1. 8-Oxoguanine DNA glycosylase-1 links DNA repair to cellular signaling via the activation of the small GTPase Rac1
- Author
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Gyorgy Hajas, Xueqing Ba, Leopoldo Aguilera-Aguirre, Istvan Boldogh, Muralidhar L. Hegde, K. Hazra Tapas, Zsolt Radak, Sanjiv Sur, and Attila Bacsi
- Subjects
rac1 GTP-Binding Protein ,Cell signaling ,Guanine ,DNA Repair ,DNA damage ,DNA repair ,Biology ,medicine.disease_cause ,Biochemistry ,Article ,DNA Glycosylases ,chemistry.chemical_compound ,Mice ,Physiology (medical) ,medicine ,Animals ,heterocyclic compounds ,Elméleti orvostudományok ,Mice, Inbred BALB C ,Neuropeptides ,NOX4 ,NADPH Oxidases ,Orvostudományok ,8-Oxoguanine ,chemistry ,DNA glycosylase ,NADPH Oxidase 4 ,Female ,Reactive Oxygen Species ,Oxidative stress ,DNA ,Signal Transduction - 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.
- Published
- 2013