Alternative titles; symbols
HGNC Approved Gene Symbol: PARP1
Cytogenetic location: 1q42.12 Genomic coordinates (GRCh38): 1:226,360,691-226,408,093 (from NCBI)
The chromatin-associated enzyme poly(ADP-ribose) polymerase (ADPRT; EC 2.4.2.30) uses NAD as substrate to catalyze both the covalent transfer of ADP-ribose to a variety of nuclear protein acceptors and subsequently the transfer of an additional 60 to 80 ADP-ribose units to the initial moiety. Nuclear proteins that become predominantly poly(ADP-ribosyl)ated include nucleosomal core histones, histone H1 (see 142711), HMG proteins (see 163910), and topoisomerases I (126420) and II (see 126430). ADP ribosyltransferase is required for cellular repair. Inhibitors of this enzyme potentiate the lethal effects of noxious agents. During repair, NAD+ is consumed and the NAD+ content of the cell decreases. Concomitantly, nuclear proteins are ADP-ribosylated. The enzyme is induced by single-strand breaks in DNA which serve as cosubstrate for the reaction (summary by Alkhatib et al., 1987).
Alkhatib et al. (1987) isolated cDNA clones for this enzyme from a human hepatoma lambda library and studied its expression. Using synthetic oligonucleotide probes based on the partial amino acid sequence of poly(ADP-ribose), Kurosaki et al. (1987) isolated and sequenced cDNA clones for the enzyme. The open reading frame encodes a protein of 1,013 amino acid residues with a molecular mass of 113,203 Da.
Loetscher et al. (1987) proposed that poly(ADP-ribose) may signal altered metabolic conditions to the chromatin. They were led to this proposal from the finding that the constitutive level of posttranslational poly(ADP-ribose) modification of chromatin proteins in mammalian cells is related to the availability of NAD, which varies in different physiologic and pathologic states.
ADP-ribosylation is a eukaryotic posttranslational modification of proteins that is strongly induced by the presence of DNA strand breaks and plays a role in DNA repair and the recovery of cells from DNA damage. Grube and Burkle (1992) found a strong positive correlation (r = 0.84; P much less than 0.001) between poly(ADP-ribose) polymerase, or PARP, activity and life span, with human cells displaying, for example, about 5 times the activity of rat cells. The cells studied were mononuclear leukocytes. Grube and Burkle (1992) suggested that higher poly(ADP-ribosyl)ation capacity may contribute to the efficient maintenance of genome integrity.
Yu et al. (2002) demonstrated that PARP1 activation is required for translocation of apoptosis-inducing factor (AIF; 300169) from the mitochondria to the nucleus and that AIF is necessary for PARP1-dependent cell death. N-methyl-N-prime-nitro-N-nitrosoguanidine, hydrogen peroxide, and NMDA induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP1-dependent cytotoxicity. Yu et al. (2002) concluded that their data support a model in which PARP1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.
Using cultured human cells from malignant cell lines, Nicholson et al. (1995) demonstrated that PARP is proteolytically cleaved at the onset of apoptosis by caspase-3 (CASP3; 600636), which they called apopain. In addition, they showed that inhibition of apopain-mediated PARP cleavage attenuates apoptosis in vitro.
Tomoda et al. (1991) found that in contrast to reactive proliferative diseases, malignant lymphomas showed increased expression of poly(ADP-ribose) synthetase as demonstrated by level of mRNA.
Cohen-Armon et al. (2004) found that poly(ADP-ribose) polymerase-1 is activated in neurons that mediate several forms of long-term memory in Aplysia. Because poly(ADP-ribosyl)ation of nuclear proteins is a response to DNA damage in virtually all eukaryotic cells, it is surprising that activation of the polymerase occurs during learning and is required for long-term memory. Cohen-Armon et al. (2004) suggested that the fast and transient decondensation of chromatin structure by poly(ADP-ribosyl)ation enables the transcription needed to form long-term memory without strand breaks in DNA.
Vasquez et al. (2001) included the PARP gene in their list of candidate genes for enhancing gene targeting. Gene targeting by homologous recombination, which was developed by Smithies et al. (1985), Thomas et al. (1986), and Thomas and Capecchi (1987), has proven highly valuable in studies of gene structure and function and offers a potential tool for gene-therapeutic applications. A limitation constraining this technology is the low rate of homologous recombination in mammalian cells and the high rate of random (nontargeted) integration of the vector DNA. Vasquez et al. (2001) considered possible ways to overcome these limitations in the framework of the current understanding of recombination mechanisms and machinery. Several studies suggested that transient alteration of the levels of recombination proteins, by overexpression or interference with expression, may be able to increase homologous recombination or decrease random integration.
Several PARPs localize to the spindle in vertebrate cells, suggesting that PARPs and/or poly(ADP-ribose) (PAR) have a role in spindle function. Chang et al. (2004) showed that PAR is enriched in the spindle and is required for spindle function. PAR hydrolysis or perturbation led to rapid disruption of spindle structure, and hydrolysis during spindle assembly blocked the formation of bipolar spindles. PAR exhibited localization dynamics that differed from known spindle proteins and were consistent with a low rate of turnover in the spindle. Thus, Chang et al. (2004) concluded that PAR is a nonproteinaceous, nonchromosomal component of the spindle required for bipolar spindle assembly and function.
Kim et al. (2004) described nucleosome binding properties of PARP1 that promoted the formation of compact, transcriptionally repressed chromatin structures. PARP1 bound in a specific manner to nucleosomes and modulated chromatin structure through NAD(+)-dependent automodification, without modifying core histones or promoting the disassembly of nucleosomes. The automodification activity of PARP1 was potently stimulated by nucleosomes, causing the release of PARP1 from chromatin. The NAD(+)-dependent activities of PARP1 were reversed by poly(ADP-ribose) glycohydrolase (PARG; 603501) and were inhibited by ATP. In vivo, PARP1 incorporation was associated with transcriptionally repressed chromatin domains that were spatially distinct from both histone H1-repressed domains and actively transcribed regions. Kim et al. (2004) concluded that PARP1 functions both as a structural component of chromatin and as a modulator of chromatin structure through its intrinsic enzymatic activity.
Pavri et al. (2005) determined that PARP1 was necessary for retinoic acid (RA)-dependent transcription in HeLa cells, and transcription required the direct interaction of PARP1 with the mediator complex (see MED6; 602984). The interaction did not require the C-terminal catalytic domain of PARP1. By chromatin immunoprecipitation of a mouse embryonic carcinoma cell line, Pavri et al. (2005) found that Parp1 localized to the RA-responsive promoter of the mouse Rarb2 gene (RARB; 180220). Parp1 was necessary for the activation of the mediator complex and for transcription from the Rarb2 promoter. Pavri et al. (2005) also found that Parp1 functioned at a step prior to the association of TFIID (see 313650) and mediator with promoter sequences.
Bryant et al. (2005) showed that PARP inhibitors trigger gamma-H2AX (see 601772) and RAD51 (179617) foci formation. They proposed that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, Bryant et al. (2005) showed that BRCA2 (600185)-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. Bryant et al. (2005) exploited this requirement in order to kill BRCA2-deficient tumors by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumor specific, because only the tumors (which are BRCA2-null) in BRCA2 heterozygous patients are defective in homologous recombination. Bryant et al. (2005) concluded that the use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumor, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.
Farmer et al. (2005) showed that BRCA1 (113705) or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest, and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. Farmer et al. (2005) concluded that their results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
Andrabi et al. (2006) and Yu et al. (2006) demonstrated that the product of PARP1 activity, poly(ADP-ribose) (PAR) polymer, mediates PARP1-induced cell death. Andrabi et al. (2006) showed PAR polymer alone could induce cell death in primary mouse cortical neurons in a caspase- and Parp1-independent manner. Degradation of PAR polymer by PAR glycohydrolase (PARG; 603501) or phosphodiesterase-1 (see PDE1A, 171890) prevented PAR polymer-induced cell death in cultured neurons, and increased Parg expression in mice reduced damage caused by ischemia following middle cerebral artery occlusion. Yu et al. (2006) showed that PAR polymer was the cell death signal that induced the release of Aif from mitochondria mouse cortical neurons and induced its translocation to nuclei. They also showed that Parg prevented Parp1-dependent Aif release. Furthermore, cells with reduced levels of Aif were resistant to Parp1-dependent cell death and PAR polymer cytotoxicity.
Apoptosis controls the final numbers of neurons during brain development. Midorikawa et al. (2006) found that mouse Kif4 (300521), a microtubule-based molecular motor, regulated apoptosis of juvenile neurons by interacting directly with Parp1. The C-terminal domain of Kif4 suppressed Parp1 enzymatic activity. When neurons were stimulated by membrane depolarization, calcium signaling mediated by Camk2 (see 114078) induced dissociation of Kif4 from Parp1, resulting in upregulation of Parp1 activity, which supported neuron survival. After dissociation from Parp1, Kif4 entered the cytoplasm from the nucleus and moved to the distal part of neurites in a microtubule-dependent manner. Midorikawa et al. (2006) concluded that KIF4 controls the activity-dependent survival of postmitotic neurons by regulating PARP1 activity in brain development.
Krishnakumar et al. (2008) used genomic and gene-specific approaches to show that 2 factors, histone H1 and PARP1, exhibit a reciprocal pattern of chromatin binding at many RNA polymerase II-transcribed promoters. PARP1 was enriched and H1 was depleted at these promoters. This pattern of binding was associated with actively transcribed genes. Furthermore, Krishnakumar et al. (2008) showed that PARP1 acts to exclude H1 from a subset of PARP1-stimulated promoters, suggesting a functional interplay between PARP1 and H1 at the level of nucleosome binding. Thus, Krishnakumar et al. (2008) concluded that although H1 and PARP1 have similar nucleosome-binding properties and effects on chromatin structure in vitro, they have distinct roles in determining gene expression in vivo.
'Synthetic lethality' as a treatment for cancer refers to an event in which tumor cell death results from lethal synergy of 2 otherwise nonlethal events. Fong et al. (2009) used this model to treat breast cancer cells that have homozygous loss of the tumor suppressor genes BRCA1 (113705) or BRCA2 (600185) with a PARP inhibitor, resulting in the induction of selective tumor cytotoxicity and the sparing of normal cells. The method aims at inhibiting PARP-mediated single-strand DNA repair in cells with deficient homologous-recombination double-strand DNA repair, which leads to unrepaired DNA breaks, the accumulation of DNA defects, and cell death. Heterozygous BRCA mutant cells retain homologous-recombination function and are not affected by PARP inhibition. In vitro, BRCA1-deficient and BRCA2-deficient cells were up to 1,000-fold more sensitive to PARP inhibition than wildtype cells, and tumor growth inhibition was also demonstrated in BRCA2-deficient xenografts. Fong et al. (2009) reported a phase 1 clinical trial of an orally active PARP inhibitor olaparib (AZD2281 or KU-0059436) in 60 patients with mainly breast or ovarian cancer (612555; 604370), including 22 BRCA mutation carriers and 1 who was likely a mutation carrier but declined genetic testing. Durable objective antitumor activity was observed only in confirmed carriers of a BRCA1 or BRCA2 mutation; no objective antitumor responses were observed in patients without known BRCA mutations. Twelve (63%) of 19 BRCA carriers with ovarian, breast, or prostate cancers showed a clinical benefit from treatment with olaparib, with radiologic or tumor-marker responses or meaningful disease stabilization. The drug had an acceptable side-effect profile and did not have the toxic effects commonly associated with conventional chemotherapy. Fong et al. (2009) concluded that PARP inhibition has antitumor activity in BRCA mutation carriers.
In mammalian cells subjected to oxidative stress, Mao et al. (2011) showed that SIRT6 (606211) is recruited to the sites of DNA double-strand breaks and stimulates double-strand break repair, through both nonhomologous end joining and homologous recombination. Mao et al. (2011) concluded that their results indicated that SIRT6 physically associates with PARP1 and mono-ADP-ribosylates PARP1 on lysine residue 521, thereby stimulating PARP1 poly-ADP-ribosylase activity and enhancing double-strand break repair under oxidative stress.
Doege et al. (2012) described an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as NANOG (607937) and ESRRB (602167). By day 4 after transduction with pluripotency factors OCT4 (164177), SOX2 (184429), KLF4 (602253), and MYC (190080) (together referred to as OSKM), 2 epigenetic modification factors necessary for induced pluripotent stem cell (iPSC) generation, namely, PARP1 and TET2 (612839), were recruited to the NANOG and ESRRB loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: PARP1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas TET2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC. Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts, Doege et al. (2012) concluded that their data, and also studies of TET2-mutant human tumor cells, argued in favor of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, PARP1 and TET2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas PARP1 induction further promotes accessibility to the OCT4 reprogramming factor. Doege et al. (2012) concluded that their findings suggested that PARP1 and TET2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.
Sajish and Schimmel (2015) showed that resveratrol, through binding to the active site of TYRRS (603623), nullifies its catalytic activity and redirects TYRRS to a nuclear function, stimulating NAD(+)-dependent auto-poly-ADP-ribosylation of PARP1. Downstream activation of key stress signaling pathways are causally connected to TYRRS-PARP1-NAD+ collaboration. This collaboration was also demonstrated in the mouse, and was specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analog. Sajish and Schimmel (2015) concluded that, in contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites, a nonspliced TYRRS catalytic null revealed a novel PARP1- and NAD(+)-dependent dimension to the physiologic mechanism of resveratrol.
Gibbs-Seymour et al. (2016) found that HPF1 (616614) interacted with PARP1 and, more weakly, with PARP2 (607725). HPF1 was recruited to DNA lesions in laser-irradiated U2OS cells in a manner that required PARP1, but not PARP1 catalytic activity. Knockdown of HPF1 in 293T cells via CRISPR/Cas9 did not alter PARP1 recruitment to sites of DNA damage, but it elevated PARP1 auto-ADP-ribosylation and reduced histone ADP-ribosylation. Inhibition of PARP1 catalytic activity trapped both PARP1 and HPF1 at sites of DNA damage. Mutation analysis revealed that the catalytic domain of PARP1 interacted with a C-terminal domain of HPF1, and that tyr238 and arg239 of HPF1 were required for the interaction. Gibbs-Seymour et al. (2016) concluded that HPF1 modulates PARP1 activity to maximize ADP-ribosylation of core histones and to limit PARP1 auto-ADP-ribosylation.
Using human cell lines, Gibson et al. (2016) found that PARP1 interacted with and ADP ribosylated NELFE (RDBP; 154040), a subunit of the negative elongation factor (NELF) complex, which promotes promoter-proximal pausing by RNA Pol II. The NELFA subunit (WHSC2; 606026) was also ADP ribosylated. ADP ribosylation of NELFE ablated the ability of NELF to bind RNA and released Pol II from NELF-dependent pausing. Depletion or inhibition of PARP1 in human cell lines, or mutation of the ADP-ribosylation sites on NELFE, promoted Pol II pausing. ADP-ribosylation of NELFE was dependent on prior phosphorylation of NELFE by PTEFB (see 603251). Gibson et al. (2016) concluded that PARP1-dependent ADP ribosylation of phosphorylated NELFE is necessary for efficient release of Pol II into productive elongation.
Li et al. (2017) showed that DBC1 (607359) binds to and inhibits PARP1, and that inhibition of PARP1 by DBC1 could be abrogated by binding of NAD+ (oxidized nicotinamide adenine dinucleotide) to the Nudix hydrolase (600312) homology domain (NHD) of DBC1. The authors found that as mice aged and NAD+ concentrations declined, DBC1 was increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+. Li et al. (2017) concluded that NAD+ directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging.
Maya-Mendoza et al. (2018) showed that inhibition of PARP increases the speed of fork elongation and does not cause fork stalling, which is in contrast to the accepted model in which inhibitors of PARP induce fork stalling and collapse. Aberrant acceleration of fork progression by 40% above the normal velocity leads to DNA damage. Depletion of the treslin (TICRR; 613298) or MTBP (605927) proteins, which are involved in origin firing, also increases fork speed above the tolerated threshold, and induces the DNA damage response pathway. Mechanistically, Maya-Mendoza et al. (2018) showed that poly(ADP-ribosyl)ation (PARylation) and the PCNA (176740) interactor p21Cip1 (p21; 116899) are crucial modulators of fork progression. PARylation and p21 act as suppressors of fork speed in a coordinated regulatory network that is orchestrated by the PARP1 and p53 (191170) proteins. Moreover, at the fork level, PARylation acts as a sensor of replication stress. During PARP inhibition, DNA lesions that induce fork arrest and are normally resolved or repaired remain unrecognized by the replication machinery. Maya-Mendoza et al. (2018) concluded that accelerated replication fork progression represents a general mechanism that triggers replication stress and the DNA damage response.
Using CRISPR screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP inhibitor, Zimmermann et al. (2018) identified a high-confidence set of 73 genes that when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, Zimmermann et al. (2018) discovered that mutations in all 3 genes encoding ribonuclease H2 (RNASEH2A, 606034; RNASEH2B, 610326; and RNASEH2C, 610330) sensitized cells to PARP inhibition and established that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase-1 (126420), resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. Zimmermann et al. (2018) concluded that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukemia may provide an opportunity to exploit these findings therapeutically.
Kam et al. (2018) found that pathologic alpha-synuclein (163890) activates PARP1, and poly ADP-ribose (PAR) generation accelerates the formation of pathologic alpha-synuclein, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP1 prevented pathologic alpha-synuclein toxicity. In a feed-forward loop, PAR converted pathologic alpha-synuclein to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with Parkinson disease (168601), suggesting that PARP activation plays a role in Parkinson disease pathogenesis.
McBride et al. (1987) concluded that a large functional PARP gene of more than 15 to 20 kb is located on chromosome 1q and that sequences on chromosomes 13 and 14 most likely represent processed pseudogenes. These localizations were achieved by probing of the DNA from panels of somatic cell hybrids.
Herzog et al. (1988) cloned a cDNA for ADPRT and localized the gene to 1q21-q22 by in situ hybridization. Herzog et al. (1989) mapped the ADPRT gene to 1q41-q42 by in situ hybridization. Using high resolution in situ hybridization techniques, Zabel et al. (1989) localized PPOL to 1q41-q42. With the conditions used, only 1 additional site of hybridization, 14q22, could be detected; this probably represented a pseudogene which had previously been identified and called ADPRTP2. By nonisotopic in situ hybridization, Baumgartner et al. (1992) confirmed localization of the functional gene to 1q42. Two other hybridization peaks, one at 13q34 and one at 14q24, suggested the location of pseudogenes.
PARP Pseudogene
A processed pseudogene or a gene with extensive identity to the ADPRT gene was studied by Bhatia et al. (1990), who mapped it to 13q33-qter. The gene was deleted in a polymorphism that was 3 times higher in frequency among blacks than Caucasians. Bhatia et al. (1990) suggested that this deletion might be a predisposing factor in several forms of malignancy.
Lyn et al. (1993) studied the 2-allele (A/B) polymorphism of the gene on 13q34. An elevated B-allele frequency was found in germline DNA in blacks with multiple myeloma (254500), prostate cancer (176807), and colon cancer (114500). They found that the A allele has a close sequence similarity (91.8%) to the PPOL cDNA coded by 1q42 and is intronless, suggesting that the gene on 13q is a processed pseudogene. They presented data indicating that the polymorphism reflects a 193-bp duplication within the processed-pseudogene sequence, with absence of this duplicated region being characteristic of the B genotype. Doll et al. (1996) confirmed the association between prostate cancer in black Americans and an allele of the pseudogene locus (which they symbolized PADPRP) on chromosome 13. Two genes in the region 13q33-q34 were viewed as potential candidates for prostate cancer: ERCC5 (133530) and RAP2A (179540).
Auer et al. (1989) demonstrated that the PARP gene is 43 kb long and split into 23 exons.
Crystal Structure
Langelier et al. (2012) reported the crystal structure of a DNA double-strand break in complex with human PARP1 domains essential for activation (Zn1, Zn3, WGR-CAT). PARP1 engages DNA as a monomer, and the interaction with DNA damage organizes PARP1 domains into a collapsed conformation that could explain the strong preference for automodification. The Zn1, Zn3, and WGR domains collectively bind to DNA, forming a network of interdomain contacts that links the DNA damage interface to the catalytic domain (CAT). The DNA damage-induced conformation of PARP1 results in structural distortions that destabilize the CAT. Langelier et al. (2012) concluded that an increase in CAT protein dynamics underlies the DNA-dependent activation mechanism of PARP1.
Suskiewicz et al. (2020) solved the crystal structure of HPF1 (616614) to 2.1-angstrom resolution. They reported a costructure of HPF1 bound to the catalytic domain of PARP2 (607725) that, in combination with NMR and biochemical data, revealed a composite active site formed by residues from HPF1 and PARP1 or PARP2. The assembly of this catalytic center is essential for the addition of ADP-ribose moieties after DNA damage in human cells. In response to DNA damage and occupancy of the NAD(+)-binding site, the interaction of HPF1 with PARP1 or PARP2 is enhanced by allosteric networks that operate within the PARP proteins, providing an additional level of regulation in the induction of the DNA damage response.
Mixed Biophysical Methods
Zandarashvili et al. (2020) used hydrogen/deuterium exchange mass spectrometry (HXMS) combined with x-ray structures and a battery of biochemical assays to interrogate the molecular impact of PARP inhibitors binding to PARP1 engaged on sites of DNA damage. These experiments revealed that the critical allosteric regulatory domain of PARP1, the helical domain, is affected in distinct ways depending on the particular PARP inhibitor engaged in the NAD(+)-binding site adjacent to the helical domain. Certain PARP inhibitors destabilized specific helical domain regions, some had no effect on the helical domain, and others actually stabilized regions of the helical domain. PARP inhibitors that destabilized the helical domain increased PARP1 affinity for DNA and retained PARP1 on DNA breaks. Zandarashvili et al. (2020) then classified PARP inhibitors into 3 types: type I, allosteric proretention on DNA; type II, nonallosteric; and type III, allosteric prorelease from DNA. They found that type I PARP inhibitors contact helix alpha-F to initiate an allosteric chain reaction that travels approximately 40 angstroms through the multidomain PARP1 molecule and culminates in increased DNA binding affinity. Zandarashvili et al. (2020) concluded that their studies provided the molecular understanding and appropriate toolset to create and evaluate tunable PARP inhibitors for clinical applications where PARP1 trapping and associated cytotoxicity are either desirable or undesirable in specific patients.
Streptozotocin (STZ) selectively destroys insulin-producing beta islet cells of the pancreas, providing a model of type I diabetes (see 222100). PARP is a nuclear enzyme whose overactivation by DNA strand breaks depletes its substrate NAD+ and then ATP, leading to cellular death from energy depletion. Pieper et al. (1999) demonstrated DNA damage and a major activation of PARP in pancreatic islets of STZ-treated mice. These mice displayed a 5-fold increase in blood glucose and major pancreatic islet damage. In mice with homozygous targeted deletion of Parp, blood glucose and pancreatic islet structure were normal, indicating virtually total protection from STZ diabetes. Partial protection occurred in heterozygous animals. Thus, PARP activation may participate in the pathophysiology of type I diabetes, for which PARP inhibitors might afford therapeutic benefit.
Using 2 different techniques, d'Adda di Fagagna et al. (1999) showed that mice lacking PARP display telomere shortening compared with wildtype mice. Telomere shortening was seen in different genetic backgrounds and in different tissues from embryos and adult mice. In vitro telomerase activity, however, was not altered in Adprt1 -/- mouse fibroblasts. Furthermore, cytogenetic analysis of mouse embryonic fibroblasts showed that lack of PARP was associated with severe chromosomal instability, characterized by increased frequency of chromosome fusions and aneuploidy. The absence of PARP does not affect the presence of single-strand overhangs, naturally present at the end of telomeres. This study, therefore, revealed an unanticipated role of PARP in telomere length regulation and provided insight into its functions in maintaining genomic integrity.
Depletion of PARP increases the frequency of recombination, gene amplification, sister chromatid exchanges, and micronuclei formation in cells exposed to genotoxic agents, implicating PARP in the maintenance of genomic stability. By flow cytometric analysis, Simbulan-Rosenthal et al. (1999) demonstrated an unstable tetraploid population in immortalized fibroblasts derived from PARP -/- mice. There were partial chromosomal gains in other regions. Neither the chromosomal gains nor the tetraploid population were apparent in PARP -/- cells stably transfected with PARP cDNA, indicating negative selection of cells with these genetic alterations after reintroduction of PARP cDNA. These results implicated PARP in the maintenance of genomic stability.
Steroid response and stress-activated genes such as Hsp70 (see 140550) undergo puffing, a local loosening of polytene chromatin structure associated with gene induction, in Drosophila larval salivary glands. Tulin and Spradling (2003) found that puffs acquired elevated levels of ADP-ribose modified proteins and that PARP was required to produce normal-sized puffs and normal amounts of Hsp70 after heat exposure. Tulin and Spradling (2003) proposed that chromosomal PARP molecules become activated by developmental or environmental cues and strip nearby chromatin proteins off DNA to generate a puff. Such local loosening may facilitate transcription and may transiently make protein complexes more accessible to modification, promoting chromatin remodeling during development.
To understand the biologic significance of PARP1 cleavage, Petrilli et al. (2004) generated a PARP1 knockin mouse model in which the caspase cleavage site of PARP1, DEVD(214), was mutated to render the protein resistant to caspases during apoptosis. The Parp1 knockin mice were highly resistant to endotoxic shock and to intestinal and renal ischemia/reperfusion, which were associated with reduced inflammatory responses in the target tissues and cells due to the compromised production of specific inflammatory mediators. Despite normal binding of nuclear factor kappa-B (see 164011) to DNA, NFKB-mediated transcription activity was impaired in the presence of caspase-resistant PARP1. Petrilli et al. (2004) concluded that the PARP1 cleavage event is physiologically relevant to the regulation of the inflammatory response in vivo.
Using flow cytometric analysis, Ambrose et al. (2008) demonstrated increased T-cell and normal B-cell numbers in Parp1 -/- mice. Basal Ig levels were abnormal due to reduced levels of IgG2a and increased levels of IgA and IgG2b. T cell-dependent antibody responses were reduced, but T cell-independent responses were normal. In vitro, activated Parp1 -/- B cells proliferated and secreted IgM normally, but they exhibited decreased switching to IgG2a and increased IgA secretion. Ambrose et al. (2008) concluded that PARP1 has essential roles in normal T cell-dependent antibody responses and in regulation of isotype expression.
Werner syndrome (WS; 277700) is a rare disorder characterized by the premature onset of a number of age-related diseases and is caused by mutation in the RECQL2 (604611) gene, which is believed to be involved in different aspects of transcription, replication, and/or DNA repair. PARP1 is also involved in DNA repair and is known to affect transcription of several genes. Deschenes et al. (2005) examined the expression profile of mouse embryonic cells lacking both Recql2 and Parp1 using microarray and RT-PCR analysis. All mutant cells exhibited altered expression of genes normally responding to oxidative stress. More than 50% of misregulated genes identified in double-mutant mouse cells were not altered in mouse cells with either the Recql2 or Parp1 mutation alone. The impact on gene expression profile when both Recql2 and Parp1 were mutated was greater than a simple addition of individual mutant genotype. In addition, double-mutant cultured mouse cells showed major misregulation of genes involved in apoptosis, cell cycle control, embryonic development, metabolism, and signal transduction. Double-mutant mouse embryos showed increased apoptosis and developmental defects with decreased survival in utero. Surviving adult double-mutant mice exhibited high levels of reactive oxygen species (ROS) and DNA oxidative damage and increased intracellular protein phosphorylation in heart and liver compared to wildtype.
By flow cytometric analysis of thymus, spleen, and lymph nodes from Parp1 -/- mice, Nasta et al. (2010) detected increased Cd4 (186940)-positive/Cd25 (IL2RA; 147730)-positive/Foxp3 (300292)-positive regulatory T lymphocytes (Tregs). The increased Tregs in the periphery resulted in impaired CD4 cell proliferation and IL2 (147680) production, which could be restored by depletion of Cd25-positive cells. Treg inhibitory function of Parp1 -/- cells was comparable to wildtype, suggesting that PARP1 affects Treg differentiation rather than function. Naive CD4 cells from Parp1 -/- mice expressed higher levels of Foxp3 and converted more cells to Foxp3-positive inducible Tregs following stimulation than their wildtype counterparts. Conversion to Th17 (see IL17; 603149) cells expressing Rorgt (602943) was not affected by Parp1 deficiency. Nasta et al. (2010) proposed that PARP1 modulation during an immune response may induce greater numbers of functional Tregs.
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