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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carcinogenesis involves multiple steps and pathways with functional alterations in a variety of genes. There is accumulating evidence that a deficiency of poly(ADP-ribose) polymerase (PARP)-1 leads to DNA repair defects, genomic instability, failure of induction of cell death and modulation of gene transcription. PARP-1 also supports the growth of tumor cells in certain situations. Genetic analyses of the PARP-1 gene have demonstrated alterations in neoplasms, and a mutation affecting the conserved amino acid E251 in germ cell tumors, as well as an association of a single-nucleotide polymorphism V762A with risk of prostate cancer. Recent development of a selective inhibitor of poly(ADP-ribose) glycohydrolase (PARG), the enzyme primarily responsible for degradation of poly(ADP-ribose), and PARG-deficient animals should facilitate studies of the relationship of poly(ADP-ribose) with carcinogenesis. Inhibitors of PARP have also suggested roles in the pathogenesis of autoimmune disease, and a promoter haplotype of PARP-1 confers a higher risk of rheumatoid arthritis. Further analysis of PARP-1, PARG and other PARP family genes should extend our understanding of the pathogenesis of cancer and autoimmune diseases. Furthermore, there is potential for sensitization to chemo- and radiation therapy of cancers as well as the treatment of autoimmune disease with development of stronger PARP inhibitors.
Cell Mol Life Sci 2005 Apr
PMID:Poly(ADP-ribosyl)ation in relation to cancer and autoimmune disease. 1586 2

Engagement of integrin cell adhesion receptors in mouse lung endothelial cells induces global sensitivity of DNA to nuclease digestion, reflecting alterations in chromatin structure. These structural changes may contribute to the antigenotoxic effects of integrin engagement in lung endothelium. Because histone acetylation and poly(ADP-ribosyl)ation modulate chromatin structure, we investigated the effects of beta1 integrin engagement with antibody on these post-translational modifications and the presence of histones at discrete DNA sequences in the mouse lung endothelial cell genome using chromatin immunoprecipitation. Integrin engagement increased acetylation of core histone H3. The presence of acetylated histone H3 at intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) promoters, and a nonpromoter sequence was also increased. As with integrin engagement, the histone deacetylase inhibitor trichostatin A caused global hypersensitivity of DNA to nuclease digestion and induced acetylation of histone H3 and its coimmunoprecipitation with VCAM-1 and ICAM-1 promoters and nonpromoter DNA. In contrast to acetyl-histone H3, the association of linker histone H1 with specific DNA sequences was either reduced or unaffected by integrin engagement and trichostatin A. Although integrin engagement and trichostatin A treatment did not affect histone H1 poly(ADP-ribosyl)ation, deletion of poly(ADP-ribose) polymerase-1 increased core histone H3 acetylation and increased its level at the iNOS promoter while decreasing the amount of histone H1. The results suggest that integrin engagement, as well as trichostatin A and PARP-1 deletion, regulate chromatin structure via core histone H3 acetylation and reduced linker histone H1-DNA association.
Mol Pharmacol 2005 Aug
PMID:Integrin engagement increases histone H3 acetylation and reduces histone H1 association with DNA in murine lung endothelial cells. 1590 51

Poly(ADP-ribose) polymerase (PARP)-1 is a DNA nick sensor that transforms ADP-ribose from betaNAD+ in the form of polymer to over 40 nuclear proteins, particularly to histones, several transcription factors, and PARP itself, modulating their activities and functions. PARP-1 activated by DNA breaks facilitates transcription, replication, and DNA base excision repair. The last studies indicate that PARP-1 is the new nuclear target for fast signals evoked in cell membranes by depolarization and cholinergic and glutaminergic receptors stimulation. Excessive activation of PARP-1 by peroxynitrate-evoked DNA damage during oxidative stress can cause cell death by NAD+/ATP depletion after ischemia-reperfusion injury, inflammation, and diabetes mellitus. The PARP-1 through interaction with nuclear factor-kappaB, p53, and other transcription factors might significantly modulate cell survival and death and a type of death pathway. The pharmacological modulation of PARP-1 might offer a new effective approach for neuroprotection.
Mol Neurobiol 2005
PMID:Poly(ADP-ribose) polymerase: the nuclear target in signal transduction and its role in brain ischemia-reperfusion injury. 1595 18

Cockayne syndrome (CS) is a rare genetic disorder characterized as a segmental premature-aging syndrome. The CS group B (CSB) protein has previously been implicated in transcription-coupled repair, transcriptional elongation, and restoration of RNA synthesis after DNA damage. Recently, evidence for a role of CSB in base excision repair of oxidative DNA lesions has accumulated. In our search to understand the molecular function of CSB in this process, we identify a physical and functional interaction between CSB and poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a nuclear enzyme that protects the integrity of the genome by responding to oxidative DNA damage and facilitating DNA repair. PARP-1 binds to single-strand DNA breaks which activate the catalytic ability of PARP-1 to add polymers of ADP-ribose to various proteins. We find that CSB is present at sites of activated PARP-1 after oxidative stress, identify CSB as a new substrate of PARP-1, and demonstrate that poly(ADP-ribosyl)ation of CSB inhibits its DNA-dependent ATPase activity. Furthermore, we find that CSB-deficient cell lines are hypersensitive to inhibition of PARP. Our results implicate CSB in the PARP-1 poly(ADP-ribosyl)ation response after oxidative stress and thus suggest a novel role of CSB in the cellular response to oxidative damage.
Mol Cell Biol 2005 Sep
PMID:Cooperation of the Cockayne syndrome group B protein and poly(ADP-ribose) polymerase 1 in the response to oxidative stress. 1610 9

Hyperoxia induces extensive DNA damage and lung cell death by apoptotic and nonapoptotic pathways. We analyzed the regulation of Poly(ADP-ribose)polymerase-1 (PARP-1), a nuclear enzyme activated by DNA damage, and its relation to cell death during hyperoxia in vitro and in vivo. In lung epithelial-derived A549 cells, which are known to die by necrosis when exposed to oxygen, a minimal amount of PARP-1 was cleaved, correlating with the absence of active caspase-3. Conversely, in primary lung fibroblasts, which die mainly by apoptosis, the complete cleavage of PARP-1 was concomitant to the induction of active caspase-3, as assessed by Western blot and caspase activity. Blockade of caspase activity by Z-VAD reduced the amount of cleaved PARP-1 in fibroblasts. Hyperoxia induced PARP activity in both cell types, as revealed by poly-ADP-ribose accumulation. In A549 cells, the final outcome of necrosis was dependent on PARP activity because it was prevented by the PARP inhibitor 3-aminobenzamide. In contrast, apoptosis of lung fibroblasts was not sensitive to 3-aminobenzamide and was not affected by PARP-1 deletion. In vivo, despite evidence of PARP activation in hyperoxia-exposed mouse lungs, absence of PARP-1 did not change the extent of lung damage, arguing for redundant oxidative stress-induced cell death pathways.
Am J Respir Cell Mol Biol 2005 Dec
PMID:Poly(ADP-ribose)polymerase activation mediates lung epithelial cell death in vitro but is not essential in hyperoxia-induced lung injury. 1615 Oct 53

Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication and/or DNA repair. The poly(ADP-ribose) polymerase-1 (PARP-1) enzyme is also involved in DNA repair and is known to affect transcription of several genes. In this study, we examined the expression profile of cells lacking the normal function of either or both enzymes. All mutant cells exhibited altered expression of genes normally responding to oxidative stress. 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. 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. In addition, double mutant cultured cells showed major misregulation of genes involved in apoptosis, cell cycle control, embryonic development, metabolism and signal transduction. More importantly, in vivo analyses of double mutant mice have confirmed the increased apoptosis and the developmental defects in embryos as well as the major increase in intracellular phosphorylation and oxidative DNA damage in adult tissues. They also exhibited a progressive increase in oxidative stress with age. Thus, a major result of this study is that changes in expression of several genes and physiological functions identified in vitro were confirmed in mouse embryonic and adult tissues.
Hum Mol Genet 2005 Nov 01
PMID:In vivo misregulation of genes involved in apoptosis, development and oxidative stress in mice lacking both functional Werner syndrome protein and poly(ADP-ribose) polymerase-1. 1619 94

Efficient DNA double-strand break (DSB) repair is critical for the maintenance of genomic integrity. In mammalian cells, DSBs are preferentially repaired by the non-homologous end-joining pathway relying on DNA-PK activity, but other mechanisms may promote end-joining. We previously described a DSB repair pathway that requires synapsis of DNA ends by poly(ADP-ribose) polymerase-1 (PARP-1) and ligation by the XRCC1/DNA ligase III complex (XL). Here, the repair of non-ligatable DNA ends by this pathway was examined in human cell extracts. The phosphorylation of the 5'-terminal end was shown to represent a limiting step for the repair process. Polynucleotide kinase (hPNK) was identified as the 5'-DNA kinase associated with the PARP-1-dependent end-joining pathway because (i) hPNK was co-recruited to DNA ends together with PARP-1 and XL, (ii) ligation of 5'-OH terminal breaks was compromised in hPNK-depleted extracts and restored upon addition of recombinant hPNK, and (iii) recombinant hPNK was necessary for end-joining of 5'-OH terminal breaks reconstituted with the PARP-1/XL complex. Also, using an assay enabling us to follow the ligation kinetics of each strand of a DSB, we established that the two strands at the junction can be processed and joined independently, so that one strand can be ligated without a ligatable nick on the other strand at the DSB site. Taken together these results reveal functional parallels between the PARP-1 and DNA-PK-dependent end-joining processes.
J Mol Biol 2006 Feb 17
PMID:Involvement of polynucleotide kinase in a poly(ADP-ribose) polymerase-1-dependent DNA double-strand breaks rejoining pathway. 1636 63

Treatment of cells with lysophosphatidyl choline and centrifugal extraction can separate poly (ADP-ribose) synthetase (PARP-1) and DNA synthetase activities, permitting the experimental analysis and comparison of both multienzyme systems. Only PARP-1 is being assayed by our system. Ca(2+) and Mg(2+) have minor activating effects, and added histones are without activating action. Short end-blocked dsDNAs at nM concentrations and spermine at mM concentrations are maximally activating coenzymes of poly (ADP-ribose) synthesis. Comparison of non-proliferating non-malignant cells with rapidly growing cancer cells demonstrates that rates of poly (ADP-ribose) synthesis and DNA synthesis are highest in pre-confluent non-malignant cells and in proliferating cancer cells, and lowest in contact-inhibited non-malignant cells. Rates of poly (ADP-ribose) synthesis correlate with the number of enzymatically activable PARP-1 molecules per cell, determined under Vmax conditions where activity is linearly proportional to enzyme protein. Contact-inhibited non-malignant cells exhibit only trans-ADP-ribosylation that is not affected by ATP, while rapid growth, especially in cancer cells, demonstrates extensive auto-poly (ADP)-ribosylation that is strongly inhibited by ATP at concentrations present in cells exhibiting normal bioenergetics. Rates of mRNA synthesis in non-proliferating non-malignant cells and in cancer cells were indistinguishable, indicating that the differences observed between cellular phenotypes are most likely due to reassembly of PARP-1 molecules in nuclei to homo-dimers (in cancer cells) and hetero-dimers (in non-cancer cells). A specific inhibitor and an inactivator of PARP-1 each inhibit DNA synthesis when intact cancer cells are pretreated with these drugs. Direct addition of these drugs to permeabilized cells performing DNA synthesis has no effect on DNA synthesis. The most striking diagnostic signal for cancer cells is activation of PARP-1 and of DNA synthesis.
Int J Mol Med 2006 Feb
PMID:Quantitative correlation between cellular proliferation and nuclear poly (ADP-ribose) polymerase (PARP-1). 1639 29

Here we describe an in vitro chromatin transcription system in which chromatin assembly and transcription are carried out with purified and defined factors. With basal (also known as general) transcription factors and sequence-specific DNA-binding activators, we observed chromatin-specific, activation domain-dependent transcription. We then examined the biochemical function of purified p300 in the absence of the endogenous factor and other related activities and found, unexpectedly, that p300 has a chromatin-specific, transcriptional repression activity that can be relieved by the addition of acetyl-CoA. This p300-mediated repression is reversible, requires the p300 bromodomain but not the acetyltransferase region, and does not involve the formation of a stable, nuclease-resistant nucleoprotein complex. Hence, the mechanism of transcriptional repression by p300 is distinct from that of histone H1, PARP-1 or Sir2. These findings reveal a novel chromatin-specific repressive function of p300.
Nat Struct Mol Biol 2006 Feb
PMID:Reconstitution of chromatin transcription with purified components reveals a chromatin-specific repressive activity of p300. 1641 79

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.
Mol Cell 2006 Mar 17
PMID:Condensin I interacts with the PARP-1-XRCC1 complex and functions in DNA single-strand break repair. 1654 52


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