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

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• 作者：Gyorgy Hajas^a ; Attila Bacsi^a ; ¹ ; Leopoldo Aguilera-Aguirre^a ; Muralidhar L. Hegde^c ; K.Hazra Tapas^b ; ^d ; ^c ; Sanjiv Sur^b ; ^d ; Zsolt Radak^a ; ² ; Xueqing Ba^a ; ³ ; Istvan Boldogh^a ; ^d ; ^{sboldogh@utmb.edu}
• 关键词：8-oxoG ; 8-oxo-7 ; 8-dihydroguanine ; 8-oxodG ; 8-oxo-7 ; 8-dihydro-2&prime ; -deoxyguanosine ; 8-OH-Ade ; 8-oxo-7 ; 8-dihydroadenine ; APE1 ; apurinic/apyrimidinic endonuclease 1 ; DNA BER ; base excision repair ; FapyG ; 2 ; 6-diamino-4-hydroxy-5-formamidopyrimidine ; FU ; fl
• 刊名：Free Radical Biology and Medicine
• 出版年：2013
• 出版时间：August, 2013
• 年：2013
• 卷：61
• 期：Complete
• 页码：384-394
• 全文大小：4538 K

文摘

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¡úGTP, but not GTP¡úGDP, 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.