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)

Poly (ADP-ribose) polymerase (PARP-1), ATM and DNA-dependent protein kinase (DNA-PK) are all involved in responding to DNA damage to activate pathways responsible for cellular survival. Here, we demonstrate that PARP-1-/- cells are sensitive to the ATM inhibitor KU55933 and conversely that AT cells are sensitive to the PARP inhibitor 4-amino-1,8-napthalamide. In addition, PARP-1-/- cells are shown to be sensitive to the DNA-PK inhibitor NU7026 and DNA-PKcs or Ku80 defective cells shown to be sensitive to PARP inhibitors. We believe PARP inhibition results in an increase in unresolved spontaneous DNA single-strand breaks (SSBs), which collapse replication forks and trigger homologous recombination repair (HRR). We show that ATM is activated following inhibition of PARP. Furthermore, PARP inhibitor-induced HRR is abolished in ATM, but not DNA-PK, inhibited cells. ATM and DNA-PK inhibition together give the same sensitivity to PARP inhibitors as ATM alone, indicating that ATM functions in the same pathways as DNA-PK for survival at collapsed forks, likely in non-homologous end joining (NHEJ). Altogether, we suggest that ATM is activated by PARP inhibitor-induced collapsed replication forks and may function upstream of HRR in the repair of certain types of double-strand breaks (DSBs).
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PMID:Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair. 1655 9

Concurrent activation of poly (ADP-ribose) polymerase (PARP) and DNA ligase was observed in cultured human epidermal keratinocytes (HEK) exposed to the DNA alkylating compound sulfur mustard (SM), suggesting that DNA ligase activation could be due to its modification by PARP. Using HEK, intracellular 3H-labeled NAD+ (3H-adenine) was metabolically generated and then these cells were exposed to SM (1 mM). DNA ligase I isolated from these cells was not 3H-labeled, indicating that DNA ligase I is not a substrate for (ADP-ribosyl)ation by PARP. In HEK, when PARP was inhibited by 3-amino benzamide (3-AB, 2 mM), SM-activated DNA ligase had a half-life that was four-fold higher than that observed in the absence of 3-AB. These results suggest that DNA repair requires PARP, and that DNA ligase remains activated until DNA damage repair is complete. The results show that in SM-exposed HEK, DNA ligase I is activated by phosphorylation catalysed by DNA-dependent protein kinase (DNA-PK). Therefore, the role of PARP in DNA repair is other than that of DNA ligase I activation. By using the DNA ligase I phosphorylation assay and decreasing PARP chemically as well as by PARP anti-sense mRNA expression in the cells, it was confirmed that PARP does not modify DNA ligase I. In conclusion, it is proposed that PARP is essential for efficient DNA repair; however, PARP participates in DNA repair by altering the chromosomal structure to make the DNA damage site(s) accessible to the repair enzymes.
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PMID:Poly (ADP-ribose) polymerase (PARP) is essential for sulfur mustard-induced DNA damage repair, but has no role in DNA ligase activation. 1690 6

Poly(ADP-ribose) polymerase 3 (PARP-3) is a novel member of the PARP family of enzymes that synthesize poly(ADP-ribose) on themselves and other acceptor proteins. Very little is known about this PARP, which is closely related to PARP-1 and PARP-2. By sequence analysis, we find that PARP-3 may be expressed in two isoforms which we studied in more detail to gain insight into their possible functions. We find that both PARP-3 isoforms, transiently expressed as GFP or FLAG fusions, are nuclear. Detection of endogenous PARP-3 with a specific antibody also shows a widespread nuclear distribution, appearing in numerous small foci and a small number of larger foci. Through co-localization experiments and immunoprecipitations, the larger nuclear foci were identified as Polycomb group bodies (PcG bodies) and we found that PARP-3 is part of Polycomb group protein complexes. Furthermore, using a proteomics approach, we determined that both PARP-3 isoforms are part of complexes comprising DNA-PKcs, PARP-1, DNA ligase III, DNA ligase IV, Ku70, and Ku80. Our findings suggest that PARP-3 is a nuclear protein involved in transcriptional silencing and in the cellular response to DNA damage.
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PMID:PARP-3 associates with polycomb group bodies and with components of the DNA damage repair machinery. 1692 74

Chemotherapy and radiation are two important modalities for cancer treatment. Many agents in clinical used have the ability to induce DNA damage, however they may be highly cytotoxic as a secondary effect. Different mechanisms are involved both, in detection and repair of DNA damage. The modulation of these pathways, has a great impact on clinical outcome and is frequently responsible of therapeutic resistance. Therefore, pharmacological inhibition of DNA damage repair pathways has been explored as a useful strategy to enhance chemo and radiosensitivity, thus it could be used for reversing drug resistance. Different agents have shown excellent results in preclinical studies in combination with radiation or chemotherapy. Early phase clinical trials are now being carried out using different DNA repair inhibitors targeting several enzymes such as PARP, DNA-PK or MGMT.
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PMID:DNA repair inhibitors in cancer treatment. 1700 66

Poly(ADP-ribose)polymerase 1 (PARP-1) recognizes DNA strand interruptions in vivo and triggers its own modification as well as that of other proteins by the sequential addition of ADP-ribose to form polymers. This modification causes a release of PARP-1 from DNA ends and initiates a variety of responses including DNA repair. While PARP-1 has been firmly implicated in base excision and single strand break repair, its role in the repair of DNA double strand breaks (DSBs) remains unclear. Here, we show that PARP-1, probably together with DNA ligase III, operates in an alternative pathway of non-homologous end joining (NHEJ) that functions as backup to the classical pathway of NHEJ that utilizes DNA-PKcs, Ku, DNA ligase IV, XRCC4, XLF/Cernunnos and Artemis. PARP-1 binds to DNA ends in direct competition with Ku. However, in irradiated cells the higher affinity of Ku for DSBs and an excessive number of other forms of competing DNA lesions limit its contribution to DSB repair. When essential components of the classical pathway of NHEJ are absent, PARP-1 is recruited for DSB repair, particularly in the absence of Ku and non-DSB lesions. This form of DSB repair is sensitive to PARP-1 inhibitors. The results define the function of PARP-1 in DSB repair and characterize a candidate pathway responsible for joining errors causing genomic instability and cancer.
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PMID:PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. 1708 86

While diverse enzymatic activities are required for transcriptional initiation, a central question remains whether additional enzymatic activities involved in other cellular processes may also be critical for regulated gene activation. Recently, we reported that signal-dependent activation of gene transcription requires topoisomerase IIbeta (Topo IIbeta)-dependent, nucleosome-specific, transient double-stranded DNA break formation with subsequent activation of poly(ADP-ribose) polymerase-1 (PARP-1) enzymatic function, which causes local changes of chromatin architecture (Ju et al., Science 2006; 312:1798-802). Here, we discussed that possible molecular mechanism underling Topo IIbeta/PARP-1/DNA-PK network in transcriptional initiation and many intriguing issues remain to be solved in the future.
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PMID:A breaking strategy for topoisomerase IIbeta/PARP-1-dependent regulated transcription. 1710 62

Hypertonicity (e.g., high NaCl) activates the transcription factor tonicity-responsive enhancer/osmotic response element-binding protein (TonEBP/OREBP), increasing transcription of protective genes. In the present studies, by stably expressing amino acids 1-547 of TonEBP/OREBP in HEK 293 cells and immunoprecipitating it plus associated proteins from the nuclei of cells exposed to high NaCl, we identify 14 proteins that are physically associated with TonEBP/OREBP. The associated proteins fall into several classes: 1) DNA-dependent protein kinase, both its catalytic subunit and regulatory subunit, Ku86; 2) RNA helicases, namely RNA helicase A, nucleolar RNA helicase II/Gu, and DEAD-box RNA helicase p72; 3) small or heterogeneous nuclear ribonucleoproteins (snRNPs or hnRNPs), namely U5 snRNP-specific 116 kDa protein, U5 snRNP-specific 200 kDa protein, hnRNP U, hnRNP M, hnRNP K, and hnRNP F; 4) heat shock proteins, namely Hsp90beta and Hsc70; and 5) poly(ADP-ribose) polymerase-1 (PARP-1). We confirm identification of most of the proteins by Western analysis and also demonstrate by electrophoretic mobility-shift assay that they are present in the large complex that binds specifically along with TonEBP/OREBP to its cognate DNA element. In addition, we find that PARP-1 and Hsp90 modulate TonEBP/OREBP activity. PARP-1 expression reduces TonEBP/OREBP transcriptional activity and the activity of its transactivating domain. Hsp90 enhances those activities and sustains the increased abundance of TonEBP/OREBP protein in cells exposed to high NaCl.
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PMID:Proteomic identification of proteins associated with the osmoregulatory transcription factor TonEBP/OREBP: functional effects of Hsp90 and PARP-1. 1714 81

Adenoviral proteins interact with host-cell proteins to either exploit or inhibit cellular functions for the purpose of viral propagation. E4orf6, the 34-kDa gene product of the E4 gene, interacts with the double-strand break repair (DSBR) protein DNA-dependent protein kinase and cooperates with binding partner E1B-55K to degrade MRE11, preventing viral DNA concatemer formation. We previously demonstrated that E4orf6 radiosensitizes human tumor cells through the inhibition of DSBR, notably in the absence of E1B-55K. Here, we report that E4orf6 prolongs the signaling of DNA damage by inhibiting the activity of protein phosphatase 2A (PP2A), the phosphatase responsible for dephosphorylating gammaH2AX. The inhibition of PP2A occurs without significant disruption of the DNA re-ligation rate. Prolonged signaling of DNA damage in the presence of E4orf6 initiates caspase-dependent and independent cell death. This is accompanied by poly(ADP-ribose) polymerase (PARP) hyperactivation and the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus. Knockdown of AIF by shRNA rescues the radiosensitization induced by E4orf6. Taken together, these data suggest that E4orf6 disrupts cellular DSBR signaling by inhibiting PP2A, leading to prolonged H2AX phosphorylation, hyperactivation of PARP, and AIF translocation to the nucleus. The function of E4orf6 as an inhibitor of PP2A and activator of PARP in the absence of other adenoviral gene products is of importance in delineating the adenovirus-host cell interplay.
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PMID:The adenoviral E4orf6 protein induces atypical apoptosis in response to DNA damage. 1717 68

In this study, we have tried to find new targets and effective drugs for imatinib-resistant chronic myelogenous leukemia (CML) cells displaying loss of Bcr-Abl kinase target dependence. The imatinib-resistant K562/R1, -R2 and -R3 cells showed profound declines of Bcr-Abl level and concurrently exhibited up-regulation of Bcl-2 and Ku70/80, and down-regulation of Bax, DNA-PKcs and BRCA1, suggesting that loss of Bcr-Abl after exposure to imatinib might be accompanied by other cell survival mechanism. K562/R3 cells were more sensitive to camptothecin (CPT)- and radiation-induced apoptosis than K562 cells, indicating hypersensitivity of imatinib-resistant cells to DNA damaging agents. Moreover, when K562 cells were treated with the combination of imatinib with CPT, the level of Bax and the cleavage of PARP-1 and DNA-PK were significantly increased in comparison with the effects of each drug. Therefore, our study suggests that CPT can be used to treat CML with loss of Bcr-Abl expression.
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PMID:Camptothecin acts synergistically with imatinib and overcomes imatinib resistance through Bcr-Abl independence in human K562 cells. 1722 57

In higher eukaryotes DNA double strand breaks (DSBs) are repaired by homologous recombination (HRR) or non-homologous end joining (NHEJ). In addition to the DNA-PK dependent pathway of NHEJ (D-NHEJ), cells employ a backup pathway (B-NHEJ) utilizing Ligase III and PARP-1. The cell cycle dependence and coordination of these pathways is being actively investigated. We examine DSB repair in unperturbed G1 and G2 phase cells using mouse embryo fibroblast (MEF) mutants defective in D-NHEJ and/or HRR. WT and Rad54(-/-) MEFs repair DSBs with similar efficiency in G1 and G2 phase. LIG4(-/-), DNA-PKcs(-/-), and Ku70(-/-) MEFs show more pronounced repair defects in G1 than in G2. LIG4(-/-)/Rad54(-/-) MEFs repair DSBs as efficiently as LIG4(-/-) MEFs suggesting that the increased repair efficiency in G2 relies on enhanced function of B-NHEJ rather than HRR. In vivo and in vitro plasmid end joining assays confirm an enhanced function of B-NHEJ in G2. The results show a new and potentially important cell cycle regulation of B-NHEJ and generate a framework to investigate the mechanistic basis of HRR contribution to DSB repair.
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PMID:Repair of radiation induced DNA double strand breaks by backup NHEJ is enhanced in G2. 1815 70


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