TY - JOUR
T1 - Activation of cellular signaling by 8-oxoguanine DNA glycosylase-1-initiated DNA base excision repair
AU - German, Peter
AU - Szaniszlo, Peter
AU - Hajas, Gyorgy
AU - Radak, Zsolt
AU - Bacsi, Attila
AU - Hazra, Tapas K.
AU - Hegde, Muralidhar L.
AU - Ba, Xueqing
AU - Boldogh, Istvan
N1 - Funding Information:
We thank David Konkel (Department of Biochemistry and Molecular Biology) and Mardelle Susman (Department of Microbiology and Immunology) for carefully editing the manuscript. This work was supported by grants NIEHS RO1 ES018948 (I.B), NIAID/AI062885-01 (I.B), the NHLBI Proteomic Center for Airway Inflammation, UTMB; N01HV00245 (I.B, Director A. Kurosky) and TAMOP-4.2.2.A-11/1/KONV-2012-0023 (A.B). We thank Leopoldo Aguilera-Aguirre (Department of Microbiology and Immunology), NIEHS Training fellow (T32 ES007254, PI: W Ameredes) for helpful advises.
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
KW - Base excision repair
KW - Cell signaling
KW - Ogg1
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U2 - 10.1016/j.dnarep.2013.06.006
DO - 10.1016/j.dnarep.2013.06.006
M3 - Article
C2 - 23890570
AN - SCOPUS:84885376540
SN - 1568-7864
VL - 12
SP - 856
EP - 863
JO - DNA Repair
JF - DNA Repair
IS - 10
ER -