxoG base is capable of binding to OGG1 with high affinity, and the complex then functions as an activator of Ras and Rho family GTPases contributing to oxidative stress related cellular responses [21][22][23]. Here, our aim was to investigate the consequence if 8-oxoG is not removed from mtDNA and the oxidatively modified mtDNA is released from the cells.…”