title: Activation of cellular signaling by 8-oxoguanine DNA glycosylase-1-initiated DNA base excision repair.
abstract: Accumulation of 8-oxo-7,8-dihydroguanine (8-oxoG) in the DNA results in genetic instability and mutagenesis, and is believed to contribute to carcinogenesis, aging processes and various aging-related diseases. 8-OxoG is removed from the DNA via DNA base excision repair (BER), initiated by 8-oxoguanine DNA glycosylase-1 (OGG1). Our recent studies have shown that OGG1 binds its repair product 8-oxoG base with high affinity at a site independent from its DNA lesion-recognizing catalytic site and the OGG1•8-oxoG complex physically interacts with canonical Ras family members. Furthermore, exogenously added 8-oxoG base enters the cells and activates Ras GTPases; however, a link has not yet been established between cell signaling and DNA BER, which is the endogenous source of the 8-oxoG base. In this study, we utilized KG-1 cells expressing a temperature-sensitive mutant OGG1, siRNA ablation of gene expression, and a variety of molecular biological assays to define a link between OGG1-BER and cellular signaling. The results show that due to activation of OGG1-BER, 8-oxoG base is released from the genome in sufficient quantities for activation of Ras GTPase and resulting in phosphorylation of the downstream Ras targets Raf1, MEK1,2 and ERK1,2. These results demonstrate a previously unrecognized mechanism for cellular responses to OGG1-initiated DNA BER.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: German
authors.forename: Peter
authors.initials: P
authors.lastname: Szaniszlo
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Hajas
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Radak
authors.forename: Attila
authors.initials: A
authors.lastname: Bacsi
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Hazra
authors.forename: Muralidhar L
authors.initials: ML
authors.lastname: Hegde
authors.forename: Xueqing
authors.initials: X
authors.lastname: Ba
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
mesh_terms: D002460:Cell Line; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D005786:Gene Expression Regulation; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018384:Oxidative Stress; D010766:Phosphorylation; D015398:Signal Transduction; D020298:U937 Cells; D018631:ras Proteins / Q000378:metabolism
chemical_list: C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D018631:ras Proteins
keywords: Base excision repair; Cell signaling; Ogg1
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