Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histones H2A and H2B are known to be reversibly post-translationally modified by ubiquitination. We previously observed in cultured tumor cells that proteasome inhibition stabilizes polyubiquitinated proteins, depletes unconjugated ubiquitin, and thereby promotes the deubiquitination of nucleosomal histones in chromatin. Provocative indirect evidence suggests that histone ubiquitination/deubiquitination cycles alter chromatin structure, which may limit accessibility of DNA repair proteins to damaged sites. In the present study, we focused on the relationship between the ubiquitination status of histone H2A, the structure of chromatin, and the efficiency of nucleotide excision repair (NER) of cisplatin-DNA adducts in human ovarian carcinoma cells exposed to the antitumor drug cisplatin. Pretreating cells with the proteasome inhibitor lactacystin (LC) or N-acetyl-leucyl-leucyl-norleucinal (ALLnL) induced deubiquitination of ubiquitinated histone H2A (uH2A) and concomitantly promoted chromatin condensation, increased the extent of cisplatin-DNA adducts, and diminished NER-dependent repair of cisplatin-DNA lesions, compared with control cells treated with cisplatin alone. Both proteasome inhibitors also prevented the increase in ERCC-1 mRNA expression that occurs in cells exposed to cisplatin. Cells treated with the combination of ALLnL and cisplatin underwent apoptosis, as indicated by caspase-dependent poly(ADP-ribose) polymerase (PARP) cleavage, more quickly than cells treated with either agent alone. Additionally, the combination of ALLnL and cisplatin potently increased p53 levels in cell lysates and stimulated the binding of p53 to chromatin. Together, these observations suggest that proteasome inhibition may be exploited therapeutically for its potential to sensitize ovarian tumor cells to cisplatin.
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PMID:Prevention of cisplatin-DNA adduct repair and potentiation of cisplatin-induced apoptosis in ovarian carcinoma cells by proteasome inhibitors. 1100 28

Poly(ADP-ribose) is formed in possibly all multicellular organisms by a familiy of poly(ADP-ribose) polymerases (PARPs). PARP-1, the best understood and until recently the only known member of this family, is a DNA damage signal protein catalyzing its automodification with multiple, variably sized ADP-ribose polymers that may contain up to 200 residues and several branching points. Through these polymers, PARP-1 can interact noncovalently with other proteins and alter their functions. Here we report the discovery of a poly(ADP-ribose)-binding sequence motif in several important DNA damage checkpoint proteins. The 20-amino acid motif contains two conserved regions: (i) a cluster rich in basic amino acids and (ii) a pattern of hydrophobic amino acids interspersed with basic residues. Using a combination of alanine scanning, polymer blot analysis, and photoaffinity labeling, we have identified poly(ADP-ribose)-binding sites in the following proteins: p53, p21(CIP1/WAF1), xeroderma pigmentosum group A complementing protein, MSH6, DNA ligase III, XRCC1, DNA polymerase epsilon, DNA-PK(CS), Ku70, NF-kappaB, inducible nitric-oxide synthase, caspase-activated DNase, and telomerase. The poly(ADP-ribose)-binding motif was found to overlap with five important functional domains responsible for (i) protein-protein interactions, (ii) DNA binding, (iii) nuclear localization, (iv) nuclear export, and (v) protein degradation. Thus, PARPs may target specific signal network proteins via poly(ADP-ribose) and regulate their domain functions.
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PMID:Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins. 1101 34

Poly(ADP-ribose) polymerase (PARP) is implicated in the maintenance of genomic integrity, given that inhibition or depletion of this enzyme increases genomic instability in cells exposed to genotoxic agents. We previously showed that immortalized fibroblasts derived from PARP(-/-) mice exhibit an unstable tetraploid population, and partial chromosomal gains and losses in PARP(-/-) mice and immortalized fibroblasts are accompanied by changes in the expression of p53, Rb, and c-Jun, as well as other proteins. A tetraploid population has also now been detected in primary fibroblasts derived from PARP(-/-) mice. Oligonucleotide microarray analysis was applied to characterize more comprehensively the differences in gene expression between asynchronously dividing primary fibroblasts derived from PARP(-/-) mice and their wild-type littermates. Of the 11,000 genes monitored, 91 differentially expressed genes were identified. The loss of PARP results in down-regulation of the expression of several genes involved in regulation of cell cycle progression or mitosis, DNA replication, or chromosomal processing or assembly. PARP deficiency also up-regulates genes that encode extracellular matrix or cytoskeletal proteins that are implicated in cancer initiation or progression or in normal or premature aging. These results provide insight into the mechanism by which PARP deficiency impairs mitotic function, thereby resulting in the genomic alterations and chromosomal abnormalities as well as in altered expression of genes that may contribute to genomic instability, cancer, and aging.
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PMID:Misregulation of gene expression in primary fibroblasts lacking poly(ADP-ribose) polymerase. 1101 56

We studied the role of PARP in X-ray-induced damage repair using V79 Chinese hamster cells and two derivative cell lines ADPRT54 and ADPRT351 deficient in poly(adenosine diphosphate-ribose) polymerase (PARP) activity. We previously demonstrated that these PARP-deficient cells had drastically reduced levels of p53. Further, these cells were also deficient in downstream endpoints of p53 signaling. In the present study we showed that exponentially growing ADPRT54 and ADPRT351 were hypersensitive to X-radiation compared to the parental V79 cells. Under this condition of growth, although the parental V79 cells exhibit G1 arrest in response to X-irradiation, the PARP-deficient cells do not undergo this specific p53-dependent cell cycle arrest. In contrast, all the cell lines showed similar sensitivity to X-radiation under growth arrested conditions. Further, all the cell lines were equally proficient in performing potentially lethal damage repair (PLDR). Our findings suggest that: i) PARP is involved in X-ray-induced damage repair in replicating cells; ii) PARP is not required for X-ray-induced damage repair in quiescent cells; iii) PARP does not participate in PLDR; iv) deficiency of PARP may potentiate the cytotoxicity of X-irradiation by interfering with the p53-dependent G1 block that occurs after X-irradiation. These results suggest the intriguing possibility that the approach of inhibition of PARP combined with X-radiation may have therapeutic potential for the treatment of fast growing tumors. However, this approach may not be beneficial for slow growing/quiescent tumors.
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PMID:X-ray-induced damage repair in exponentially growing and growth arrested confluent poly(adenosine diphosphate-ribose) polymerase-deficient V79 chinese hamster cell line. 1102 98

We have previously reported that in cells ectopically expressing temperature-sensitive p53(135val) mutant, p53 formed tight complexes with poly(ADP-ribose) polymerase (PARP). At elevated temperatures, p53(135val) protein, adopting the mutant phenotype, was localized in the cytoplasm and sequestered the endogenous PARP. To prove whether an excess of p53(135val) protein led to this unusual intracellular distribution of PARP, we have established cell lines overexpressing p53(135val) + c-Ha-ras alone or in combination with PARP. Interestingly, immunostaining revealed that PARP is sequestered in the cytoplasm by mutant p53 in cells overexpressing both proteins. Simultaneous overexpression of PARP had no effect on temperature-dependent cell proliferation and only negligibly affected the kinetics of p53-mediated G(1) arrest. However, if the cells were completely growth arrested at 32 degrees C and then shifted up to 37 degrees C, coexpressed PARP dramatically delayed the reentry of transformed cells into the cell cycle. Even after 72 h at 37 degrees C the proportion of S-phase cells was reduced to 20% compared to those expressing only p53(135val) + c-Ha-ras. The coexpressed PARP stabilized wt p53 protein and its enzymatic activity was necessary for stabilization.
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PMID:Overexpressed poly(ADP-ribose) polymerase delays the release of rat cells from p53-mediated G(1) checkpoint. 1102 56

Most malignant astrocytomas (gliomas) express a high level of Fas, whereas the surrounding normal tissues such as neurons and astrocytes express a very low level of Fas. Thus, transduction of Fas ligand would selectively kill malignant astrocytoma cells. On the other hand, glioma cells harboring p53 mutation have been reported to be resistant to conventional therapies including radiation. To override the resistance mechanism of glioma cells with p53 mutation to radiation, we transduced U-373MG malignant astrocytoma (glioma) cells harboring mutant p53 with Fas ligand via an adenovirus (Adv) vector in combination with X-ray irradiation, and evaluated the degree of apoptosis. The degree of apoptosis in U-373MG cells infected with the Adv for Fas ligand (Adv-FL) and treated with irradiation (81%) was much higher than that in U-373MG cells infected with Adv-FL and not treated with irradiation (0.8%) or that in U-373MG cells infected with the control Adv for lacZ and treated with irradiation (5.0%). In U-373MG cells infected with Adv-FL, irradiation increased the expression of Fas ligand. Coincident with the increase in Fas ligand, there was a marked reduction in the caspase-3 level and a marked increase in the cleaved form of poly(ADP-ribose) polymerase (PARP), which are downstream components of Fas ligand-mediated apoptosis. This suggests that the enhanced activation of caspase-3 by the transduction of Fas ligand combined with irradiation, induced extensive apoptosis in U-373MG cells. In summary, transduction of Fas ligand may override the resistance mechanism to radiotherapy in glioma cells harboring p53 mutation.
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PMID:Adenovirus-mediated transfer of Fas ligand gene augments radiation-induced apoptosis in U-373MG glioma cells. 1105 Apr 76

The effect of trichostatin A (TSA), histone deacetylase inhibitor, on cell growth and the mechanism of growth modulation was examined in 8 gastric and 3 oral carcinoma cell lines which included 9-cis-retinoic acid resistant (MKN-7 and Ho-1-N-1) and IFN-beta resistant cell lines (MKN-7, -28 and -45). TSA inhibited growth in all cell lines examined. Apoptotic cell death was confirmed by apoptotic ladder formation and induction of a cleaved form (85 kDa) of poly (ADP-ribose) polymerase (PARP) induction. TSA enhanced the protein expression of p21(WAF1), CREB-binding protein, cyclinE, cyclin A, Bak and Bax, while it reduced the expression of E2F-1, E2F-4, HDAC1, p53 and hyperphosphorylated form of Rb. Furthermore, TSA induced morphological changes, such as elongation of cytoplasm and cell-to-cell detachment, in gastric and oral carcinoma cell lines. These results suggest that TSA may inhibit cell growth and induce apoptosis of gastric and oral carcinoma cells through modulation of the expression of cell cycle regulators and apoptosis-regulating proteins.
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PMID:Effect of trichostatin A on cell growth and expression of cell cycle- and apoptosis-related molecules in human gastric and oral carcinoma cell lines. 1109 26

In mammals, visual experience during early postnatal life is critical for normal development of the visual system. Here we report that monocular deprivation for 2, 7, and 14 consecutive days causes p53 accumulation, cell death, and progressive loss of neurones in the dorsal lateral geniculate nucleus (dLGN) of newborn rats and these are prevented by NMDA and non-NMDA glutamate receptor antagonists, and by L-NAME, an inhibitor of nitric oxide synthesis. Monocular deprivation also increases dLGN levels of citrulline, the coproduct of nitric oxide synthesis, and this, as well as cell death and neuronal loss, is abolished by antagonists of glutamate receptors and by L-NAME. Finally, poly-(ADP-ribose) polymerase (PARP) knock-out mice appear to be protected from monocular deprivation-induced cell death. In conclusion, during early postnatal development of the rat visual system monocular deprivation causes excitotoxic, nitric oxide-mediated, cell death in the dLGN that appears to be apoptotic and also requires activation of PARP.
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PMID:Apoptosis in the dorsal lateral geniculate nucleus after monocular deprivation involves glutamate signaling, NO production, and PARP activation. 1109 43

Poly(ADP-ribose) polymerase (PARP) takes part mainly in regulation of DNA repair, thereby maintaining genomic stability in the nucleus. However, what role PARP plays in mitotic cells is not known. Centrosomes play an important role in maintaining the fidelity of chromosome distribution during cell division. Loss of these functions might cause chromosomal instability and aneuploidy. p53 and BRCA1 were recently found to localize to the centrosome at mitosis. We found that PARP is localized to the centrosomes and the chromosomes at cell-division phase and interphase by indirect immunofluorescence. Furthermore, by analysis of isolated centrosomes PARP protein was found to associate with the centrosomes during mitosis. These data suggest that PARP may be involved in maintenance of chromosomal stability.
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PMID:Poly(ADP-ribose) polymerase localizes to the centrosomes and chromosomes. 1109 46

DNA single-strand breaks induced by cell treatment with hydrogen peroxide are repaired and simultaneously trigger programmed cell death in resting human blood lymphocytes. Apoptosis is accompanied by special morphological changes in lymphocytes (15% of total cell number), internucleosomal DNA degradation, and p53 level elevation. According to morphological criteria, a major part (up to 40% of total cell number) displayed necrotic death features. Nicotinamide inhibited repair in cells with 2.5-fold elevation of the apoptotic cell proportion, whereas the fraction of cells with necrotic nuclear morphology decreased 4.5-fold. Both the inhibition of repair and the protective effect of nicotinamide against necrotic death indicate that the repair process and related poly(ADP-ribose)polymerase (PARP) activation induce a decrease in intracellular NAD+ and ATP contents below the threshold at which necrosis becomes the preferential mechanism of cell death. The mixed pattern of cell death induced by hydrogen peroxide observed in resting lymphocytes can be explained in the context of a concept of cell de-energization as a consequence of effective single-stand break repair during the first hours after removing the genotoxic agent.
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PMID:Hydrogen peroxide-induced DNA repair and death of resting human blood lymphocytes. 1111 44


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