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Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice
Virginie Pétrilli, … , Salvatore Cuzzocrea, Zhao-Qi Wang
Virginie Pétrilli, … , Salvatore Cuzzocrea, Zhao-Qi Wang
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1072-1081. https://doi.org/10.1172/JCI21854.
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Article Genetics

Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice

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Abstract

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-κB to DNA, NF-κB–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.

Authors

Virginie Pétrilli, Zdenko Herceg, Paul O. Hassa, Nimesh S.A. Patel, Rosanna Di Paola, Ulrich Cortes, Laura Dugo, Helder-Mota Filipe, Christoph Thiemermann, Michael O. Hottiger, Salvatore Cuzzocrea, Zhao-Qi Wang

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Figure 1

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Generation of PARP-1KI/KI mice. (A) Structure of the targeting vector an...
Generation of PARP-1KI/KI mice. (A) Structure of the targeting vector and partial restriction map of the PARP-1 locus before and after homologous recombination and Cre-mediated recombination. Exons are indicated by black boxes, and positions of two Southern blot probes are represented by open boxes. Targeted allele and KI allele of PARP-1 after gene targeting and Cre-mediated recombination, respectively, are shown. Lox-P sites are represented by open triangles. The point mutation (D214N) is indicated by an asterisk. Restriction enzymes: HindIII (H); BamHI (B); XhoI (X); SalI (S). Crossed letter H represents the HindIII site that is abolished during cloning of a targeting vector. (B and C) Southern blot analysis of PARP-1–targeted (+/T) (B) and PARP-1+/KI (+/KI) (C) ES cell DNA after digestion with XhoI and HindIII, respectively, and hybridization with probe 1 (B) and probe 2 (C). Cre-mediated recombination causes a deletion of the neo/tk cassette resulting in a size reduction after HindIII digestion. The genotype of individual ES clones is indicated above of the gels. (D) Genotyping of offspring from intercrosses of PARP-1+/KI heterozygous mice by Southern blotting using probe 2. The genotype of individual animals is indicated above the blot. (E) Results of sequencing of DNA obtained from a wild-type (PARP-1+/+; +/+) and a PARP-1KI/KI (KI/KI) mouse. Arrows indicate the presence of G Ø A transition at codon 214 in the PARP-1KI/KI mouse.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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