期刊
DNA REPAIR
卷 12, 期 10, 页码 856-863出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.dnarep.2013.06.006
关键词
Ogg1; Base excision repair; Cell signaling
资金
- NIEHS [RO1 ES018948, NIAID/AI062885-01]
- NHLBI Proteomic Center for Airway Inflammation, UTMB [N01HV00245]
- [TAMOP-4.2.2.A-11/1/KONV-2012-0023]
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 OGG-1.8-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 Raft MEK1,2 and ERK1,2. These results demonstrate a previously unrecognized mechanism for cellular responses to OGG1-initiated DNA BER. Published by Elsevier B.V.
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