Human 8-Oxoguanine DNA Glycosylase Suppresses the Oxidative Stress–Induced Apoptosis through a p53-Mediated Signaling Pathway in Human Fibroblasts

Abstract

Human 8-oxoguanine DNA glycosylase (hOGG1) is the main defense enzyme against mutagenic effects of cellular 7,8-dihydro-8-oxoguanine. In this study, we investigated the biological role of hOGG1 in DNA damage -related apoptosis induced by hydrogen peroxide (H 2 O 2 ) -derived oxidative stress. The down-regulated expression of hOGG1 by its small interfering RNA prominently triggers the H 2 O 2 -induced apoptosis in human fibroblasts GM00637 and human lung carcinoma H1299 cells via the p53-mediated apoptotic pathway. However, the apoptotic responses were specifically inhibited by hOGG1 overexpression.

Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial Cells

“…Our results herein showing p53 mitochondrial expression in the setting of mtDNA damage concur with our earlier study showing that p53 mediates asbestos-induced AEC p53 mitochondrial translocation and intrinsic apoptosis (19). In accord with our findings, p53 activation is required for H 2 O 2 -induced apoptosis in hOgg1-deficient human fibroblast cells (28), and mitochondrial matrix p53 sensitizes HepG2 cells to oxidative stress by reducing mtDNA (43). Several lines of evidence demonstrate a potentially key association between p53, Ogg1, and Aco-2 including; 1) p53 regulates the transcription of the OGG1 gene in colon and renal epithelial cells (28), 2) p53-deficient cells have reduced Ogg1 protein expression and activity (28), and 3) p53 can reduce Aco-2 gene expression as well as Aco-2 activity (44,45).…”

“…In accord with our findings, p53 activation is required for H 2 O 2 -induced apoptosis in hOgg1-deficient human fibroblast cells (28), and mitochondrial matrix p53 sensitizes HepG2 cells to oxidative stress by reducing mtDNA (43). Several lines of evidence demonstrate a potentially key association between p53, Ogg1, and Aco-2 including; 1) p53 regulates the transcription of the OGG1 gene in colon and renal epithelial cells (28), 2) p53-deficient cells have reduced Ogg1 protein expression and activity (28), and 3) p53 can reduce Aco-2 gene expression as well as Aco-2 activity (44,45). However, p53 has diverse functions in the nucleus and the mitochondria that can promote cell survival or cell death depending upon the experimental conditions.…”

“…We reason that Aco-2 is necessary for the protective effects of mt-hOgg1-Mut but not mt-hOgg1-WT because the former is incapable of repairing mtDNA damage and Aco-2, and its mtDNA chaperone function is depleted by siACO-2 (11,25). Our findings concur with investigations showing that Ogg1 depletion promotes oxidant-induced apoptosis and extends these studies by demonstrating that Ogg1 and Aco-2 function coordinately to preserve mtDNA in the setting of oxidative stress (28,38). Aco-2 is a bifunctional mitochondrial protein that is vital for energy metabolism in the TCA cycle converting citrate to isocitrate as well as important for mtDNA maintenance in yeast.…”

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

“…All three types of treatments increased the levels of H2AXS139ph when compared with the control transfected cells. As expected, UV and H 2 O 2 treatment increased the levels of the DNA repair proteins TRP53BP1 [23,24] and RAD51 [25][26][27], indicating the presence of DNA damage and supporting the use of H2AXS139ph as marker for DNA-DSB under these conditions. Interestingly, while Hmga2 transfection did not change the levels of DNA repair proteins, it increased the levels of GATA6, demonstrating a novel function of H2AXS139ph during transcriptional activation.…”

Green Tea epigallocatechin-3-gallate Protects Against Oxidative Stress-Induced Nuclear Translocation of p53 and Apoptosis in Retinal Pigment Epithelial Cells, ARPE-19

“…Dysfunction of RPE contributes to retinal diseases such as retinitis pigmentosa (RP) (Strauss, 2005) and age-related macular degeneration (AMD) (Zarbin, 2004) leading to visual impairment. H 2 O 2 has been widely used as the oxidative stress-induced apoptosis model in RPE (Godley, Jin, Guo, & Hurst, 2002;Jin, Hurst, & Godley, 2001), and has been shown to mediate apoptosis through p53 dependent pathway in several circumstances cells such as human fibroblasts (Youn et al, 2007), glioma cells (Datta, Babbar, Srivastava, Sinha, & Chattopadhyay, 2002) and RPE cells (Jin et al, 2001). The present study, therefore, aimed to investigate the protective effects of EGCG against H 2 O 2 -induced apoptosis in ARPE-19 cells focusing on the lineage of p53 dependent pathway.…”