Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice.
Petrilli, Virginie 1; Herceg, Zdenko 1; Hassa, Paul O. 2; Patel, Nimesh S.A. 3; Paola, Rosanna Di 4; Cortes, Ulrich 1; Dugo, Laura 4; Filipe, Helder-Mota 5; Thiemermann, Christoph 3; Hottiger, Michael O. 2; Cuzzocrea, Salvatore 4; Wang, Zhao-Qi 1
[Article]
Journal of Clinical Investigation.
Celebrating our 80th anniversary 1924-2004. 114(8):1072-1081, October 2004.
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Poly(ADP-ribosyl)ation is rapidly formed in cells following DNA damage and is regulated by poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is known to be involved in various cellular processes, such as DNA repair, genomic stability, transcription, and cell death. During apoptosis, PARP-1 is cleaved by caspases to generate 89-kDa and 24-kDa fragments, a hallmark of apoptosis. This cleavage is thought to be a regulatory event for cellular death. In order to understand the biological significance of PARP-1 cleavage, we generated a PARP-1 knockin (PARP-1KI/KI) mouse model, in which the caspase cleavage site of PARP-1, DEVD214, was mutated to render the protein resistant to caspases during apoptosis. While PARP-1KI/KI mice developed normally, they were highly resistant to endotoxic shock and to intestinal and renal ischemia-reperfusions, which were associated with reduced inflammatory responses in the target tissues and cells due to the compromised production of specific inflammatory mediators. Despite normal binding of NF-[kappa]B to DNA, NF-[kappa]B-mediated transcription activity was impaired in the presence of caspase-resistant PARP-1. This study provides a novel insight into the function of PARP-1 in inflammation and ischemia-related pathophysiologies.
Copyright (C) 2004 The American Society for Clinical Investigation, Inc.