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Defective transcription factor activation for proinflammatory gene expression in poly(ADP-ribose) polymerase 1-deficient glia.

ABSTRACT: Poly(ADP-ribose) polymerase 1 (PARP-1) activity is detected in both neuronal and nonneuronal cells in the CNS, and excessive PARP-1 activity is known to be detrimental to tissue because of the cellular energy loss. Accordingly, PARP-1-deficient (PARP-1(-/-)) mice have been shown to be resistant to cerebral ischemia and several forms of inflammation. Recently, PARP-1 in glial cells has been shown to mediate the expression of proinflammatory genes in response to inflammatory stimuli by, in part, enhancing cognate DNA-binding capacities of transcription factors such as NF-kappaB and activator protein 1. Here, we demonstrate an additional mechanism whereby a significant reduction of proinflammatory gene expression such as IL-1beta, tumor necrosis factor alpha, and inducible nitricoxide synthase in PARP-1(-/-) glial cells is linked to defective inflammatory stimuli-induced p38MAPK-mediated phosphorylation of ATF-2 and cAMP-response element-binding protein and phosphorylation of NF-kappaB p65. Importantly, an inflammatory stimuli-induced p38MAPK activation is impaired in PARP-1(-/-) glial cells in a signaling pathway- and cell/tissue type-specific manner. These findings indicate that PARP-1 is an essential host factor among factors that actively mediate excessive production of proinflammatory molecules in glial cells, which may in turn contribute to the initiation of neuronal injuries.

SUBMITTER: Ha HC

PROVIDER: S-EPMC387378 | biostudies-other | 2004 Apr

REPOSITORIES: biostudies-other

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Transcriptional regulation by poly(ADP-ribose) polymerase-1 during T cell activation.

Project description:Accumulating evidence suggests an important role for the enzyme poly(ADP-ribose) polymerase-1 (PARP-1) as an integral part of the gene expression regulatory machinery during development and in response to specific cellular signals. PARP-1 might modulate gene expression through its catalytic activity leading to poly(ADP-ribosyl)ation of nuclear proteins or by its physical association with relevant proteins. Recently, we have shown that PARP-1 is activated during T cell activation. However, the proposed role of PARP-1 in reprogramming T cell gene expression upon activation remains largely unexplored.In the present study we use oligonucleotide microarray analysis to gain more insight into the role played by PARP-1 during the gene expression reprogramming that takes place in T cells upon activation with anti-CD3 stimulation alone, or in combination with anti-CD28 co-stimulation. We have identified several groups of genes with expression modulated by PARP-1. The expression of 129 early-response genes to anti-CD3 seems to be regulated by PARP-1 either in a positive (45 genes) or in a negative manner (84 genes). Likewise, in the presence of co-stimulation (anti-CD3 + anti-CD28 stimulation), the expression of 203 genes is also regulated by PARP-1 either up (173 genes) or down (30 genes). Interestingly, PARP-1 deficiency significantly alters expression of genes associated with the immune response such as chemokines and genes involved in the Th1/Th2 balance.This study provides new insights into changes in gene expression mediated by PARP-1 upon T cell activation. Pathway analysis of PARP-1 as a nuclear signalling molecule in T cells would be of relevance for the future development of new therapeutic approaches targeting PARP-1 in the acquired immune response.

| S-EPMC2375913 | biostudies-literature

Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma.

Project description:PURPOSE OF REVIEW:In 2012, two publications revealed a particular sensitivity of Ewing sarcoma cells to the inhibition of poly(ADP-ribose) polymerase (PARP). This review updates the reader on PARP function, the development of PARP inhibitors (PARPi) and the evidence for targeting PARP in Ewing sarcoma. It concludes with a description of ongoing/emerging PARPi clinical trials in patients with Ewing sarcoma. RECENT FINDINGS:PARP has a major role in DNA repair, and is a transcription regulator. The oncoprotein in Ewing sarcoma, EWS-FLI1, is proposed to interact with PARP-1, driving PARP-1 expression, which further promotes transcriptional activation by EWS-FLI1. Thus, there are two rationales for PARPi in the treatment of Ewing sarcoma: to disrupt the interaction between EWS-FLI1 and PARP, and for chemo-potentiation or radio-potentiation. The first clinical trial with a single agent PARPi failed to show significant responses, but preclinical evidence for combinations of PARPi with chemotherapy or radiotherapy is very promising. SUMMARY:Despite initial excitement for the potential of PARPi as single agent therapy in Ewing sarcoma, the emerging preclinical data now strongly support testing PARPi in combination with chemo/radiotherapy clinically.

| S-EPMC4059819 | biostudies-literature

Elevated poly-(ADP-ribose)-polymerase activity sensitizes retinoblastoma-deficient cells to DNA damage-induced necrosis.

Project description:The retinoblastoma (Rb) tumor suppressor is a key regulator of cell cycle checkpoints but also protects against cell death induced by stresses such as DNA damage and death receptor ligation. We report here that cell death of Rb-deficient cells exposed to key genotoxic agents was associated with increased expression of S phase-specific E2F target genes and cell death consistently occurred in the S phase of the cell cycle. Cell cycle arrest induced by serum starvation prevented S phase entry, attenuated DNA damage, and promoted survival, suggesting that Rb-null cells die due to a failure to prevent S phase entry. DNA damage-induced death of Rb-null cells was associated with nucleotide depletion, higher activity of poly-ADP-ribose-polymerase (Parp), and cell death that was primarily necrotic. Knockdown of Parp-1 or chemical inhibition of Parp activity prevented nucleotide depletion and restored the viability of Rb-deficient cells to wild-type levels. Furthermore, chemical inhibition of Parp activity in vivo attenuated the cytotoxic effects of cisplatin against Rb-deficient tumors, arguing that Parp inhibitors should not be used therapeutically in combination with genotoxic drugs against tumors that are inactivated for the Rb tumor suppressor.

| S-EPMC2994938 | biostudies-literature

Poly(ADP) ribose polymerase promotes DNA polymerase theta-mediated end joining by activation of end resection.

Project description:The DNA polymerase theta (Polθ)-mediated end joining (TMEJ) pathway for repair of chromosomal double strand breaks (DSBs) is essential in cells deficient in other DSB repair pathways, including hereditary breast cancers defective in homologous recombination. Strand-break activated poly(ADP) ribose polymerase 1 (PARP1) has been implicated in TMEJ, but the modest specificity of existing TMEJ assays means the extent of effect and the mechanism behind it remain unclear. We describe here a series of TMEJ assays with improved specificity and show ablation of PARP activity reduces TMEJ activity 2-4-fold. The reduction in TMEJ is attributable to a reduction in the 5' to 3' resection of DSB ends that is essential for engagement of this pathway and is compensated by increased repair by the nonhomologous-end joining pathway. This limited role for PARP activity in TMEJ helps better rationalize the combined employment of inhibitors of PARP and Polθ in cancer therapy.

| S-EPMC9352658 | biostudies-literature

Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells.

Project description:Poly(ADP-ribose) polymerase (PARP) inhibitors are strikingly toxic to cells with defects in homologous recombination (HR). The mechanistic basis for these findings is incompletely understood. Here, we show that PARP inhibitor treatment induces phosphorylation of DNA-dependent protein kinase substrates and stimulates error-prone nonhomologous end joining (NHEJ) selectively in HR-deficient cells. Notably, inhibiting DNA-dependent protein kinase activity reverses the genomic instability previously reported in these cells after PARP inhibition. Moreover, disabling NHEJ by using genetic or pharmacologic approaches rescues the lethality of PARP inhibition or down-regulation in cell lines lacking BRCA2, BRCA1, or ATM. Collectively, our results not only implicate PARP1 catalytic activity in the regulation of NHEJ in HR-deficient cells, but also indicate that deregulated NHEJ plays a major role in generating the genomic instability and cytotoxicity in HR-deficient cells treated with PARP inhibitors.

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Loss of E2F7 confers resistance to poly-ADP-ribose polymerase (PARP) inhibitors in BRCA2-deficient cells.

Project description:BRCA proteins are essential for homologous recombination (HR) DNA repair, and their germline or somatic inactivation is frequently observed in human tumors. Understanding the molecular mechanisms underlying the response of BRCA-deficient tumors to chemotherapy is paramount for developing improved personalized cancer therapies. While PARP inhibitors have been recently approved for treatment of BRCA-mutant breast and ovarian cancers, not all patients respond to this therapy, and resistance to these novel drugs remains a major clinical problem. Several mechanisms of chemoresistance in BRCA2-deficient cells have been identified. Rather than restoring normal recombination, these mechanisms result in stabilization of stalled replication forks, which can be subjected to degradation in BRCA2-mutated cells. Here, we show that the transcriptional repressor E2F7 modulates the chemosensitivity of BRCA2-deficient cells. We found that BRCA2-deficient cells are less sensitive to PARP inhibitor and cisplatin treatment after E2F7 depletion. Moreover, we show that the mechanism underlying this activity involves increased expression of RAD51, a target for E2F7-mediated transcriptional repression, which enhances both HR DNA repair, and replication fork stability in BRCA2-deficient cells. Our work describes a new mechanism of therapy resistance in BRCA2-deficient cells, and identifies E2F7 as a putative biomarker for tumor response to PARP inhibitor therapy.

| S-EPMC6158596 | biostudies-literature

Activation of the abundant nuclear factor poly(ADP-ribose) polymerase-1 by Helicobacter pylori.

Project description:Modification of eukaryotic proteins is a powerful strategy used by pathogenic bacteria to modulate host cells during infection. Previously, we demonstrated that Helicobacter pylori modify an unidentified protein within mammalian cell lysates in a manner consistent with the action of a bacterial ADP-ribosylating toxin. Here, we identified the modified eukaryotic factor as the abundant nuclear factor poly(ADP-ribose) polymerase-1 (PARP-1), which is important in the pathologies of several disease states typically associated with chronic H. pylori infection. However, rather than being ADP-ribosylated by an H. pylori toxin, the intrinsic poly(ADP-ribosyl) polymerase activity of PARP-1 is activated by a heat- and protease-sensitive H. pylori factor, resulting in automodification of PARP-1 with polymers of poly(ADP-ribose) (PAR). Moreover, during infection of gastric epithelial cells, H. pylori induce intracellular PAR-production by a PARP-1-dependent mechanism. Activation of PARP-1 by a pathogenic bacterium represents a previously unrecognized strategy for modulating host cell signaling during infection.

| S-EPMC2785281 | biostudies-literature

Hippocampal poly(ADP-Ribose) polymerase 1 and caspase 3 activation in neonatal bornavirus infection.

Project description:Infection of neonatal rats with Borna disease virus results in a characteristic behavioral syndrome and apoptosis of subsets of neurons in the hippocampus, cerebellum, and cortex (neonatal Borna disease [NBD]). In the NBD rat hippocampus, dentate gyrus granule cells progressively degenerate. Apoptotic loss of granule cells in NBD is associated with accumulation of zinc in degenerating neurons and reduced zinc in granule cell mossy fibers. Excess zinc can trigger poly(ADP-ribose) polymerase 1 (PARP-1) activation, and PARP-1 activation can mediate neuronal death. Here, we evaluate hippocampal PARP-1 mRNA and protein expression levels, activation, and cleavage, as well as apoptosis-inducing factor (AIF) nuclear translocation and executioner caspase 3 activation, in NBD rats. PARP-1 mRNA and protein levels were increased in NBD hippocampi. PARP-1 expression and activity were increased in granule cell neurons and glia with enhanced ribosylation of proteins, including PARP-1 itself. In contrast, levels of poly(ADP-ribose) glycohydrolase mRNA were decreased in NBD hippocampi. PARP-1 cleavage and AIF expression were also increased in astrocytes in NBD hippocampi. Levels of activated caspase 3 protein were increased in NBD hippocampi and localized to nuclei, mossy fibers, and dendrites of granule cell neurons. These results implicate aberrant zinc homeostasis, PARP-1, and caspase 3 activation as contributing factors in hippocampal neurodegeneration in NBD.

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Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics.

Project description:The year of 2005 was a watershed in the history of poly(ADP-ribose) polymerase (PARP) inhibitors due to the important findings of selective killing in BRCA-deficient cancers by PARP inhibition. The findings made PARP inhibition one of the most promising new therapeutic approaches to cancers, especially to those with specific defects. With AZD2281 and BSI-201 entering phase III clinical trials, the final application of PARP inhibitors in clinic would come true soon. This current paper will review the major advances in targeting PARP for cancer therapy and discuss the existing questions, the answers to which may influence the future of PARP inhibitors as cancer therapeutics.

| S-EPMC4002295 | biostudies-literature

Family-wide analysis of poly(ADP-ribose) polymerase activity.

Project description:The poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) protein family generates ADP-ribose (ADPr) modifications onto target proteins using NAD(+) as substrate. Based on the composition of three NAD(+) coordinating amino acids, the H-Y-E motif, each PARP is predicted to generate either poly(ADPr) (PAR) or mono(ADPr) (MAR). However, the reaction product of each PARP has not been clearly defined, and is an important priority since PAR and MAR function via distinct mechanisms. Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. We identify automodification sites on seven PARPs, and demonstrate that MAR and PAR generating PARPs modify similar amino acids, suggesting that the sequence and structural constraints limiting PARPs to MAR synthesis do not limit their ability to modify canonical amino-acid targets. In addition, we identify cysteine as a novel amino-acid target for ADP-ribosylation on PARPs.

| S-EPMC4123609 | biostudies-literature

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