Role of poly(ADP-ribose) polymerase-1 in cell death

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Role of poly(ADP-ribose) polymerase-1 in cell death Among the earliest responses of higher eukaryotic cells to DNA damage is catalytic activation of a constitutively expressed nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP). This activation serves many purposes ranging from protecting the cells if the damage can be repaired, but more importantly this enzyme also helps in elimination of badly damaged cells because survival of such damaged and altered cells may be more harmful than good for the body. The process of elimination or cell death can follow variety of routes; and our work supported by NSERC and work of many others indicate that PARP is implicated in two major death routes, namely apoptosis and necrosis. We hypothesize that the decision to die by apoptosis or necrosis is controlled by various activities of this enzyme including its product: a polymer of ADP-ribose, its fragmentation by death-related proteases during cell death and its interaction with different cellular partner proteins. The specific objectives of the project are to determine whether: 1) PARP and its fragments created during cell death control different modes of cell death via interaction with different cellular partners. 2) PARP as an enzyme that makes the product polymer of ADP-ribose and also causes intracellular acidification in response to DNA damage can influence death events through its enzymatic activities. 3) PARP acts in concert with an RNA-cleaving enzyme Dicer-1 that creates mature microRNA or PARP via its influence on autophagy, a pro-survival process, can influence the mode of cell death. The long-term goal of this program is to understand how PARP with its various activities is able to determine the final journey of the cell to its own destruction for the benefit of rest of the body.