Role of poly(ADP-ribose) polymerase-1 as a controlling switch between DNA damage-induced apoptosis and necrosis

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ROLE OF POLY(ADP-RIBOSE) POLYMERASE-1 AS A CONTROLLING SWITCH BETWEEN DNA DAMAGE-INDUCED APOPTOSIS AND NECROSIS         In a rapid response to DNA damage, poly(ADP-ribose) polymerase-1 (PARP), a nuclear enzyme present in higher eukaryotes, is catalytically activated to consume NAD and form polymers of ADP-ribose, which transiently modify functions of selected chromatin structure- and DNA metabolism-related proteins. Recent studies, including those from our NSERC-supported research, have shown in different models of cell death that early PARP activation in response to high levels of DNA damage can influence key initiating events which can lead to either apoptosis or necrosis, such as depletion of NAD and ATP, nuclear translocation of apoptosis inducing factor, intracellular acidification, etc. Hence, we hypothesize that in a given cell exposed to varying levels of DNA damage, the decision to die by apoptosis or necrosis is influenced by a balance of these immediate actions of PARP. We will use cells with or without functional PARP, cells expressing wild type or caspase 3-resistant mutant PARP; and cells which are proficient or deficient in proton-removal pump Na/H+ exchanger-1 with or without functional PARP. In these models, we will examine mode of death in responses to different levels of DNA damage and correlate it with PARP-related events that control the mode of cell death.         The specific objectives of the project are to determine: 1) Whether the presence and actions of PARP influence apoptotic or necrotic response of cells to varying levels of DNA damage; 2) The mechanism by which cleavage of PARP by caspases 3 promotes apoptosis; 3) The mechanism by which PARP-mediated cellular acidification blocks apoptosis and allows necrosis; and 4) The death-related genes whose expression is controlled by PARP during initiation of apoptosis or necrosis.