- RESEARCH AREA
PARylation is a posttranslational protein modification carried out by PAR polymerase (PARP) enzymes. The best known member of the PARP family is PARP1, a DNA nick sensor enzyme that becomes activated by DNA breaks. Activated PARP1 cleaves NAD into nicotinamide and ADP-ribose and covalently attaches a PAR polymer to itself and other suitable acceptors such as histones. Via PARylation or protein-protein interactions PARP1 regulates among others chromatin organization, DNA repair, transcription and replication. Excessive DNA damage can also trigger a PARP-mediated necrotic cell death pathway. The peroxynitrite-PARP activation pathway is an important target in stroke, myocardial ischemia-reperfusion injury, inflammations, shock, diabetes and related complications. PARP inhibitors may also be used as adjuvant chemotherapeutic agents in cancer.
Of special interest is for us the role of PARP activation in cell death. In 1998 Laszlo Virag and Csaba Szabo were the first to show that despite of the widely held view at the time, necrotic cell death is not necessarily accidental or passive but may be amenable to intervention. In these early papers (Virag et al Immunology
1998; Virag et al J. Immunol.
1998) we have shown that peroxynitrite or hydrogen peroxide-induced necrosis is mediated by overactivation of PARP1. Later, brilliant work from Valina and Ted Dawson's laboratory identified the key events in this new regulated necrotic cell death pathway. PAR polymer translocates from the nucleus to the mitochondria to trigger AIF (apoptosis-inducing factor) release. In turn, AIF moves to the nucleus to trigger DNA fragmentation. This novel cell death pathway termed parthanathos is now recognized as a form of necroptosis (regulated necrosis).
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