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• W1977270003 abstract "To ensure the accurate transmission of genetic information in dividing cells, specific biochemical pathways maintain integrity. Fundamental to these pathways is the recognition, by specific proteins, of genomic lesions, which signal the presence of DNA damage to other nuclear and cytoplasmic factors. DNA strand breaks, generated either directly by genotoxic agents (oxygen radicals, ionizing radiations, or monofunctional alkylating agents) or indirectly after enzymatic incision of a DNA-base lesion, trigger the synthesis of poly(ADP-ribose) by the enzyme poly(ADP-ribose) polymerase (PARP [E.C.2.4.2.30]). PARP is a nuclear zinc-finger DNA–binding protein that detects DNA strand breaks. At a breakage site, PARP catalyzes the transfer of the ADP-ribose moiety, from the respiratory coenzyme NAD+ to a limited number of protein acceptors. These PARP substrates may influence chromatin architecture, as with histones H1, H2B, and lamin B, or they may act in DNA metabolism, as with DNA-replication factors and PARP itself (reviewed by de Murcia and Menissier-de Murcia de Murcia and Menissier de Murcia, 1994de Murcia G Menissier de Murcia J Poly(ADP-ribose) polymerase: a molecular nick-sensor.Trends Biochem Sci. 1994; 19: 172-176Abstract Full Text PDF PubMed Scopus (739) Google Scholar; Oei et al. Oei et al., 1997Oei S Griesenbeck J Schweuger M The role of poly(ADP-ribosyl)ation.Rev Physiol Biochem Pharmacol. 1997; 131: 127-173PubMed Google Scholar). Because of the high negative charge on ADP-ribose polymers (fig. 1A), poly(ADP-ribosylated) proteins lose their affinity for DNA and hence, in many cases, their biological activities. PARP and other modified proteins may be restored to their native state after poly(ADP-ribose) glycohydrolase. Therefore, poly(ADP-ribosylation) is an immediate posttranslational modification of nuclear DNA–binding proteins, induced by DNA damaging agents. The physiological role of PARP has been much debated during this past decade, but molecular and genetic approaches have been exploited only recently to study the role of the immediate poly(ADP-ribose) synthesis that occurs in response to DNA strand breaks. In this review, we summarize the most recent findings on PARP, which define unambiguously its role in cell response to DNA damage and repair, including cell death by apoptosis and some newly reported biological functions for PARP in different pathologies related to inflammatory injury to the cell. PARP activity is stimulated >500-fold on binding to DNA strand breaks. The human protein spans 1,014 amino acids and comprises three main sequence modules: an N-terminal DNA-binding domain (DBD) bearing two zinc fingers (FI and FII), which acts as a molecular nick sensor; a central automodification domain containing auto-poly(ADP-ribosylation) sites, which regulate PARP-DNA interactions; and a C-terminal catalytic domain, which performs nick-binding–dependent poly(ADP-ribose) synthesis (fig. 1; reviewed by de Murcia and Menissier-de Murcia de Murcia and Menissier de Murcia, 1994de Murcia G Menissier de Murcia J Poly(ADP-ribose) polymerase: a molecular nick-sensor.Trends Biochem Sci. 1994; 19: 172-176Abstract Full Text PDF PubMed Scopus (739) Google Scholar). Independent experimental approaches have identified two surfaces on which PARP interacts with its partners (fig. 1A). Interestingly, in a two-hybrid screen we identified the base-excision repair (BER) factor XRCC1 (x-ray cross-complementing-1) as a partner of PARP (Masson et al. Masson et al., 1998Masson M Niedergang C Schreiber V Muller S Menissier-de Murcia J de Murcia G XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage.Mol Cell Biol. 1998; 18: 3563-3571Crossref PubMed Scopus (794) Google Scholar). Both proteins interact by their BRCT (BRCA-1 C-terminus) motifs, and XRCC1 interacts with DNA ligase III by a second BRCT motif (Caldecott et al. Caldecott et al., 1996Caldecott K Aoufouchi S Johnson P Shall S XRCC1 polypeptide interacts with DNA polymerase β and possibly poly(ADP-ribose) polymerase, and DNA ligase III is a novel molecular “nick sensor” in vitro.Nucleic Acids Res. 1996; 24: 4387-4394Crossref PubMed Scopus (526) Google Scholar). This interaction provides strong evidence that PARP is a member of a BER multiprotein complex that comprises nick sensors (PARP and DNA ligase III), an adaptor factor (XRCC1), and the direct mediators of DNA repair (DNA polymerase β and DNA ligase III). PARP knockout mice were developed to provide definitive answers about the physiological role of PARP in different cellular processes. We generated three PARP knockout mice independently, by disrupting exon 1 (Wang et al. Wang et al., 1997Wang ZQ Stingl L Morrison C Jantsch M Los M Schulze-Osthoff K Wagner EF PARP is important for genomic stability but dispensable in apoptosis.Genes Dev. 1997; 11: 2347-2358Crossref PubMed Scopus (505) Google Scholar), exon 2 (Menissier-de Murcia et al. Menissier-de Murcia et al., 1997Menissier-de Murcia J Niedergang C Trucco C Ricoul M Dutrillaux B Mark M Oliver FJ et al.Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells.Proc Natl Acad Sci USA. 1997; 94: 7303-7307Crossref PubMed Scopus (913) Google Scholar), or exon 4 (Masutani et al. Masutani et al., 1999Masutani M Suzuki H Kamada N Watanabe M Ueda O Nozaki T Jishage K et al.Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes.Proc Natl Acad Sci USA. 1999; 96: 2301-2304Crossref PubMed Scopus (252) Google Scholar) by homologous recombination. We reported that PARP-deficient mice are hypersensitive to monofunctional alkylating agents, such as N-methyl-N-nitrosourea (MNU) and γ-rays, which are potent PARP activators in wild-type (wt) littermates. These results were confirmed in two other constructs, at the animal level (Wang et al. Wang et al., 1997Wang ZQ Stingl L Morrison C Jantsch M Los M Schulze-Osthoff K Wagner EF PARP is important for genomic stability but dispensable in apoptosis.Genes Dev. 1997; 11: 2347-2358Crossref PubMed Scopus (505) Google Scholar) and at the cellular level (Masutani et al. Masutani et al., 1999Masutani M Suzuki H Kamada N Watanabe M Ueda O Nozaki T Jishage K et al.Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes.Proc Natl Acad Sci USA. 1999; 96: 2301-2304Crossref PubMed Scopus (252) Google Scholar). As expected, MNU and γ-ray irradiation of mutant mice led to an increase in reciprocal exchange of DNA segments in sister chromatids. These data demonstrate the crucial role of PARP in the processing of DNA lesions induced by monofunctional alkylating agents and γ-ray irradiation, both of which trigger the BER pathway. We evaluated the DNA-repair capacity of PARP-deficient cells, by single-cell electrophoresis, using the “comet assay,” which monitors the level of broken DNA in a given cell. After treatment with genotoxins, PARP-deficient cells display a considerably prolonged delay in DNA strand–break rejoining, compared with a wt cell line (Trucco et al. Trucco et al., 1998Trucco C Oliver FJ de Murcia G Menissier-de Murcia J DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines.Nucleic Acids Res. 1998; 26: 2644-2649Crossref PubMed Scopus (299) Google Scholar). Whole-cell extracts from PARP-deficient cell lines are also defective in the BER pathway's polymerization step, which replaces long patches of basic sites (Dantzer et al., Dantzer et al., 1991Dantzer FSV Niedergang C Trucco C Flatter E de la Rubia G Oliver FJ Rolli V Menissier-de-Murcia J et al.Role of poly(ADP-ribose) polymerase in base excision repair.Biochimie. 1991; 81: 69-75Crossref Scopus (295) Google Scholar), which is consistent with evidence that PARP interacts with XRCC1. Apoptosis, or programmed cell death, is a fundamental biological process that plays an important role in early development, cell homeostasis, and diseases such as neurodegenerative disorders and cancer (reviewed by Evan and Littlewood Evan and Littlewood, 1998Evan G Littlewood T A matter of life and cell death.Science. 1998; 281: 1317-1322Crossref PubMed Scopus (1342) Google Scholar; also see other reviews in the same issue of Science). Apoptosis can occur in response to a number of stimuli, such as genotoxic damage and withdrawal of growth factors, or after activation of specific receptors, such as CD95 and the TNF receptor. Morphologically, this form of cell death is characterized by membrane blebbing, cell shrinkage, chromatin condensation, and DNA cleavage, until finally the cell is fragmented into membrane-bound apoptotic bodies. There is increasing biochemical evidence that the caspase family of cysteine proteases mediates the highly ordered process leading to cell death. Caspases are responsible for the disabling of critical homeostatic and repair enzymes, as well as of key structural components during apoptosis. Caspases exist in the cytoplasm as inactive proenzymes, which are processed to a large and a small subunit to form the active enzyme (Thornberry and Lazebnik Thornberry and Lazebnik, 1998Thornberry NA Lazebnik Y Caspases: enemies within.Science. 1998; 281: 1312-1316Crossref PubMed Scopus (6010) Google Scholar). Kaufmann et al. (Kaufmann et al., 1993Kaufmann SH Desnoyers S Ottaviano Y Davidson NE Poirier GG Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis.Cancer Res. 1993; 53: 3976-3985PubMed Google Scholar) showed that PARP is cleaved by caspases at a single site at an early stage of apoptosis, thus separating PARP DBD from its catalytic domain and inactivating the enzyme. PARP cleavage has been shown in almost all forms of apoptosis, but, whenever apoptosis is inhibited by such mechanisms as Bcl-2 overexpression or caspases inhibition, PARP cleavage is also blocked (Duriez and Shah Duriez and Shah, 1997Duriez PJ Shah GM Cleavage of poly(ADP-ribose) polymerase: a sensitive parameter to study cell death.Biochem Cell Biol. 1997; 75: 337-349Crossref PubMed Scopus (402) Google Scholar). These findings suggest that loss of PARP function is required for the efficient completion of apoptosis. To address this model, we expressed a noncleavable variant of the enzyme in PARP-deficient cells. Cells that express the PARP mutant D214A-PARP were exposed to anti-CD95 antibody, a treatment that induces apoptosis in wt cells, and we observed a significant delay in cell death (Oliver et al. Oliver et al., 1998Oliver FJ de la Rubia G Rolli V Ruiz-Ruiz MC de Murcia G Menissier-de Murcia J Role of PARP and PARP cleavage in apoptosis: lesson from an uncleavable mutant.J Biol Chem. 1998; 273: 33533-33539Crossref PubMed Scopus (635) Google Scholar). Morphological analysis also showed significantly retarded cell shrinkage and nuclear condensation, indicating that the cleavage of PARP during apoptosis facilitates cellular disassembly, particularly of the nucleus, and ensures the completion and irreversibility of this process. We propose that caspases cleavage of PARP promotes apoptosis in two respects: (1) the absence of PARP—and also of the DNA-dependent protein kinase, another early target of caspases (Casciola-Rosen et al. Casciola-Rosen et al., 1996Casciola-Rosen L Nicholson DW Chong T Rowan KR Thornberry NA Miller DK Rosen A Apopain/CPP32 cleaves proteins that are essential for cellular repair: a fundamental principle of apoptotic death.J Exp Med. 1996; 183: 1957-1964Crossref PubMed Scopus (569) Google Scholar)—disables key aspects of the cellular genomic surveillance mechanism and prevents unnecessary DNA repair that would delay chromatin degradation; and (2) PARP cleavage improves endonuclease access to chromatin. DNA fragmentation during apoptosis is produced by numerous single-strand nicks in the linker regions of chromatin, and PARP interacts preferentially with single-stranded DNA breaks (Le Cam et al. Le Cam et al., 1994Le Cam E Fack F Menissier-deMurcia MJ Cognet JA Barbin A Sarantoglou V Revet B et al.Conformational analysis of a 139 base-pair DNA fragment containing a single-stranded break and its interaction with human poly(ADP-ribose) polymerase.J Mol Biol. 1994; 235: 1062-1071Crossref PubMed Scopus (86) Google Scholar). In this manner, PARP probably helps recruit BER proteins to repair damaged DNA. A recent study by Smulson et al. (Smulson et al., 1998Smulson ME Pang D Jung M Dimtchev A Chasovskikh S Spoonde A Simbulan-Rosenthal C et al.Irreversible binding of poly(ADP)ribose polymerase cleavage product to DNA ends revealed by atomic force microscopy: possible role in apoptosis.Cancer Res. 1998; 58: 3495-3498PubMed Google Scholar) showed that the DNA-binding domain of PARP, which is isolated when it is cleaved by caspase-3, irreversibly binds internucleosomal DNA in apoptotic cells. This proteolytic fragment may contribute to the irreversibility of apoptosis, by preventing the access of DNA-repair enzymes to the lesion. The localization of PARP to the nuclear envelope (Dantzer et al. Dantzer et al., 1998Dantzer F Nasheuer HP Vonesch JL de Murcia GA Ménissier-de Murcia J Functional association of poly(ADP-ribose) polymerase with DNA polymerase alpha-primase complex: a link between DNA strand break detection and DNA replication.Nucleic Acids Res. 1998; 26: 1891-1898Crossref PubMed Scopus (132) Google Scholar) also suggests that its cleavage during apoptosis participates in nuclear disassembly and facilitates downstream events, all of which are delayed by the expression of the uncleavable PARP mutant. The consequences of cleaving several caspase substrates have been probed in a similar manner, by the expression of uncleavable variants of these target proteins in cells that would otherwise undergo normal apoptosis. Sakahira et al. (Sakahira et al., 1998Sakahira H Enari M Nagata S Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis.Nature. 1998; 391: 96-99Crossref PubMed Scopus (1381) Google Scholar) provided an elegant example of this approach in their study of caspase-activated deoxyribonuclease. Cells expressing an uncleavable variant of this protein failed to degrade DNA, but they displayed all the other characteristics of apoptosis. Cells that express a corresponding mutation in lamin, on the other hand, showed no signs of chromatin condensation or of nuclear shrinkage during apoptosis (Rao et al. Rao et al., 1996Rao L Perez D White E Lamin proteolysis facilitates nuclear events during apoptosis.J Cell Biol. 1996; 135: 1441-1455Crossref PubMed Scopus (486) Google Scholar). Inhibition of caspase activity causes a switch from a apoptosis to necrosis (fig. 2; also see also Hirsch et al. Hirsch et al., 1997Hirsch T Marchetti P Susin SA Dallaporta B Zamzami N Marzo I Geuskens M et al.The apoptosis-necrosis paradox: apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death.Oncogene. 1997; 15: 1573-1581Crossref PubMed Scopus (419) Google Scholar), a distinct form of cell death that often arises in cells deprived of ATP (Leist et al. Leist et al., 1997Leist M Single B Castoldi AF Kuhnle S Nicotera P Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis.J Exp Med. 1997; 185: 1481-1486Crossref PubMed Scopus (1595) Google Scholar), as in ischemia. Induction of apoptosis therefore protects an organism from necrotic-tissue damage, and the inactivation of apoptosis may be important in many pathologies. Interestingly, PARP is also cleaved during necrosis, although the fragments differ from those found in apoptotic cells (Gillouf Guillouf et al., 1999Guillouf C Wang TS Liu J Walsh CE Poirier GG Moustacchi E Rosselli F Fanconi anemia C protein acts as a switch between apoptosis and necrosis in mitomycin C-induced cell death.Exp Cell Res. 1999; 246: 384-394Crossref PubMed Scopus (29) Google Scholar) and retain biological activity for a longer time. Thus, as depicted in figure 2, the failure of cells to fully inactivate PARP could lead to massive NAD+ consumption and energy depletion, which together contribute to cell death by necrosis (Szabo and Dawson Szabo and Dawson, 1998Szabo C Dawson VL Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion.Trends Pharmacol Sci. 1998; 19: 287-298Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar). DNA damage, such as is caused by treatment of cells with alkylating agents, activates PARP in normal cells (Menissier-de Murcia et al. Menissier-de Murcia et al., 1997Menissier-de Murcia J Niedergang C Trucco C Ricoul M Dutrillaux B Mark M Oliver FJ et al.Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells.Proc Natl Acad Sci USA. 1997; 94: 7303-7307Crossref PubMed Scopus (913) Google Scholar; Oliver et al. Oliver et al., 1998Oliver FJ de la Rubia G Rolli V Ruiz-Ruiz MC de Murcia G Menissier-de Murcia J Role of PARP and PARP cleavage in apoptosis: lesson from an uncleavable mutant.J Biol Chem. 1998; 273: 33533-33539Crossref PubMed Scopus (635) Google Scholar) but also causes PARP−/− splenocytes to undergo apoptosis extremely rapidly (Wang et al. Wang et al., 1997Wang ZQ Stingl L Morrison C Jantsch M Los M Schulze-Osthoff K Wagner EF PARP is important for genomic stability but dispensable in apoptosis.Genes Dev. 1997; 11: 2347-2358Crossref PubMed Scopus (505) Google Scholar; Oliver et al. Oliver et al., 1998Oliver FJ de la Rubia G Rolli V Ruiz-Ruiz MC de Murcia G Menissier-de Murcia J Role of PARP and PARP cleavage in apoptosis: lesson from an uncleavable mutant.J Biol Chem. 1998; 273: 33533-33539Crossref PubMed Scopus (635) Google Scholar). The extreme sensitivity of PARP−/− cells to these agents could be explained by the accumulation of unrepaired DNA damage. This view is supported by the observation that DNA rejoining, as measured by the comet assay, is prolonged in PARP−/− cells (Trucco et al. Trucco et al., 1998Trucco C Oliver FJ de Murcia G Menissier-de Murcia J DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines.Nucleic Acids Res. 1998; 26: 2644-2649Crossref PubMed Scopus (299) Google Scholar). In contrast to our findings and to those of Wang et al. (Wang et al., 1998Wang X Ohnishi K Takahashi A Ohnishi T Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation.Oncogene. 1998; 17: 2819-2825Crossref PubMed Scopus (76) Google Scholar), Simbulan-Rosenthal et al. (Simbulan-Rosenthal et al., 1998bSimbulan-Rosenthal CM Rosenthal DS Iyer S Boulares AH Smulson ME Transient poly(ADP-ribosyl)ation of nuclear proteins and role of poly(ADP-ribose) polymerase in the early stages of apoptosis.J Biol Chem. 1998b; 273: 13703-13712Crossref PubMed Scopus (253) Google Scholar) reported that PARP-deficient cells are resistant to cell death after CD95 treatment. This discordant finding would seem to indicate that PARP activates apoptosis only under some conditions. However, the use, in that study, of immortalized clones of stably transfected PARP−/− embryonic fibroblasts—rather than primary cells—may have altered the cells' responses to CD95. Overall, the current data suggest that PARP is a passive rather than an active player in the apoptotic process. A number of studies have suggested a role for PARP and/or poly(ADP-ribose) in p53-mediated DNA damage, although the nature and the consequence of this interaction are controversial. Some groups have reported that inhibition or genetic disruption of PARP result in increased p53 accumulation due to the persistence of unrepaired DNA. In their pioneering study, Lu and Lane (Lu and Lane, 1993Lu X Lane DP Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes?.Cell. 1993; 75: 765-778Abstract Full Text PDF PubMed Scopus (769) Google Scholar) found that x-ray–induced p53 accumulation increased in cells treated with the PARP inhibitor, 3-aminobenzamide. Our own results with splenocytes, bone-marrow cells, and primary embryonic fibroblasts from PARP-deficient mice show an increased accumulation of p53 after treatment with an alkylating agent (Menissier-de Murcia et al. Menissier-de Murcia et al., 1997Menissier-de Murcia J Niedergang C Trucco C Ricoul M Dutrillaux B Mark M Oliver FJ et al.Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells.Proc Natl Acad Sci USA. 1997; 94: 7303-7307Crossref PubMed Scopus (913) Google Scholar; F. J. Oliver, G. de la Rubia, J. Menissier-de Murcia, and G. de Murcia, unpublished data). A recent report by Simbulan-Rosenthal et al. (Simbulan-Rosenthal et al., 1998aSimbulan-Rosenthal CM Rosenthal DS Ding R Bhatia K Smulson ME Prolongation of the p53 response to DNA strand breaks in cells depleted of PARP by antisense RNA expression.Biochem Biophys Res Commun. 1998a; 253: 864-868Crossref PubMed Scopus (18) Google Scholar) suggested that inactivation of PARP affects the duration but not the magnitude of p53 accumulation in γ-ray–irradiated Burkitt lymphoma cells. On the other hand, other groups have identified PARP as a necessary step for p53 expression and activation. Whitacre et al. (Whitacre et al., 1995Whitacre CM Hashimoto H Tsai ML Chatterjee S Berger SJ Berger NA Involvement of NAD-poly(ADP-ribose) metabolism in p53 regulation and its consequences.Cancer Res. 1995; 55: 3697-3701PubMed Google Scholar) suggested that cell lines that were defective in poly(ADP-ribosylation) had lower basal p53 levels than were seen in the parental cell line and that they failed to activate p53 in response to etoposide. Similar results were obtained with cells cultured in the absence of nicotinamide. A recent report by Wang et al. (Wang et al., 1998Wang X Ohnishi K Takahashi A Ohnishi T Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation.Oncogene. 1998; 17: 2819-2825Crossref PubMed Scopus (76) Google Scholar) suggested that, in some cultured cells, poly(ADP-ribosylation) is required for rapid accumulation of p53, as well as for activation of sequence-specific DNA binding and trans-activation by p53 after DNA damage. Results obtained with PARP−/− fibroblasts from one group's knockout mice suggest that the p53 accumulation is controlled by PARP-dependent and PARP-independent pathways but that p53 activation is largely independent of PARP (Agarwal et al. Agarwal et al., 1997Agarwal ML Agarwal A Taylor WR Wang ZQ Wagner EF Stark GR Defective induction but normal activation and function of p53 in mouse cells lacking poly-ADP-ribose polymerase.Oncogene. 1997; 15: 1035-1041Crossref PubMed Scopus (88) Google Scholar). It has been proposed that, at the molecular level, PARP induces p53 induction, either by direct protein-to-protein interaction or by poly(ADP-ribosylation) (Malanga et al. Malanga et al., 1998Malanga M Pleschke JM Kleczkowska HE Althaus FR Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions.J Biol Chem. 1998; 273: 11839-11843Crossref PubMed Scopus (188) Google Scholar). PARP also has been shown to stimulate DNA-PK activity in vitro by the enzyme's catalytic subunit, which, in turn, regulates p53 activity by phosphorylation (Ruscetti et al. Ruscetti et al., 1998Ruscetti T Lehnert BE Halbrook J Le Trong H Hoekstra MF Chen DJ Peterson SR Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) polymerase.J Biol Chem. 1998; 273: 14461-14467Crossref PubMed Scopus (200) Google Scholar). Indeed, mice deficient in both PARP and the catalytic subunit of DNA-PK (the product of the Scid gene; Maizels Maizels, 1999Maizels N Immunoglobulin class-switch recombination: will genetics provide new clues to mechanism?.Am J Hum Genet. 1999; 64 (in this issue): 1270-1275Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar [in this issue]) are highly prone to T-cell lymphomas. Neither genetic deficiency alone is sufficient to cause this phenotype, so it appears that PARP and DNA-PK cooperate to help maintain the integrity of the genome (Morrison et al. Morrison et al., 1997Morrison C Smith GC Stingl L Jackson SP Wagner EF Wang ZQ Genetic interaction between PARP and DNA-PK in V(D)J recombination and tumorigenesis.Nat Genet. 1997; 17: 479-482Crossref PubMed Scopus (165) Google Scholar). Thus, the role of PARP in p53 activation could be more complex than a direct activation. PARP might act via DNA-PK and/or other proteins to signal DNA damage to p53 (fig. 2). The phenotypes of mice with other combinations of genetic defects, such as ATM with PARP or P53 with PARP, should clarify the complex interaction between the different pathways involved in signaling from DNA damage and transduction to p53. Studies from several laboratories indicate that PARP acts in the inflammatory response and in pathologies, such as brain ischemia, diabetes, and septic shock, that are associated with inflammatory cell damage. Several mechanisms have been proposed to explain why inactivation of PARP (either pharmacologically or with genetically engineered animals that lack PARP) improves the clinical outcome of animals with those conditions. Szabo and Dawson (Szabo and Dawson, 1998Szabo C Dawson VL Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion.Trends Pharmacol Sci. 1998; 19: 287-298Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar) recently reviewed the evidence for the following model: either after inflammatory stress or during reperfussion after cerebral ischemia macrophages and endothelial cells activate a massive synthesis of nitric oxide (NO), which, in turn, is converted into a cytotoxic derivative, peroxytrite. This compound rapidly induces DNA single-strand breaks, leading to overactivation of PARP in neighboring cells. Depletion of cellular energy then causes mitochondria to generate free radicals and to kill the cells by a necrotic mechanism (fig. 2). Results from our group (F. J. Oliver, J. Menissier-de Murcia, and G. de Murcia, unpublished data) show a functional association between PARP and NF-κB, a key regulator of transcription during inflammation. Through this association, PARP—and, probably, poly(ADP-ribosylation)—regulate NF-κB–dependent transcription. Thus, PARP appears to promote inflammation, both by mediating the cytotoxicity of NO derivatives and by its affect on NF-κB. One or both of these mechanisms might explain the resistance of PARP−/− mice to brain ischemia, in which synthesis of NO and TNF-α up-regulation play a crucial role (Barone et al. Barone et al., 1997Barone FC Arvin B White RF Miller A Webb CL Willette RN Lysko PG et al.Tumor necrosis factor-alpha: a mediator of focal ischemic brain injury.Stroke. 1997; 28: 1233-1244Crossref PubMed Scopus (701) Google Scholar). Two very recent reports, by Masutani et al. (Masutani et al., 1999Masutani M Suzuki H Kamada N Watanabe M Ueda O Nozaki T Jishage K et al.Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes.Proc Natl Acad Sci USA. 1999; 96: 2301-2304Crossref PubMed Scopus (252) Google Scholar) and Burkart (Burkart et al., 1999Burkart V Wang Z-Q Radons JR Heller B Herceg Z Stingl L Wagner EF et al.Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin.Nat Med. 1999; 5: 314-319Crossref PubMed Scopus (313) Google Scholar), indicate that PARP-mutant mice enjoy an increased resistance to streptozotocin-induced diabetes. Interestingly, this autoimmune condition results in part from inflammatory damage to pancreatic-islet β-cells. Several studies have also implicated PARP in systemic lupus erythematosus (SLE), an autoimmune disorder characterized by production of autoantibodies against intracellular antigens, including DNA. In one study, individuals with SLE showed a 70% decrease in PARP activity (Lee et al. Lee et al., 1994Lee JS Haug BL Sibley JT Decreased mRNA levels coding for poly(ADP-ribose) polymerase in lymphocytes of patients with SLE.Lupus. 1994; 3: 113-116Crossref PubMed Scopus (14) Google Scholar). Moreover, a genetic susceptibility to SLE has been linked to 1q41-q42, which contains the PARP gene (Tsao et al. Tsao et al., 1997Tsao BP Cantor RM Kalunian KC Chen CJ Badsha H Singh R Wallace DJ et al.Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus.J Clin Invest. 1997; 99: 725-731Crossref PubMed Scopus (238) Google Scholar; Moser et al. Moser et al., 1998Moser KL Neas BR Salmon JE Yu H Gray-McGuire C Asundi N Bruner GR et al.Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.Proc Natl Acad Sci USA. 1998; 95: 14869-14874Crossref PubMed Scopus (410) Google Scholar). However, inheritance of this condition appears to be complex, and the chromosomal locus implicated also includes other plausible candidate genes, including the major-histocompatibility-complex gene. Throughout the past several years, PARP has been shown to interact with a variety of transcription factors in addition to p53. The transcription factors YY1, AP2 (Oei et al. Oei et al., 1998Oei SL Griesenbeck J Schweiger M Ziegler M Regulation of RNA polymerase II-dependent transcription by poly(ADP- ribosyl)ation of transcription factors.J Biol Chem. 1998; 273: 31644-31647Crossref PubMed Scopus (108) Google Scholar), OCT1 (Nie et al. Nie et al., 1998Nie J Sakamoto S Song D Qu Z Ota K Taniguchi T Interaction of Oct-1 and automodification domain of poly(ADP-ribose) synthetase.FEBS Lett. 1998; 424: 27-32Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar), mCAT (Butler and Ordahl Butler and Ordahl, 1999Butler AJ Ordahl CP Poly(ADP-ribose) polymerase binds with transcription enhancer factor 1 to MCAT1 elements to regulate muscle-specific transcription.Mol Cell Biol. 1999; 19: 296-306Crossref PubMed Scopus (169) Google Scholar), and DF4 (Plaza et al. Plaza et al., 1999Plaza S Aumercier M Bailly M Dozier C Saule S Involvement of poly(ADP-ribose)-polymerase in the Pax-6 gene regulation in neuroretina.Oncogene. 1999; 18: 1041-1051Crossref PubMed Scopus (37) Google Scholar) all either interact with PARP in vitro or are found to be poly(ADP-ribosylated). Interestingly, the automodification domain of PARP, which encompasses a BRCT domain (Leadon Leadon, 1999Leadon SA Transcription-coupled repair of DNA damage: unanticipated players, unexpected complexities.Am J Hum Genet. 1999; 64 (in this issue): 1259-1263Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar [in this issue]), is responsible for complex formation between PARP and Oct-1 or DF4 (fig. 1). The BRCT domain of BRCA1 contains the minimal transcriptional activation domain of this protein and regulates p53-dependent gene expression (Ouchi et al. Ouchi et al., 1998Ouchi T Monteiro AN August A Aaronson SA Hanafusa H BRCA1 regulates p53-dependent gene expression.Proc Natl Acad Sci USA. 1998; 95: 2302-2306Crossref PubMed Scopus (328) Google Scholar). In spite of increasing evidence that PARP influences the transcriptional activation of a number of genes, further experimental approaches are needed to elucidate the molecular interaction between PARP and the transcription machinery. In this regard, the propensity of PARP to bind with DNA crossovers and to induce DNA loops in undamaged DNA deserves more attention (de Murcia and Menissier-de Murcia de Murcia and Menissier de Murcia, 1994de Murcia G Menissier de Murcia J Poly(ADP-ribose) polymerase: a molecular nick-sensor.Trends Biochem Sci. 1994; 19: 172-176Abstract Full Text PDF PubMed Scopus (739) Google Scholar). This property, which PARP shares with topoisomerases (Zechiedrich and Osheroff Zechiedrich and Osheroff, 1990Zechiedrich EL Osheroff N Eukaryotic topoisomerases recognize nucleic acid topology by preferentially interacting with DNA crossovers.EMBO J. 1990; 9: 4555-4562Crossref PubMed Scopus (203) Google Scholar), may have important implications for both the anchoring of chromatin loops to the nuclear matrix and the loading of transactivators at specific sites. Poly(ADP ribosylation) of histone H1 may represent a relative simple means by which the cell destabilizes higher-order chromatin structures (de Murcia et al. de Murcia et al., 1986de Murcia G Huletsky A Lamarre D Gaudreau A Pouyet J Daune M Poirier GG Modulation of chromatin superstructure induced by poly(ADP-ribose) synthesis and degradation.J Biol Chem. 1986; 261: 7011-7017Abstract Full Text PDF PubMed Google Scholar) and improves the access of transcription factors to regulatory sequences. We postulate that PARP also ADP ribosylates DNA-bound transcription factors and modulates their biological activity, as has been shown for p53 (Malanga et al. Malanga et al., 1998Malanga M Pleschke JM Kleczkowska HE Althaus FR Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions.J Biol Chem. 1998; 273: 11839-11843Crossref PubMed Scopus (188) Google Scholar). Finally, ADP ribosylation may also regulate the level of DNA methylation (Zardo and Caiafa Zardo and Caiafa, 1998Zardo G Caiafa P The unmethylated state of CpG islands in mouse fibroblasts depends on the poly(ADP-ribosyl)ation process.J Biol Chem. 1998; 273: 16517-16520Crossref PubMed Scopus (50) Google Scholar), a well-known marker of promoter activity. Although for many years it had been assumed that PARP activity is associated with a single protein, this assumption has been challenged by the recent discovery of two PARP homologues: (1) tankyrase, a protein with regions homologous to ankyrins and to the PARP catalytic domain (Smith et al. Smith et al., 1998Smith S Giriat I Schmitt A de Lange T Tankyrase, a poly(ADP-ribose) polymerase at human telomeres.Science. 1998; 282: 1484-1487Crossref PubMed Scopus (863) Google Scholar), which binds to and negatively regulates TRF1, a factor involved in telomere maintenance; and (2) PARP-2, a novel mammalian DNA-damage–dependent poly(ADP-ribose) polymerase recently cloned in our laboratory (J. C. Amé, V. Rolli, V. Schreiber, Menissier-de Murcia, and G. de Murcia, unpublished data). The PARP-2 gene maps to chromosomes 14C1 and 14q11.2 in mouse and human, respectively. Although it lacks a classic zinc-finger module, the recombinant mouse PARP-2 binds to damaged DNA in vitro and catalyzes the formation of poly(ADP-ribose) polymers in a DNA-dependent manner. This novel PARP homologue localizes to the cell nucleus and may serve as a backup in cell lines that lack the 113-kD PARP protein. It is clear that more work will be necessary to unravel the properties of these enzymes and to develop animal models in which PARP activity is totally abolished. We are indebted to our colleagues of the PARP group—A. Agustin, J. C. Amé, F. Dantzer, C. Niedergang, V. Rolli, B. Rinaldi, G. de la Rubia, and V. Schreiber—for their contribution to the work summarized in this review. We are grateful to Dr. S. Shall for critical reading of the manuscript. We apologize for the exclusion, because of the length limit of this review, of very important references. This work was supported by the Association pour la Recherche contre le Cancer, Electricité de France, le Commissariat à l'Énergie Atomique, and la Fondation pour la Recherche Médicale." @default.
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• W1977270003 title "Poly(ADP-Ribose) Polymerase in the Cellular Response to DNA Damage, Apoptosis, and Disease" @default.
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