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)

DNA damage signaling is crucial for the maintenance of genome integrity. In higher eukaryotes a NAD+-dependent signal transduction mechanism has evolved to protect cells against the genome destabilizing effects of DNA strand breaks. The mechanism involves 2 nuclear enzymes that sense DNA strand breaks, poly(ADP-ribose) polymerase-1 and -2 (PARP-1 and PARP-2). When activated by DNA breaks, these PARPs use NAD+ to catalyze their automodification with negatively charged, long and branched ADP-ribose polymers. Through recruitment of specific proteins at the site of damage and regulation of their activities, these polymers may either directly participate in the repair process or coordinate repair through chromatin unfolding, cell cycle progression, and cell survival-cell death pathways. A number of proteins, including histones, DNA topoisomerases, DNA methyltransferase-1 as well as DNA damage repair and checkpoint proteins (p23, p21, DNA-PK, NF-kB, XRCC1, and others) can be targeted in this manner; the interaction involves a specific poly(ADP-ribose)-binding sequence motif of 20-26 amino acids in the target domains.
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PMID:The role of poly(ADP-ribose) in the DNA damage signaling network. 1595 61

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.
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PMID:Involvement of polynucleotide kinase in a poly(ADP-ribose) polymerase-1-dependent DNA double-strand breaks rejoining pathway. 1636 63

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

The aim of the present study was to identify proteins that bind nicked DNA intermediates formed in the course of base excision repair (BER) in cell free extracts of Saccharomyces cerevisiae. In mammalian cells, nicks in DNA are targets of proteins such as PARP-1 or XRCC1 that have no homologues in yeast. One of the most promising methodologies to trap proteins that interact with damaged DNA lies in using a photocrosslinking technique with photoactivable dNTP analogues such as exo-N-{2-[N-(4-azido-2,5-difluoro-3-chloropyridine-6-yl)-3-aminopropionyl]-aminoethyl}-2'-deoxycytidine-5'-triphosphate (FAP-dCTP) for enzymatic synthesis of DNA probes with a photoreactive dNMP residue at the 3'-margin of a nick. Using this approach, we identified a major covalent DNA-protein adduct between a nick-containing 34-mer DNA duplex and a protein of a molecular mass of around 100-kDa. Unexpectedly, the formation of the 100-kDa adduct did not require the incorporation of the photoreactive dNMP residue at the 3'-margin of the nick nor exposure to near UV-light. However, the formation of the 100-kDa adduct strictly required a nick or a short gap in the DNA probe. Furthermore, the 100-kDa adduct was not detected in yeast extracts lacking DNA topoisomerase I (Top1). To further establish the nature of crosslinked protein, yeast Top1 was tagged with a Myc-epitope. In this case, the mobility of the Top1-DNA adduct increased by 7- kDa. Therefore, our data speak in favor of Top1 trapping by nicked DNA. In support of this hypothesis, purified yeast Top1 was also crosslinked to nicked DNA structures. Undamaged, uracil- and abasic (AP) site-containing DNAs were unable to trap Top1 under the same assay conditions. Since nicked DNA structures are frequently formed in the course of BER, their covalent linkage to Top1 has the potential to interfere with BER in vivo.
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PMID:Trapping of DNA topoisomerase I on nick-containing DNA in cell free extracts of Saccharomyces cerevisiae. 1671 56

Changes in chromatin structure emanating from DNA breaks are among the most initiating events in the damage response of the cell. In higher eukaryotes, poly(ADP-ribose) polymerase-1 (PARP-1) translates the occurrence of DNA breaks detected by its zinc-finger domain into a signal, poly ADP-ribose, synthesized and amplified by its DNA-damage dependent catalytic domain. This epigenetic mark on chromatin, induced by DNA discontinuities, is now considered as a part of a survival program aimed at protecting primarily chromatin integrity and stability. In this chapter we describe some of our methods for determining in vivo and in vitro PARP-1 activation in response to DNA strand breaks. Poly(ADP-ribosyl)ation is a posttranslational modification of nuclear proteins induced by DNA strand-breaks that contributes to the survival of injured proliferating cells (D'Amours et al., 1999). 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 is immediately stimulated by DNA strand-breaks (Ame et al., 2004). PARP-1 fulfils several key functions in repairing an interruption of the sugar phosphate backbone. It efficiently detects the presence of a break by its N-terminal zinc-finger domain; the occurrence of a break is immediately translated into a posttranslational modification of histones H1 and H2B leading to chromatin structure relaxation and therefore to increased DNA accessibility. As an amplified DNA damage signal, auto-poly(ADP-ribosyl)ation of PARP-1 triggers the recruitment of XRCC1, which coordinates and stimulates the repair process, to the DNA damage sites in less than 15 s in living cells (Okano et al., 2003). Although dispensable in a test tube DNA repair experiment, in vivo these three properties positively influence the overall kinetics of a DNA damage-detection/signaling pathway leading rapidly to the resolution of DNA breaks. Accordingly, poly ADP-ribose (PAR) synthesis and the accompanying NAD consumption are now considered as bona fide marks of DNA interruptions in the genome. In this chapter we describe several methods for determining PARP activation in response to the occurrence of DNA breaks in vitro and in vivo.
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PMID:Poly(ADP-ribose) polymerase-1 activation during DNA damage and repair. 1679 20

PARP-1 (poly(ADP-ribose) polymerases) modifies proteins with poly(ADP-ribose), which is an important signal for genomic stability. ADP-ribose polymers also mediate cell death and are degraded by poly(ADP-ribose) glycohydrolase (PARG). Here we show that the catalytic domain of PARG interacts with the automodification domain of PARP-1. Furthermore, PARG can directly down-regulate PARP-1 activity. PARG also interacts with XRCC1, a DNA repair factor that is recruited by DNA damage-activated PARP-1. We investigated the role of XRCC1 in cell death after treatment with supralethal doses of the alkylating agent MNNG. Only in XRCC1-proficient cells MNNG induced a considerable accumulation of poly(ADP-ribose). Similarly, extracts of XRCC1-deficient cells produced large ADP-ribose polymers if supplemented with XRCC1. Consequently, MNNG triggered in XRCC1-proficient cells the translocation of the apoptosis inducing factor from mitochondria to the nucleus followed by caspase-independent cell death. In XRCC1-deficient cells, the same MNNG treatment caused non-apoptotic cell death without accumulation of poly(ADP-ribose). Thus, XRCC1 seems to be involved in regulating a poly(ADP-ribose)-mediated apoptotic cell death.
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PMID:MNNG-induced cell death is controlled by interactions between PARP-1, poly(ADP-ribose) glycohydrolase, and XRCC1. 1696 44

Single-base lesions in DNA are repaired predominantly by base excision repair (BER). DNA polymerase beta (pol beta) is the polymerase of choice in the preferred single-nucleotide BER pathway. The characteristic phenotype of mouse fibroblasts with a deletion of the pol beta gene is moderate hypersensitivity to monofunctional alkylating agents, e.g., methyl methanesulfonate (MMS). Increased sensitivity to MMS is also seen in the absence of pol beta partner proteins XRCC1 and PARP-1, and under conditions where BER efficiency is reduced by synthetic inhibitors. PARP activity plays a major role in protection against MMS-induced cytotoxicity, and cells treated with a combination of non-toxic concentrations of MMS and a PARP inhibitor undergo cell cycle arrest and die by a Chk1-dependent apoptotic pathway. Since BER-deficient cells and tumors are similarly hypersensitive to the clinically used chemotherapeutic methylating agent temozolomide, modulation of DNA damage-induced cell signaling pathways, as well as BER, are attractive targets for potentiating chemotherapy.
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PMID:Hypersensitivity phenotypes associated with genetic and synthetic inhibitor-induced base excision repair deficiency. 1711 33

Cancer is a common multifactor human disease resulting from complex interactions between many genetic and environmental factors. In this study, we used a multifaceted analytic approach to explore the relationship between eight single nucleotide polymorphisms in base excision repair (BER) pathway genes, smoking, and bladder cancer susceptibility in a hospital-based case-control study. Overall, we did not find an association between any single BER gene single nucleotide polymorphism and bladder cancer risk. However, in stratified analysis, the OGG1 S326C variant genotypes in ever smokers (odds ratio, 0.74; 95% confidence interval, 0.56-0.99) and ADP-ribosyltransferase (ADPRT) V762A variant genotypes in never smokers (odds ratio, 0.58; 95% confidence interval, 0.37-0.91) conferred a significantly reduced risk. Using logistic regression, we observed that there was a two-way interaction between ADPRT V762A and smoking status. We next used classification and regression tree analysis to explore high-order gene-gene and gene-environment interactions. We found that smoking is the most important influential factor for bladder cancer risk. Consistent with the above findings, we found that the ADPRT V762A was only significantly involved in bladder cancer risk in never smokers and the OGG1 S326C was only significantly involved in ever smokers. We also observed gene-gene interactions among OGG1 S326C, XRCC1 R194W, and MUTYH H335Q in ever smokers. Using multifactor dimensionality reduction approach, the four-factor model, including smoking status, OGG1 S326C (rs1052133), APEX1 D148E (rs3136820), and ADPRT762 (rs1136410), had the best ability to predict bladder cancer risk with the highest cross-validation consistency (100%) and the lowest prediction error (37.02%; P < 0.001). These results support the hypothesis that genetic variants in BER genes contribute to bladder cancer risk through gene-gene and gene-environmental interactions.
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PMID:High-order interactions among genetic variants in DNA base excision repair pathway genes and smoking in bladder cancer susceptibility. 1722 Mar 34

Genotoxic stress activates nuclear poly(ADP-ribose) (PAR) metabolism leading to PAR synthesis catalyzed by DNA damage activated poly(ADP-ribose) polymerases (PARPs) and rapid PAR turnover by action of nuclear poly(ADP-ribose) glycohydrolase (PARG). The involvement of PARP-1 and PARP-2 in responses to DNA damage has been well studied but the involvement of nuclear PARG is less well understood. To gain insights into the function of nuclear PARG in DNA damage responses, we have quantitatively studied PAR metabolism in cells derived from a hypomorphic mutant mouse model in which exons 2 and 3 of the PARG gene have been deleted (PARG-Delta2,3 cells), resulting in a nuclear PARG containing a catalytic domain but lacking the N-terminal region (A domain) of the protein. Following DNA damage induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we found that the activity of both PARG and PARPs in intact cells is increased in PARG-Delta2,3 cells. The increased PARG activity leads to decreased PARP-1 automodification with resulting increased PARP activity. The degree of PARG activation is greater than PARP, resulting in decreased PAR accumulation. Following MNNG treatment, PARG-Delta2,3 cells show reduced formation of XRCC1 foci, delayed H2AX phosphorylation, decreased DNA break intermediates during repair, and increased cell death. Our results show that a precise coordination of PARPs and PARG activities is important for normal cellular responses to DNA damage and that this coordination is defective in the absence of the PARG A domain.
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PMID:Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase. 1727 27

The aim of this study was to evaluate radiosensitivity of cervical cancer cells in vitro and to assess the relationship between genetic polymorphisms in DNA repair genes and the response of cells to ionizing radiation. The alkaline comet assay as a predictive assay of radiosensitivity was used to examine the susceptibility of four human cervical cancer cell lines (CaSki, C-33A, HeLa and SiHa) to radiation damages. The initial DNA damage and the residual DNA damage at 15, 30, 45 and 60 min after irradiation were assessed. Genotypes of DNA repair genes (XRCC1, hOGG1, PARP, XPD, XRCC3 and XRCC4) were analyzed by PCR-RFLP assays. The comet data clearly indicate a variable but dose-dependent increase in the initial DNA damage in all cell lines. The highest slope of dose response curve was observed in C-33A cells and this cell line was assumed to be radiosensitive. All cell lines repaired DNA damage in a similar manner, the level of DNA strand breakage has returned near the background level within 45 min after irradiation. According to the genotype we found that C-33A cells are polymorphic in the majority of analyzed DNA repair genes. This pilot study indicated associations between polymorphisms in DNA repair genes and cell radiosensitivity.
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PMID:Radiosensitivity of cervical cancer cell lines: the impact of polymorphisms in DNA repair genes. 1744 49


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