title: Dual role of poly(ADP-ribose) glycohydrolase in the regulation of cell death in oxidatively stressed A549 cells.
abstract: Activation of poly(ADP-ribose) polymerase-1 (PARP1) has been shown to mediate cell death induced by genotoxic stimuli. The role of poly(ADP-ribose) glycohydrolase (PARG), the enzyme responsible for polymer degradation, has been largely unexplored in the regulation of cell death. Using lentiviral gene silencing we generated A549 lung adenocarcinoma cell lines with stably suppressed PARG and PARP1 expression (shPARG and shPARP1 cell lines, respectively) and determined parameters of apoptotic and necrotic cell death following hydrogen peroxide exposure. shPARG cells accumulated large amounts of poly(ADP-ribosyl)ated proteins and exhibited reduced PARP activation. Hydrogen peroxide-induced cell death is regulated by PARG in a dual fashion. Whereas the shPARG cell line (similarly to shPARP1 cells) was resistant to the necrotic effect of high concentrations of hydrogen peroxide, these cells exhibited stronger apoptotic response. Both shPARP1 and especially shPARG cells displayed a delayed repair of DNA breaks and exhibited reduced clonogenic survival following hydrogen peroxide treatment. Translocation of apoptosis-inducing factor could not be observed, but cells could be saved by methyl pyruvate and alpha-ketoglutarate, indicating that energy failure may mediate cytotoxicity in our model. These data indicate that PARG is a survival factor at mild oxidative damage but contributes to the apoptosis-necrosis switch in severely damaged cells.
authors: Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, H-4032 Debrecen, Hungary.
authors: Katalin
authors: K
authors: Erdélyi
authors: Péter
authors: P
authors: Bai
authors: István
authors: I
authors: Kovács
authors: Eva
authors: E
authors: Szabó
authors: Gábor
authors: G
authors: Mocsár
authors: Annamária
authors: A
authors: Kakuk
authors: Csaba
authors: C
authors: Szabó
authors: Pál
authors: P
authors: Gergely
authors: László
authors: L
authors: Virág
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D053960:DNA Breaks; D006026:Glycoside Hydrolases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009336:Necrosis; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology
chemical_list: C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase