title: 8-Oxoguanine DNA glycosylase-1-mediated DNA repair is associated with Rho GTPase activation and α-smooth muscle actin polymerization.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Jixian
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Koa
authors.initials: K
authors.lastname: Hosoki
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Attila
authors.initials: A
authors.lastname: Bacsi
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Radak
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Muralidhar L
authors.initials: ML
authors.lastname: Hegde
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA; Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Sur
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA; Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Hazra
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA; Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Ba
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA; Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. Electronic address: sboldogh@utmb.edu.
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D022502:Stress Fibers / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C544013:alpha-smooth muscle actin, mouse; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D020741:rho GTP-Binding Proteins
keywords: Base excision repair; Cytoskeleton; Free radicals; OGG1; ROS; Rho–GTP