title: Ataxia-telangiectasia-mutated-dependent activation of Ku in human fibroblasts exposed to hydrogen peroxide.
abstract: DNA is damaged in cells during cell replication, by infection, or by various environmental stresses. The damaged cells stop cell cycle, repair damaged DNA, and when repaired progress into the next cell cycle stage. But when the attempt to repair the damage fails, the cells undergo apoptosis. The most deleterious damage of all is double-strand DNA breaks (DSBs), where ATM (ataxia-telangiectasia-mutated) serves as a sensor. The ATM pathway culminates in DNA repair through nonhomologous end-joining or through homologous recombination. Upon DNA damage, the DNA repair protein Ku70/80 translocates into the nucleus, which may be mediated by ATM. Previously, we found that pancreatic acinar cells undergo apoptosis upon oxidative stress, and the cell death stems from nuclear loss of Ku70/80. This study aims to investigate whether ATM has a role in Ku activation and prevention of cell death induced by oxidative stress (hydrogen peroxide) using A-T fibroblasts stably transfected with human full-length ATM cDNA or empty vector. As a result, hydrogen peroxide-induced cell death was augmented in A-T cells transfected with empty vector while cell death was prevented in A-T fibroblasts stably transfected with human full-length ATM cDNA. Ku DNA-binding activity induced by hydrogen peroxide treatment was increased in the A-T fibroblasts stably transfected with human full-length ATM cDNA compared to that in A-T cells transfected with empty vector. The results suggest that ATM may be essential for Ku activation to repair DNA damage from oxidative stress and prevent cell death caused by oxidative stress.
authors.affiliation: Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Jong Hwa
authors.initials: JH
authors.lastname: Lee
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.forename: Hyeyoung
authors.initials: H
authors.lastname: Kim
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D000072200:Ku Autoantigen; D016877:Oxidants / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016877:Oxidants; D025521:Tumor Suppressor Proteins; D006861:Hydrogen Peroxide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen