Disease relevance of Parp1

• Extensive activation of poly(ADP-ribose) polymerase-1 (PARP-1) by DNA damage is a major cause of caspase-independent cell death in ischemia and inflammation [1].
• METHODS AND MATERIALS: Clonogenic cell survival of V79-379A and CHO-K1 hamster fibroblasts, T98G and U373-MG human glioma cells, and 3T3 mouse embryo fibroblast PARP-1 knockout cells was measured using a precise flow cytometry-based plating assay [2].
• The aim of the present study was to examine the effects of 3-aminobenzamide (3-AB), an inhibitor of PARP activity, in the development of acute pancreatitis caused by cerulein in mice [3].
• Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the colon injury associated with experimental colitis [3].
• NF-kappaB-dependent, as well as human immunodeficiency virus type-1 (HIV-1) long terminal repeat (LTR)-dependent, reporter gene expression was significantly impaired in cells derived from poly(ADP-ribose) polymerase-1 (PARP-1)-knockout (PARP-1 -/-) mice [4].

High impact information on Parp1

• Here we show that mice with a disrupted gene coding for poly (ADP-ribose) polymerase (PARP-/- mice) are completely resistant to the development of diabetes induced by the beta-cell toxin streptozocin [5].
• Our results identify NAD+ depletion caused by PARP activation as the dominant metabolic event in islet-cell destruction, and provide information for the development of strategies to prevent the progression or manifestation of the disease in individuals at risk of developing type 1 diabetes [5].
• Although PARP is specifically cleaved during apoptosis, cells lacking this molecule apoptosed normally in response to treatment with anti-Fas, tumor neurosis factor alpha, gamma-irradiation, and dexamethasone, indicating that PARP is dispensable in apoptosis and that PARP-/- thymocytes are not hypersensitive to ionizing radiation [6].
• Whereas embryonic fibroblasts lacking PARP exhibit normal DNA excision repair, they grow more slowly in vitro [6].
• PARP is important for genomic stability but dispensable in apoptosis [6].

Chemical compound and disease context of Parp1

• PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes [7].
• We show that three teratogens, hyperthermia, cyclophosphamide and sodium arsenite induce an increase in cell death in day 9.0 mouse embryos with concurrent induction of DNA fragmentation, activation of caspase-3 and the cleavage of poly (ADP-ribose) polymerase (PARP) [8].
• PARP-1 knockout mice are protected against myocardial infarction, streptozotocin-induced diabetes, lipopolysaccharide-induced septic shock, and zymosan-induced multiple organ failure, indicating that PARP-1 is involved in the regulation of the pathogenesis of these disorders [9].
• Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the new potent phenanthridinone PARP inhibitor PJ34 [the hydrochloride salt of N-(oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide], we studied whether the impaired cardiac function in endotoxic shock is dependent upon the PARP pathway [10].
• Local Administration of the Poly ADP-Ribose Polymerase (PARP) Inhibitor, PJ34 During Hindlimb Ischemia Modulates Skeletal Muscle Reperfusion Injury [11].

Biological context of Parp1

• PARP-1-deficient mice display a severe defect in the base excision repair pathway leading to radiosensitivity and genomic instability [12].
• Thus, PARP-1 does not have a major role in telomere metabolism, not even in the context of telomerase deficiency [13].
• So, the impact on gene expression profile when both Wrn and PARP-1 are mutated was greater than a simple addition of individual mutant genotype [14].
• Thus, it is possible that chromosomal instability known in PARP-1-null cells can be attributed to the centrosomal dysfunction [15].
• Moreover, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1alpha) was compromised by PARP inhibition or in PARP-1-deficient cells, as measured by gene reporter assays and the expression of key target genes for HIF-1alpha [16].

Anatomical context of Parp1

• We show here that PARP-1 localizes to centrosomes and catalyzes poly(ADP-ribosyl)ation of centrosomal proteins [15].
• In PARP-1-expressing fibroblasts treated with a combination of MMS and 4-AN, a complete inhibition of DNA synthesis is apparent after 4 h, and by 24 h, all cells are arrested in S-phase of the cell cycle [17].
• Cultured mouse astrocytes were treated with the cytotoxic concentrations of N-methyl-N'-nitro-N-nitrosoguanidine or 3-morpholinosydnonimine to induce DNA damage and PARP-1 activation [1].
• Furthermore, both cyclosporin A and NAD(+) blocked translocation of the apoptosis-inducing factor from mitochondria to nuclei, a step previously shown necessary for PARP-1-induced cell death [1].
• This up-regulation was blocked in PARP-1-/- microglia and in wt microglia by the PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2h)-isoquinolinone [18].

Associations of Parp1 with chemical compounds

• Synthesis of ADP-ribose polymers catalyzed by poly-(ADP-ribose) polymerase-1 (PARP-1) has been implicated in transcriptional regulation [19].
• Nuclear content of phosphorylated mitogen-activated protein kinase kinase-4 was observed in PARP-1-deficient cells after peroxynitrite challenge only [20].
• PARP-1 physically interacts with the Mediator [21].
• Sub-micromolar concentrations of cyclosporin A blocked MPT and cell death, suggesting that MPT is a necessary step linking PARP-1 activation to cell death [1].
• Here we show that PARP-1 is acetylated in vivo at specific lysine residues by p300/CREB-binding protein upon stimulation [21].

Physical interactions of Parp1

• Electrophoretic mobility shift assay revealed that PARP-1 inhibitors and the antisense RNA for PARP-1 mRNA reduced the LPS-induced DNA binding of NF-kappaB [19].
• We provided evidence that PARP-1 constitutively interacts with DNA polymerase beta [22].

Enzymatic interactions of Parp1

• We found that centrosomal p53 is poly(ADP-ribosyl)ated in vivo and centrosomal PARP-1 directly catalyzes poly(ADP-ribosyl)ation of p53 in vitro [15].
• RB58-induced cytotoxicity was not inhibited by addition of the pan-caspase inhibitor zVAD, and Western blot analyses of RB58-infected HeLa cells indicated that neither caspase 3 nor 7 was cleaved and PARP remained in its full-length active form [23].
• Blockade of caspase activity by Z-VAD reduced the amount of cleaved PARP-1 in fibroblasts [24].

Regulatory relationships of Parp1

• Microglial activation is regulated in part by NF-kappaB, and the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) enhances NF-kappaB binding to DNA [18].
• Western blotting analysis for AP-1 subunits indicated that c-Fos was similarly expressed in wild-type and PARP-1-deficient cells [20].
• The reduction was well correlated with decreased levels of p53 phosphorylation at serine-18, suggesting that the apoptosis depends on the p53-mediated apoptosis pathway that is positively regulated by PARP-1 [25].
• By using high-density microarrays, we examined early tumor necrosis factor alpha (TNF-alpha)-stimulated gene expression profiles in PARP-1(+/+) and PARP-1(-/-) murine heart endothelial cells [26].

Other interactions of Parp1

• The abrogation of the oxydated status of p53(-/-) cells, due to the absence of parp-1, may be the cause of the delay in the onset of tumorigenesis in parp-1(-/-)p53(-/-) mice [12].
• Interestingly, more than 58% of misregulated genes identified in double mutant cells were not altered in cells with either the Wrn or PARP-1 mutation alone [14].
• Additional biochemical and immunocytochemical studies indicated that of several DNA repair enzymes investigated, only PARP was increased in scid mice, possibly in response to elevated DNA strand breaks [27].
• Poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear factor kappaB (NF-kappaB) have both been demonstrated to play a pathophysiological role in a number of inflammatory disorders [21].
• We investigated the role of PARP-1 on the AP-1 pathway, which is involved in the signal transduction of the inflammatory process [20].
• Haploid loss of Parp1 is sufficient to induce lethality of Brca1-deficient cells, suggesting that partial inhibition of PARP1 may represent a practical chemopreventive/therapeutic approach for BRCA1-associated breast cancer [28].

Analytical, diagnostic and therapeutic context of Parp1

• In addition, epidermis of parp-1(-/-) mice did not show increased proliferation rates after treatment with carcinogen [29].
• Mice genetically deficient of PARP-1 (PARP-1(-/-) mice) exhibited a significant reduction of myocardial damage after occlusion and reperfusion of the left anterior descending branch of the coronary artery compared with their wild-type littermates [30].
• Poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme activated in response to DNA strand breaks, has been implicated in cell dysfunction in myocardial reperfusion injury [30].
• Microarray analysis revealed that expression of several AP-1-dependent genes of proinflammatory mediators and HSPs was altered in PARP-1(-/-) mice [30].
• CONCLUSION: Low-dose radiosensitization of actively dividing tumor cells by PARP-1 inhibitors suggests that they may have a role in enhancing the efficacy of ultrafractionated or low-dose-rate radiotherapy regimens [2].

References