TY - JOUR
T1 - 8-Oxoguanine DNA glycosylase-1 links DNA repair to cellular signaling via the activation of the small GTPase Rac1
AU - Hajas, Gyorgy
AU - Bacsi, Attila
AU - Aguilera-Aguirre, Leopoldo
AU - Hegde, Muralidhar L.
AU - Tapas, K. Hazra
AU - Sur, Sanjiv
AU - Radak, Zsolt
AU - Ba, Xueqing
AU - Boldogh, Istvan
N1 - Funding Information:
This work was supported by grants NIEHS RO1 ES018948 (I.B.), NIA/AG 021830 ( I.B. ), NIAID/AI062885 (I.B.), NINDS R01NS073976 (T.H.K., I.B.), and the NHLBI Proteomic Center , N01HV00245 (Dr. A. Kurosky). L. Aguilera-Aguirre is an Environmental Toxicology Research Training Fellow ( NIEHS T32 ES007254 ). The work was also supported by the TAMOP 4.2.2.A-11/1/KONV-2012-2023 project (A.B.), which is cofinanced by the European Union and the European Social Fund . A.B. was also supported by the Janos Bolyai Fellowship from the Hungarian Academy of Sciences . We thank Drs. Miral Dizdaroglu and Pawel Jaruga (Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, MD USA) for GC/MS measurements of the 8-oxoG and for the gift of FapyG. We thank Drs. Sankar Mitra and Miral Dizdaroglu for their scientific input, and Dr. David Konkel (Department of Biochemistry and Molecular Biology) and Mardelle Susman (Department of Microbiology and Immunology) for critically editing the manuscript. We also thank the anonymous reviewers for their suggestions, thoughts, and concept, which improved the quality of our paper.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - 8-Oxoguanine
KW - 8-Oxoguanine DNA glycosylase-1
KW - Rac1 GTPase
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U2 - 10.1016/j.freeradbiomed.2013.04.011
DO - 10.1016/j.freeradbiomed.2013.04.011
M3 - Article
C2 - 23612479
AN - SCOPUS:84878009944
SN - 0891-5849
VL - 61
SP - 384
EP - 394
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -