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Dual role of poly(ADP-ribose) glycohydrolase in the regulation of cell death in oxidatively stressed A549 cells

Katalin Erdélyi^*,, Péter Bai^*, István Kovács^*, Éva Szabó, Gábor Mocsár^,, Annamária Kakuk^*, Csaba Szabó^||, Pál Gergely^*, and László Virág^*,,1

^* Department of Medical Chemistry,

Department of Dermatology, and

Department of Biophysics and Cell Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary;

Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, Research Center for Molecular Medicine, Debrecen, Hungary; and

^|| Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA

¹ Correspondence: Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Élettudományi Épület 3.311, Nagyerdei krt 98., H-4032 Debrecen, Hungary. E-mail: lvirag{at}dote.hu

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 -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.—Erdélyi, K., Bai, P., Kovács, I., Szabó, E., Mocsár, G., Kakuk, A., Szabó, C., Gergely, P., Virág, L. Dual role of poly(ADP-ribose) glycohydrolase in the regulation of cell death in oxidatively stressed A549 cells.

Key Words: DNA damage • gene silencing • apoptosis • necrosis • hydrogen peroxide • apoptosis-inducing factor