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PubMed2004

The PARP superfamily.

Poly(ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins that contributes to the survival of injured proliferating cells. Poly(ADP-ribose) polymerases (PARPs) now constitute a large family of 18 proteins, encoded by different genes and displaying a conserved catalytic domain in which PARP-1 (113 kDa), the founding member, and PARP-2 (62 kDa) are so far the sole enzymes whose catalytic activity has been shown to be immediately stimulated by DNA strand breaks. A large repertoire of sequences encoding novel PARPs now extends considerably the field of poly(ADP-ribosyl)ation reactions to various aspects of the cell biology including cell proliferation and cell death. Some of these new members interact with each other, share common partners and common subcellular localizations suggesting possible fine tuning in the regulation of this post-translational modification of proteins. This review summarizes our present knowledge of this emerging superfamily, which might ultimately improve pharmacological strategies to enhance both antitumor efficacy and the treatment of a number of inflammatory and neurodegenerative disorders. A provisional nomenclature is proposed.

Amino Acid Sequence↗
PubMed2006

Protective effects of the PARP-1 inhibitor PJ34 in hypoxic-reoxygenated cardiomyoblasts.

To clarify the role of poly(ADP-ribose)polymerase-1 (PARP-1) in myocardial ischemia-reperfusion injury, we explored some effects of PJ34, a highly specific inhibitor of this enzyme, in hypoxic-reoxygenated (HR) H9c2 cardiomyoblasts. Compared to the control, HR cells showed signs of oxidative stress, marked PARP-1 activation, NAD(+) and ATP depletion and impaired mitochondrial activity. HR cardiomyoblasts were affected by both necrosis and apoptosis, the latter involving the nuclear translocation of apoptosis-inducing factor. In HR cardiomyoblasts treated with PJ34, oxidative stress and PARP-1 activity were decreased, and NAD(+) and ATP depletion, as well as mitochondrial impairment, were attenuated. Above all, PJ34 treatment improved the survival of HR cells; not only was necrosis significantly diminished, but apoptosis was also reduced and shifted from a caspase-independent to a caspase-dependent pathway. These results suggest that PARP-1 modulation by a selective inhibitor such as PJ34 may represent a promising approach to limit myocardial damage due to post-ischemic reperfusion.

Adenosine Triphosphate↗
PubMed2006

Protective effects of PARP inhibition on liver microcirculation and function after haemorrhagic shock and resuscitation in male rats.

OBJECTIVE: The aim of this study was to investigate the impact of the water-soluble poly-(ADP)-ribose-polymerase (PARP) inhibitor 5-aminoisoquinolinone (5-AIQ) on liver microcirculation and function after haemorrhagic shock and resuscitation. DESIGN: Controlled, randomized animal study. SETTING: University animal care facility and research laboratory. SUBJECT: Male Sprague-Dawley rats were subjected to haemorrhagic shock for 1 h, followed by resuscitation with shed blood and crystalloid solution for a total of 5 h. INTERVENTIONS: The PARP inhibitor 5-AIQ (3 mg/kg; n=7) or vehicle (n=7) was administered 5 min prior to resuscitation. Sham-operated animals without induction of shock served as controls (n=7). MEASUREMENTS AND RESULTS: Using intravital fluorescence microscopy hepatic microcirculation was assessed at baseline, end of shock phase as well as 1 h and 5 h after resuscitation. Systemic arterial blood pressure and bile flow were continuously monitored. 5-AIQ treatment attenuated shock/resuscitation-induced increase of intrahepatic leukocyte-endothelial cell interaction with a marked reduction of both sinusoidal leukostasis and venular leukocyte adherence. Moreover, nutritive perfusion was found improved, guaranteeing sufficient oxygen supply to tissue, as indicated by low NADH autofluorescence, which was not different to that in controls. Most notably, excretory liver function reached baseline level over 5 h of reperfusion in 5-AIQ-treated animals. CONCLUSIONS: In the present setting of shock/resuscitation in male rats the PARP inhibitor 5-AIQ proved to be very effective in ameliorating compromised liver microcirculation and function. Further research has to confirm that PARP inhibition is a suitable tool in the acute treatment of patients suffering from reduced circulating blood volume and thus microcirculatory organ dysfunction.

Animals↗
PubMed1996

Ligation of CD40 rescues Ramos-Burkitt lymphoma B cells from calcium ionophore- and antigen receptor-triggered apoptosis by inhibiting activation of the cysteine protease CPP32/Yama and cleavage of its substrate PARP.

The new and growing family of interleukin-1beta-converting enzyme (ICE) cysteine proteases are now recognised to be major effectors of cellular death by apoptosis. Like other members of this family, the CPP32/Yama proform is activated by processing to its active heterodimeric enzyme or apopain when it likely contributes to the process of apoptosis by cleaving poly(ADP-ribose) polymerase (PARP) and thereby inhibiting much of its DNA repair activity. Apoptosis plays a fundamental role in the regulation of the immune system where it is involved in the selection of both T and B lymphocytes bearing antigen receptor (AgR) for non-self. Cells of the Ramos Epstein-Barr virus (EBV)-genome-negative Burkitt lymphoma (BL) B cell line (Ramos-BL) can be triggered into growth arrest and apoptosis by treating with the calcium ionophore ionomycin or by crosslinking their surface AgR with antibodies directed against immunoglobulin (Ig)M (anti-IgM). Ionomycin- and AgR-triggered growth arrest and apoptosis are arrested by signals transduced through the surface CD40 of Ramos-BL B cells. Both ionomycin and anti-IgM trigger activation of CPP32 and cleavage of PARP prior to the onset of apoptosis; this process is abrogated by treatment with anti-CD40 and is independent of Bcl-2 expression. A tripeptide inhibitor of ICE family cysteine proteases, Z-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) inhibits ionomycin- and AgR-triggered CPP32 activation, PARP cleavage and apoptosis, but not growth arrest, in Ramos-BL B cells. Thus, in this report we demonstrate that in a physiological system, activation of endogenous members of the ICE family, including CPP32, and cleavage of the death substrate PARP act as major effectors of apoptotic death.

Amino Acid Chloromethyl Ketones↗
PubMed1994

Single-stranded DNA-protein binding in the procyclic acidic repetitive protein (PARP) promoter of Trypanosoma brucei.

We performed gel retardation analyses of DNA-protein interactions using DNA from the procyclic acidic repetitive protein (PARP) promoter of the protozoan parasite Trypanosoma brucei. The PARP genes of Trypanosoma brucei are transcribed in an alpha-amanitin resistant manner, and it has been proposed that RNA polymerase I, rather than RNA polymerase II, transcribes the PARP genes. Double-stranded restriction fragments containing the essential PARP-promoter regions bound only sequence-nonspecific nuclear factors, even though protein factors that bind specifically to double-stranded DNA from the snRNA U2 promoter were present in the extracts. In contrast, single-stranded DNA-binding proteins bound with high affinity, nucleotide-sequence and strand-specificity to the -69/-55 element and the coding and non-coding strands of the -37/-11 element.

Animals↗
PubMed2005

Theophylline prevents NAD+ depletion via PARP-1 inhibition in human pulmonary epithelial cells.

Oxidative DNA damage, as occurs during exacerbations in chronic obstructive pulmonary disease (COPD), highly activates the nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1). This can lead to cellular depletion of its substrate NAD+, resulting in an energy crisis and ultimately in cell death. Inhibition of PARP-1 results in preservation of the intracellular NAD+ pool, and of NAD+-dependent cellular processes. In this study, PARP-1 activation by hydrogen peroxide decreased intracellular NAD+ levels in human pulmonary epithelial cells, which was found to be prevented in a dose-dependent manner by theophylline, a widely used compound in the treatment of COPD. This enzyme inhibition by theophylline was confirmed in an ELISA using purified human PARP-1 and was found to be competitive by nature. These findings provide new mechanistic insights into the therapeutic effect of theophylline in oxidative stress-induced lung pathologies.

Cell Line, Tumor↗
PubMed2006

Down-regulation of PARP-1, but not of Ku80 or DNA-PKcs', results in higher gene targeting efficiency.

The viability of non-homologous end-joining (NHEJ)-defective mice suggests that homologous recombination (HR) might take over its role in DNA repair. To test this hypothesis, we examined gene targeting frequencies (TF) in DNA-PK(cs), Ku80 and poly(ADP-ribose) polymerase (PARP-1) nullizygous cells. We observed a 3-fold TF increase in PARP-1 knockout embryonic stem (ES) cells, which is consistent with the predicted role of PARP-1 as a switch between HR and NHEJ. To a lesser extent, such effect could be reproduced upon chemical inhibition of PARP-1. However, TF was not enhanced in Ku80- or DNA-PK(cs)-defective cells. Our study also suggests an unexpected involvement of DNA-PK(cs) in HR.

Animals↗
PubMed2006

Expression of adhesion molecular proteins in the cochlear lateral wall of normal and PARP-1 mutant mice.

Sound can damage peripheral cochlear function through a number of mechanisms, and emerging evidence suggests that inflammation may be one of them. Using immunohistochemistry and poly (ADP-ribose) polymerase-1 (PARP-1) mutant mice, we tested whether PARP-1 contributes to loud-sound induced cochlear lateral wall damage by triggering inflammatory effects, including upregulating intercellular adhesion molecule-1 (ICAM-1), P-selectin and platelet-endothelial cell-adhesion molecule-1 (PECAM-1). In control conditions, we found that there was no detectable poly-ADP-ribose (PAR) in the marginal cells and microvessels. ICAM-1 was expressed only at low levels in the vessels of the stria vascularis and the spiral ligament. P-selectin and PECAM-1 were barely detected and only in the vessels of the spiral ligament. Following loud-sound exposure, PAR was detected in numbers of marginal cells and some vessels of the spiral ligament. Also, an elevated expression of ICAM-1 was demonstrated in some vessels of the stria vascularis and spiral ligament. Increased expression of P-selectin and PECAM-1 were mainly located in the vessels of the spiral ligament, while increased populations of non-migrated and migrated leukocytes were observed in the area of the spiral ligament. However, neither increased expression of adhesion proteins nor increased population of leukocytes, were observed in the PARP-1 knockout mouse. We thus conclude that loud-sound stress activates the expression of adhesion molecular proteins in the lateral wall and that PARP-1 modulates inflammation-linked protein expression and leukocyte migration.

Animals↗
PubMed2004

Neuroprotective effects of ONO-1924H, an inhibitor of poly ADP-ribose polymerase (PARP), on cytotoxicity of PC12 cells and ischemic cerebral damage.

N-[3-(4-Oxo-3,4-dihydro-phthalazin-1-yl)phenyl]-4-(morpholin-4-yl) butanamide methanesulfonate monohydrate (ONO-1924H) is a novel inhibitor of poly ADP-ribose polymerase (PARP). In this study, we examined the effects of ONO-1924H on cytotoxicity induced by hydrogen peroxide in PC12 cells in vitro and cerebral damage and neurological deficits induced by middle cerebral artery (MCA) thrombus occlusion in vivo in rat. In the in vitro cytotoxicity assay, exposure to 0.5 mmol/L hydrogen peroxide induced cell death in differentiated PC12 cells. ONO-1924H, a PARP inhibitor (Ki=0.21 micromol/L), reduced cell death in a concentration-dependent manner that was correlated with inhibition of PARP activation. A 50% reduction in cell death (EC50) was achieved with 2.4 micromol/L ONO-1924H. In the MCA occlusion model, ONO-1924H was injected intravenously at doses of 3, 10 and 30 mg/kg/h for 3 h, and cerebral damage and neurological deficits were estimated 24 h after MCA occlusion. ONO-1924H treatment led to a significant decrease in cerebral damage in the 10 mg/kg/h-treated group (P < 0.05) and the 30 mg/kg/h-treated group (P < 0.01). Further, ONO-1924H at doses of 30 mg/kg/h significantly (P < 0.05) improved neurological deficits. These findings suggest that the novel PARP inhibitor, ONO-1924H, affords effective neuroprotection and is a useful therapeutic candidate for the treatment of ischemic stroke.

Animals↗
PubMed2006

In vitro effect of the potent poly(ADP-ribose) polymerase (PARP) inhibitor INO-1001 alone and in combination with aspirin, eptifibatide, tirofiban, enoxaparin or alteplase on haemostatic parameters.

It has been shown that PARP inhibition is protective in several models of ischemia-reperfusion injury including cardiac, cerebral and renal ones. Due to their ability to reduce myocardial necrosis and to improve myocardial function PARP inhibitors emerged as candidates for treating various cardiovascular diseases including acute myocardial ischemia. Since the pathophysiology of acute ischemic cardiac diseases involves haemostatic impairment and the therapeutic regimen includes antithrombotic drugs, we investigated the effect of the potent poly(ADP-ribose) polymerase (PARP) inhibitor INO-1001 alone and in combination with platelet aggregation inhibitors (aspirin, eptifibatide and tirofiban), unfractionated heparin, low molecular weight heparin (enoxaparin) or the recombinant fibrinolytic drug (alteplase), on various haemostatic parameters in vitro. ADP- and epinephrine-induced platelet aggregation was evaluated by optical aggregometry in the presence or absence of different concentrations of INO-1001, in combination with aspirin, tirofiban, eptifibatide or saline on ten healthy volunteers' platelet rich plasma (PRP). Activated partial thromboplastin time, Anti-Xa activity and euglobulin lysis time were determined in the presence or absence of different concentrations of INO-1001, in combination with sodium heparin, enoxaparin or alteplase, respectively. INO-1001, on its own does not affect the measured platelet, and haemostatic functions, i.e. does not reduce the respective anti-platelet, anti-coagulant and thrombolytic activity of therapeutically relevant concentrations of aspirin, tirofiban, eptifibatide, enoxaparin and alteplase in vitro. INO-1001 enhanced the effects of heparins above therapeutic ranges; the magnitude of this effect was negligible. Consequently, the PARP inhibitor INO-1001 can be safely applied together with the drugs tested.

Aspirin↗
PubMed2006

Condensin I interacts with the PARP-1-XRCC1 complex and functions in DNA single-strand break repair.

Condensins are essential protein complexes critical for mitotic chromosome organization. Little is known about the function of condensins during interphase, particularly in mammalian cells. Here we report the interphase-specific interaction between condensin I and the DNA nick-sensor poly(ADP-ribose) polymerase 1 (PARP-1). We show that the association between condensin I, PARP-1, and the base excision repair (BER) factor XRCC1 increases dramatically upon single-strand break damage (SSB) induction. Damage-specific association of condensin I with the BER factors flap endonuclease 1 (FEN-1) and DNA polymerase delta/epsilon was also observed, suggesting that condensin I is recruited to interact with BER factors at damage sites. Consistent with this, DNA damage rapidly stimulates the chromatin association of PARP-1, condensin I, and XRCC1. Furthermore, depletion of condensin in vivo compromises SSB but not double-strand break (DSB) repair. Our results identify a SSB-specific response of condensin I through PARP-1 and demonstrate a role for condensin in SSB repair.

Adenosine Triphosphatases↗
PubMed2005

Ageing and PARP.

Poly(ADP-ribosyl)ation, which is the posttranslational modification of proteins with poly(ADP-ribose), is catalysed by poly(ADP-ribose) polymerases. DNA-strand break induced catalytic activation of two PARP isoforms, namely PARP-1 and -2, are in involved in DNA base-excision repair and other repair pathways. A body of correlative data suggests a link between DNA-damage induced poly(ADP-ribosyl)ation and mammalian longevity. This notion was reinforced by recently published evidence for interactions between PARP-1 and the Werner syndrome protein, deficiency of which causes premature ageing in humans. Recent research on PARPs and poly(ADP-ribose) provides several candidate mechanisms through which poly(ADP-ribosyl)ation might contribute to keeping the ageing process at slow pace.

Aging↗
PubMed2004

Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling.

Different cell-death mechanisms control many physiological and pathological processes in humans. Mitochondria play important roles in cell death through the release of pro-apoptotic factors such as cytochrome c and apoptosis-inducing factor (AIF), which activate caspase-dependent and caspase-independent cell death, respectively. Poly(ADP-ribose) polymerase 1 (PARP-1) is emerging as an important activator of caspase-independent cell death. PARP-1 generates the majority of long, branched poly(ADP-ribose) (PAR) polymers following DNA damage. Overactivation of PARP-1 initiates a nuclear signal that propagates to mitochondria and triggers the release of AIF. AIF then shuttles from mitochondria to the nucleus and induces peripheral chromatin condensation, large-scale fragmentation of DNA and, ultimately, cytotoxicity. Identification of the pro-death and pro-survival signals in the PARP-1-mediated cell-death program might provide novel therapeutic targets in human diseases.

Apoptosis Inducing Factor↗
PubMed2003

Towards new neuroprotective agents: design and synthesis of 4H-thieno[2,3-c] isoquinolin-5-one derivatives as potent PARP-1 inhibitors.

An excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme able to catalyze the transfer of ADP-ribose from NAD to acceptor proteins, is involved in the progression of neuronal damage after brain insult. Potent and selective PARP-1 inhibitors have neuroprotective properties in experimental models of brain ischemia. As a follow up of our previous structure-activity relationship study and in search for novel potent PARP-1 inhibitors, a series of 4H-thieno[2,3-c]-isoquinolin-5-one derivatives was designed and synthesized. Tested for their ability to inhibit PARP-1, these novel derivatives showed high inhibitory potency. The unsubstituted derivative TIQ was selected for further characterization and found to be endowed with strong neuroprotective properties in models of cerebral ischemia.

Animals↗
PubMed2001

Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death.

Poly(ADP-ribose) polymerase (PARP) is responsible for post-translational modification of proteins in the response to numerous endogenous and environmental genotoxic agents. PARP and poly(ADP-ribosyl)ation are proposed to be important for the regulation of many cellular processes such as DNA repair, cell death, chromatin functions and genomic stability. Activation of PARP is one of the early DNA damage responses, among other DNA sensing molecules, such as DNA-PK, ATM and p53. The generation and characterization of PARP deficient mouse models have been instrumental in defining the biological role of the molecule and its involvement in the pathogenesis of various diseases including diabetes, stroke, Parkinson disease, general inflammation as well as tumorigenesis, and have, therefore, provided information for the development of pharmaceutical strategies for the treatment of diseases.

Animals↗
PubMed2002

CDP-choline reduces pro-caspase and cleaved caspase-3 expression, nuclear DNA fragmentation, and specific PARP-cleaved products of caspase activation following middle cerebral artery occlusion in the rat.

Citicoline has been demonstrated to be beneficial in several models of cerebral ischaemia. We tested the hypothesis that citicoline may provide apoptotic pathways following focal cerebral ischaemia. Focal cerebral ischaemia was produced by distal, permanent middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. The animals were randomised into four groups: (B+A) Citicoline 500 mg/kg IP 24 and 1 h before MCAO, and 23 h after MCAO; (A) citicoline 500 mg/kg IP, within 30 min after MCAO, and 23 h after MCAO; (C) vehicle IP; and (D) sham-operated. The animals were sacrificed at 12 h (n=8 per group) and 24 h (n=8 per group) after MCAO. Immunohistochemistry was performed on free-floating tissue sections with goat polyclonal antibodies to procaspase-1, -2, -3, -6 and -8, and in paraffin-embedded sections processed for cleaved caspase-3 (17 kDa) immunohistochemistry. Finally, some sections were stained with the method of in situ end-labelling of nuclear DNA fragmentation. For gel electrophoresis and Western blotting, antibodies to poly (ADP-ribose) polymerase (PARP) products of 89 kDa were used to reveal specific cleavage substrates of caspases. MCAO induced the expression of all procaspases and the expression of PARP products of 89 kDa, as well as cells with nuclear DNA fragmentation, at 12 and 24 h, in the infarcted core and penumbra. Citicoline reduced the expression of all procaspases at 12 and 24 h after MCAO, as well as the expression of cleaved caspase-3 in cells in the penumbra area. This was accompanied by a reduction in the number of cells bearing nuclear DNA fragments. The expression of caspase-cleaved products of PARP (PARP 89 kDa) was reduced in citicoline-treated ischaemic rats. These results show that citicoline inhibits the expression of proteins involved in apoptosis following MCAO.

Animals↗
PubMed2001

H2O2-induced cell death in human glioma cells: role of lipid peroxidation and PARP activation.

Reactive oxygen species (ROS) have been implicated in the pathogenesis of a number of neurodegenerative disorders. However, the underlying mechanism of ROS-induced cell injury remains to be defined. This study was undertaken to examine the role of lipid peroxidation and poly (ADP-ribose) polymerase (PARP) activation in H2O2-induced cell death in A172 cells, a human glioma cell line. H2O2 induced a dose- and time-dependent cell death. The cell death was prevented by thiols (dithiothreitol and glutathione), iron chelators (deferoxamine and phenanthroline), H2O2 scavengers (catalase and pyruvate), and a hydroxyl radical scavenger (dimethylthiourea). Antioxidants N,N'-diphenyl-p-phenylenediamine (DPPD) and Trolox had no effect on the H2O2-induced cell death. Lipid peroxidation did not increase in human glioma cells exposed to H2O2. The PARP inhibitor 3-aminobenzamide prevented the cell death induced by H2O2. The PARP activity was increased by H2O2 and the H2O2 effect was prevented by 3-aminobenzamide, dithiothreitol, and phenanthroline. The ATP depletion induced by H2O2 was prevented by catalase, dithiothreitol, phenanthroline, and 3-aminobenzamide, but not by DPPD. These results indicate that the H2O2-induced cell death is mediated by PARP activation but not by lipid peroxidation in human glioma cells.

Benzamides↗
PubMed2006

Pyruvate improves recovery after PARP-1-associated energy failure induced by oxidative stress in neonatal rat cerebrocortical slices.

Previous neuron and glial cell culture studies of excessive poly (ADP-ribose) polymerase (PARP-1) activation found NAD(+) depletion, glycolytic arrest, and cell death that could be avoided by exogenous tricarboxylic acid cycle (TCA) metabolites, especially pyruvate (pyr). Pyruvate neuroprotection has been attributed to cytosolic NAD(+) replenishment, TCA metabolism, and antioxidant activity. We investigated the first two mechanisms in respiring cerebrocortical slices after a 1-h H(2)O(2) exposure to activate PARP-1. H(2)O(2) was followed by a 4-h recovery with oxy-artificial cerebrospinal fluid superfusion having either: (1) no glucose (glc) or pyruvate; (2) 10 mmol/L glc only; (3) 10 mmol/L pyruvate only; (4) both 10 mmol/L glc and 10 mmol/L pyruvate. Poly-ADP-ribosylation was quantified from Western blots and immunohistochemistry. Perchloric acid extracts were quantified with 14.1 T (31)P nuclear magnetic resonance spectroscopy. Just after H(2)O(2) exposure, ATP and NAD(+) decreased by approximately 50%, PCr decreased by 75%, and the ADP/ATP ratio approximately doubled. ATP and NAD(+) changes, but not PCr changes, were nearly eliminated if PARP inhibitors accompanied the H(2)O(2). Recovery with both pyruvate and glc was better than with glc alone, having higher ATP (0.161 versus 0.075, P<0.01) and PCr levels (0.144 versus 0.078, P<0.01), and higher viable cell counts in TUNEL and Fluoro-Jade B staining. Two-dimensional [(1)H-(13)C] HSQC spectra showed metabolism during recovery of (13)C glc or pyr. Pyruvate metabolism was primarily via pyruvate dehydrogenase, with some via pyruvate carboxylation. Pyruvate superfusion of PARP-injured brain slices helps replenish NAD(+) while providing metabolic fuel. Although this augments recovery, a strong antioxidant role for pyruvate has not been ruled out.

Animals↗