TY - JOUR
T1 - 8-Oxoguanine DNA glycosylase-1-mediated DNA repair is associated with Rho GTPase activation and α-smooth muscle actin polymerization
AU - Luo, Jixian
AU - Hosoki, Koa
AU - Bacsi, Attila
AU - Radak, Zsolt
AU - Hegde, Muralidhar L.
AU - Sur, Sanjiv
AU - Hazra, Tapas K.
AU - Brasier, Allan R.
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.), and NIAID/AI062885 (I.B.) and the NHLBI Proteomic Center, N01HV00245 (Dr. A. Kurosky); the International Science–Technology Collaboration Foundation ( 20120728 ) of Jilin Province in China (X.B.); and the TAMOP 4.2.1/B-09/1/KONV-2010-2007 project, 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 Dr. David Konkel (Institute for Translational Sciences, UTMB) and Mardelle Susman (Microbiology and Immunology, UTMB) for their scientific input and critical editing of the manuscript.
PY - 2014/8
Y1 - 2014/8
N2 - Reactive oxygen species (ROS) are activators of cell signaling and modify cellular molecules, including DNA. 8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the prominent lesions in oxidatively damaged DNA, whose accumulation is causally linked to various diseases and aging processes, whereas its etiological relevance is unclear. 8-OxoG is repaired by the 8-oxoguanine DNA glycosylase-1 (OGG1)-initiated DNA base excision repair (BER) pathway. OGG1 binds free 8-oxoG and this complex functions as an activator of Ras family GTPases. Here we examined whether OGG1-initiated BER is associated with the activation of Rho GTPase and mediates changes in the cytoskeleton. To test this possibility, we induced OGG1-initiated BER in cultured cells and mouse lungs and used molecular approaches such as active Rho pull-down assays, siRNA ablation of gene expression, immune blotting, and microscopic imaging. We found that OGG1 physically interacts with Rho GTPase and, in the presence of 8-oxoG base, increases Rho-GTP levels in cultured cells and lungs, which mediates α-smooth muscle actin (α-SMA) polymerization into stress fibers and increases the level of α-SMA in insoluble cellular/tissue fractions. These changes were absent in cells lacking OGG1. These unexpected data and those showing that 8-oxoG repair is a lifetime process suggest that, via Rho GTPase, OGG1 could be involved in the cytoskeletal changes and organ remodeling observed in various chronic diseases.
AB - Reactive oxygen species (ROS) are activators of cell signaling and modify cellular molecules, including DNA. 8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the prominent lesions in oxidatively damaged DNA, whose accumulation is causally linked to various diseases and aging processes, whereas its etiological relevance is unclear. 8-OxoG is repaired by the 8-oxoguanine DNA glycosylase-1 (OGG1)-initiated DNA base excision repair (BER) pathway. OGG1 binds free 8-oxoG and this complex functions as an activator of Ras family GTPases. Here we examined whether OGG1-initiated BER is associated with the activation of Rho GTPase and mediates changes in the cytoskeleton. To test this possibility, we induced OGG1-initiated BER in cultured cells and mouse lungs and used molecular approaches such as active Rho pull-down assays, siRNA ablation of gene expression, immune blotting, and microscopic imaging. We found that OGG1 physically interacts with Rho GTPase and, in the presence of 8-oxoG base, increases Rho-GTP levels in cultured cells and lungs, which mediates α-smooth muscle actin (α-SMA) polymerization into stress fibers and increases the level of α-SMA in insoluble cellular/tissue fractions. These changes were absent in cells lacking OGG1. These unexpected data and those showing that 8-oxoG repair is a lifetime process suggest that, via Rho GTPase, OGG1 could be involved in the cytoskeletal changes and organ remodeling observed in various chronic diseases.
KW - Base excision repair
KW - Cytoskeleton
KW - Free radicals
KW - OGG1
KW - Rho-GTP
KW - ROS
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U2 - 10.1016/j.freeradbiomed.2014.03.030
DO - 10.1016/j.freeradbiomed.2014.03.030
M3 - Article
C2 - 24681335
AN - SCOPUS:84905125583
SN - 0891-5849
VL - 73
SP - 430
EP - 438
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -