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PARP1 (poly(ADP-ribose) polymerase 1)

Written2019-11Sinem Tunçer, Kubra Kavak
Vocational School of Health Services, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey Biotechnology Application and Research Center, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey; sinem.tuncer@bilecik.edu.tr (ST); Department of Molecular Biology and Genetics, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey; kubrakavak2@gmail.com (KK)

Abstract PARP1 (poly(ADP-ribose) polymerase 1) is a nuclear protein involved in the regulation of various biological processes including apoptosis, DNA repair for the maintenance of genome integrity, epigenetic marking of chromatin, assembly of higher-order chromatin structures, transcriptional activation, differentiation, proliferation, and cell cycle. Particularly, due to its decisive role in several DNA repair pathways, the inhibition of PARP1 has emerged as a prominent therapeutic option in cancer treatment, by improving the efficiency of chemotherapeutics or radiation therapy.

Keywords PARylation, DNA repair, cancer, inflammation, neurodegenerative diseases, viral infections

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)PARP-1, ADPRT, ARTD1, PPOL, ADP-Ribosyltransferase NAD(+), Poly(ADP Ribosyl)Transferase, Poly(ADP-Ribose) Synthetase, EC 2.4.2., PADPRT-1, EC 2.4.2, ADPRT1, PARP
HGNC (Hugo) PARP1
HGNC Alias symbPARP
HGNC Previous namePPOL
 ADPRT
HGNC Previous nameADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase)
 poly (ADP-ribose) polymerase family, member 1
LocusID (NCBI) 142
Atlas_Id 586
Location 1q42.12  [Link to chromosome band 1q42]
Location_base_pair Starts at 226360691 and ends at 226408093 bp from pter ( according to hg19-Feb_2009)  [Mapping PARP1.png]
Local_order Starts at 226360691 and ends at 226408093 (GRCh38.p13 Assembly) (Figure 1).
 
  Figure 1. Genomic location of human PARP1 (Chromosome 1 - NC_000001.11, GRCh38.p13 Assembly)
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note PARP1 has been found to be related with almost all the biological events and signalling pathways.

DNA/RNA

Note The poly (ADP-ribose) polymerase (PARP) proteins have been characterized as enzymes that catalyse the attachment of the ADP-ribose subunits to itself and to multiple target proteins by using NAD+ as the substrate (Citarelli, Teotia, & Lamb, 2010; Ray Chaudhuri & Nussenzweig, 2017). This post-transcriptional modification is called Poly(ADP-ribosyl)ation (PARylation) (Citarelli et al., 2010). PARylation is a reversible modification: it is accomplished by the concerted actions of poly(ADP-ribose) polymerase (PARP) enzymes and poly(ADP-ribose) (PAR) hydrolysing enzymes such as PAR glycohydrolase (PARG) and ADP-ribosyl hydrolase 3 (ADPRHL2) (Virág, Robaszkiewicz, Rodriguez-Vargas, & Oliver, 2013). The removal of terminal ADP-ribose unit is achieved by the hydrolytic activity of macrodomain proteins (MACROD1, MACROD2, and OARD1) (Perina et al., 2014).
PARylation is a widely used process in eukaryotes. In eukaryotic species, the distribution of PARP proteins strictly follows the distribution of PARGs and at least one of the macrodomain proteins is also always present (Perina et al., 2014). On the other hand, PARP proteins are less common in bacteria and are thought to be acquired through horizontal gene transfer (Alemasova & Lavrik, 2019; Perina et al., 2014). In thermophilic archaeon Sulfolobus solfataricus, a protein with oligo(ADP-ribosyl) transferase activity was identified (Faraone-Mennella, Gambacorta, Nicolaus, & Farina, 1998) and in a number of dsDNA viruses have also been found to possess PARP homologues (Perina et al., 2014).
Based on the sequence homology, humans are assumed to express 17 defined PARPs (Vyas, Chesarone-Cataldo, Todorova, Huang, & Chang, 2013). PARP1, the first PARP purified and cloned from human, is a constitutive and the best studied member of the PARP family of proteins (Citarelli et al., 2010). The PARP1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, C.elegans, A.thaliana, rice, and frog (Table 1).
Table 1. Pairwise alignment of PARP1 gene (in distance from human) (HomoloGene:1222, NCBI).
Gene SpeciesGene SymbolIdentity (%) DNA
vs. P.troglodytesPARP199,2
vs. M.mulattaPARP197,7
vs. C.lupusPARP188,4
vs. B.taurusPARP188,4
vs. M.musculusParp186,5
vs. R.norvegicusParp186,1
vs. G.gallusPARP175,2
vs. X.tropicalisparp172
vs. D.rerioparp169,5
vs. D.melanogasterParp49,5
vs. A.gambiaeAgaP_AGAP00323053,1
vs. C.eleganspme-148,2
vs. A.thalianaPARP150,2
vs. O.sativaOs07g041370051,7
 
  Figure 2. Display of human PARP1 gene transcript exons (Ensembl release 98 - September 2019)
Description The PARP1 gene is a protein-coding gene. It is located at 1q42.12 on the minus strand and consists of 23 exons spanning ∼43 kb (starts at 226360691 and ends at 226408093; GRCh38.p13 Assembly, NCBI).
Transcription This gene has 10 transcripts (splice variants) depending on Ensembl release 98 - September 2019 (Table 2 and Figure 2).
The human PARP1 promoter region does not contain typical regulatory elements, such as TATA or CAAT boxes. A near 40-base-pair region surrounding the transcription start site described as containing a near-consensus initiator element capable of initiating RNA polymerase II transcription (Abbotts & Wilson, 2017). Detailed analyses of the promoter regions of PARP1 genes in humans, rats, and mice showed that PARP1 promoter sequences have binding sites for transcription factors SP1, AP-2, YY1, ETS1, and NF1. In the distal promoter region of human PARP1 gene Candidate binding sites for several other factors including CDE, KLF4 (GKLF), BARB, RRM1 (MAZF), RREB1, HOX, GSX1 (GSH-1), CEBPB, NFIL3 (E4BP4), STAT6, cETSZ-1, PBX1, LEF1 (TCF), NF-kB, REL, ZNF148 (ZBP-89), KLF6 (CPBP), USF, CDF-1, EGR1, and IKZF1 (Ikaros 1) were also identified (Doetsch, Gluch, Poznanovic, Bode, & Vidakovic, 2012). Additionally, at the post-transcriptional level, miR-124, MIR223, let-7a, miR-7-5p, and MIR125B2 were shown to regulate cellular PARP1 expression (Dash et al., 2017; J. Lai et al., 2019; Wielgos et al., 2017).
Table 2. Transcripts of human PARP1 gene (Ensembl release 98 - September 2019)
PARP1-201ENST00000366790.3570--Protein coding
PARP1-202ENST00000366792.3553--Protein coding
PARP1-203ENST00000366794.103978CCDS1554 NM_001618.4Protein coding
PARP1-204ENST00000463968.5830--lncRNA
PARP1-205ENST00000468608.1438--lncRNA
PARP1-206ENST00000469663.1542--lncRNA
PARP1-207ENST00000490921.53165--lncRNA
PARP1-208ENST00000491816.1416--lncRNA
PARP1-209ENST00000498787.1628--lncRNA
PARP1-210ENST00000629232.1477--Protein coding
Pseudogene There are two known pseudogenes of PARP1: PARP1P1 and PARP1P2 located on chromosomes 13 and 14, respectively (Table 3). A germline, two-allele (A/B) polymorphism of PARP1P1 on chromosome 13q34-qter has been identified. In the B-allele, a 193 bp deletion was determined and this deletion has been shown to be associated with cancer predisposition to multiple myeloma, monoclonal gammopathies, prostate cancer, and lung cancers in African Americans. On the other hand, more recent studies do not support the earlier findings which suggest that the PARP1P1 genotype plays a critical role in cancer susceptibility (Lockett, Snowhite, & Hu, 2005). Analyses, comprising a larger cohort that is selected based on case/control differences rather than racial/ethnic differences, are needed to clarify if there is any significant role of this pseudogene in cancer predisposition.
Table 3. Pseudogenes of human PARP1 gene (GRCh38 Assembly, NCBI)
Name/Gene IDDescriptionLocation (bp)Aliases
PARP1P2 (ID: 145)poly(ADP-ribose) polymerase 1 pseudogene 2 Chr 14, NC_000014.9 (63123001..63123935)ADPRTP2, PPOLP2
PARP1P1 (ID: 144)poly(ADP-ribose) +B7:D7polymerase 1 pseudogene 1Chr 13, NC_000013.11 (110936624..110940232)ADPRTP1, PPOLP1

Protein

Note Encoded proteins by PARP1 gene in human are given in Table 4 and PARP1 protein similarity across species are given in Table 5.
Table 4. Protein products of human PARP1 gene (Ensembl release 98 - September 2019)
NameTranscript IDProteinChargeIsoelectric PointMolecular WeightCCDSUniProtRefSeq
PARP1-201ENST00000366790.3155aa10,09,4862 17,324.99 g/mol-Q5VX85-
PARP1-202ENST00000366792.3108aa3,07,7272 12,234.02 g/mol-Q5VX84-
PARP1-203ENST00000366794.101014aa31,59,3322113,083.79 g/mol CCDS1554A0A024R3T8 P09874NM_001618.4
PARP1-210ENST00000629232.1108aa3,07,727212,234.02 g/mol -Q5VX84-

Table 5. Pairwise alignment of PARP1 protein sequences (in distance from human) (HomoloGene:1222, NCBI)
Gene SpeciesGene SymbolIdentity (%) PROTEIN
vs. P.troglodytesPARP199
vs. M.mulattaPARP198,2
vs. C.lupusPARP194,1
vs. B.taurusPARP190,4
vs. M.musculusParp192,2
vs. R.norvegicusParp191,6
vs. G.gallusPARP179,5
vs. X.tropicalisparp175,7
vs. D.rerioparp172,1
vs. D.melanogasterParp43,8
vs. A.gambiaeAgaP_AGAP00323046,5
vs. C.eleganspme-141,1
vs. A.thalianaPARP142,3
vs. O.sativaOs07g041370042,7
 
  Figure 3. Domain organization of PARP1: ZF1-3: zinc finger domains 1-3; BRCT: BRCA1 C terminus domain; WGR: tryptophan-glycine-arginine rich domain; PRD: PARP regulatory domain; ART: catalytic domain, highly-conserved in other ADP-ribosyl transferases; NLS: Nuclear Localization Signal. The figure is modified from (Abbotts & Wilson, 2017).
Description PARP1 encodes poly (ADP-ribosyl) transferase (EC 2.4.2.30) (NCBI Homo sapiens Annotation Release 109). Poly (ADP-ribose) polymerase1 (PARP1) is an isoform of the PARP enzyme family (Pacher & Szabó, 2007). Full length PARP1 protein comprises three major functional domains: an amino-terminal DNA-binding domain, a carboxy-terminal catalytic domain (CD; also called as CAT), and a central auto modification domain (called as AMD or AD) (Altmeyer, Messner, Hassa, Fey, & Hottiger, 2009; Gross, Kotova, Maluchenko, Pascal, & Studitsky, 2016). DBD contains two zinc finger domains (ZFI/ZF1 and ZFII/ZF2; also known as Zn1 and Zn2). Langelier et al. reported that the ZF2 domain exhibits high binding affinity to DNA compared to the ZF1 domain and Gradwohl et al. showed that disruption of the metal-binding ability of the ZF2 dramatically reduces the binding to target DNA (Gradwohl et al., 1990). In addition, in both in vitro and in vivo, the ZF1 domain was found to be necessary for DNA-dependent PARP1 activity whereas the ZF2 domain was not required strictly (Langelier, Planck, Roy, & Pascal, 2011). An additional zinc finger domain (ZFIII/ZF3; also known as Zn3) presents after DBD and it mediates inter-domain contacts, important for the PARP1 activation. (Langelier et al., 2011; Tao, Gao, Hoffman, & Liu, 2008). A bipartite nuclear localization signal (NLS) also lies in DBD and contains a caspase cleavage site DEVD214 (Castri et al., 2014). The AMD region is located in the central region of the enzyme and the region has acceptor amino acids for the covalent attachment of PAR. Moreover, a weak leucine-zipper motif has been described in the amino-terminal region of the AMD, which suggests that this motif may function in homo- and/or hetero-dimerization. The AMD of PARP1 also includes a breast cancer 1 protein (BRCA1) C-terminus (BRCT) domain as well as an unstructured loop that connects the AMD with the PARP homology domain (Altmeyer et al., 2009). The carboxy-terminal CD is the most conserved region across PARP family of proteins in different species. This domain has the 'PARP signature' characterized by NAD acceptor sites and critical residues involved in the initiation (the attachment of the first ADP-ribose moiety onto an acceptor amino acid), elongation (the addition of further ADP-ribose units onto already existing ones) and branching (the generation of branching points) of PAR (Altmeyer et al., 2009; Simonin et al., 1990). Followed by the CD, there is a WGR region, named after the identification of conserved amino acid sequence in the motif: Tryptophan-W, Glycine-G, Arginine-R. WGR region functions in DNA binding and inter-domain contacts essential for DNA damage-dependent activation (Altmeyer et al., 2009; Dawicki-McKenna et al., 2015; Langelier, Planck, Roy, & Pascal, 2012). The domain organization of PARP1 is shown in Figure 3.
PARP1 is known to be activated by mono-ADP-ribosylation, acetylation, increased cellular calcium concentration, or by binding to tyrosyl tRNA synthase. On the other hand, self-PARylation and sumoylation were shown to inhibit PARP1 activity. PARP1 can also be phosphorylated in a reversible manner and the phosphorylation can activate (e.g., AMP-activated protein kinase [AMPK]) or inhibit (e.g., protein kinase C) PARP-1 activity (Bai, 2015). In addition, physical interactions with other proteins, including histones, HPF1, HMGN1, XPA, NEIL1, OGG1, DDB2, TP53, and MAPK1 (ERK2) found to regulate PARP1 activity (Alemasova & Lavrik, 2019). It was also reported that dimerization of PARP1 enhances its enzymatic activity while further multimerization or dissociation to single PARP1 molecules leads to decreased enzymatic activity (Alemasova & Lavrik, 2019).
Expression PARP1 is an abundantly and ubiquitously expressed protein in most tissues (Schiewer & Knudsen, 2014). Compared to normal counterparts, enhanced PARP1 expression is found in various types of tumors, but the most striking differences in PARP1 expression have been found in breast, ovarian, endometrial, lung, skin cancers and non-Hodgkin's lymphoma (Galia et al., 2012; Ossovskaya, Koo, Kaldjian, Alvares, & Sherman, 2010).
Localisation PARP1 is primarily localized to the nucleus, but a distinct fraction was also detected in the mitochondria. Unlike nuclear PARP1, mitochondrial PARP1 has been shown to affect mitochondrial DNA repair negatively (Szczesny, Brunyanszki, Olah, Mitra, & Szabo, 2014).
PARP1 is one of several known cellular substrates of CASP3 and CASP7 (caspase 3 and caspase 7) and cleavage of PARP1 by these caspases is considered to be a hallmark of apoptosis. Upon cleavage, two specific fragments of PARP1 are generated: an 89 kDa fragment containing AMD and the catalytic domain of the enzyme and a 24 kDa containing DBD. The 89 kDa fragment has a greatly reduced DNA binding capacity and is liberated from the nucleus into the cytosol. On the other hand, the 24 kDa cleaved fragment with 2 zinc-finger motifs does not leave the nucleus where it binds to nicked DNA irreversibly and therefore acts as a trans-dominant inhibitor of active PARP1 (Chaitanya, Alexander, & Babu, 2010).
Function ADP-ribosylation is a posttranslational modification. By using the oxidized form of NAD+ as a substrate, PARP enzymes bind and cleave NAD+ to nicotinamide (NAM) and ADP-ribose (ADPR) and catalyze the covalent binding of ADPR units onto glutamate, aspartate, tyrosine, lysine, and serine residues of target proteins (Rodrèguez-Vargas, Oliver-Pozo, & Dantzer, 2019). PARP1, PARP2, tankyrase 1 ( TNKS), and tankyrase 2 ( TNKS2) synthesize branched PAR polymers and the remaining PARP enzymes are either mono or oligo ADPR-transferases. No enzymatic activity has been identified for ZC3HAV1 (PARP13) (Bai, 2015). PARP1 is the prototype member of the PARP family of enzymes and more than 80% of stimulated and basal cellular PARP activity are exerted by PARP1 (Bai, 2015; Rajamohan et al., 2009).
Although PARP1 has been long defined as a DNA-damage response protein, recent investigations highlight multiple functions of PARP1 including transcription, replication, aging, viral protection, cell cycle regulation, modification of chromosome structure, differentiation, inflammation, metabolic regulation, proteasomal degradation, and RNA processing (Bai, 2015; Rodrèguez-Vargas et al., 2019) (Figure 4).
PARP1 functions in DNA repair
Genotoxic stress results in various types of DNA lesions, including DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). If not repaired, accumulated damage can disrupt genomic integrity. Fortunately, cells have evolved different DNA-damage repair responses that repair these DNA lesions to insure genomic stability (C. Liu, Vyas, Kassab, Singh, & Yu, 2017).
PARP1 recognizes both SSBs and DSBs and transfers the ADP-ribose moiety of NAD+ to the side chains of asparagine, aspartic acid, glutamic acid, arginine, lysine, serine and cysteine residues on its target proteins. Through their PAR-binding domains, these PAR chains form a platform and recruit DNA repair proteins. Therefore, PARP1 is an important DNA damage sensor for both SSBs and DSBs (Ray Chaudhuri & Nussenzweig, 2017).
PARP1 modulates chromatin structure and transcription
PARP1 functions in chromatin compaction, decondensation and it modulates epigenetic marks via PARylating histones and chromatin remodeling enzymes (Quénet, El Ramy, Schreiber, & Dantzer, 2009). Being as a component of enhancer/promoter-binding complexes, besides its effects on chromatin structure, PARP1 can bind to most of the RNA polymerase II transcribed genes and mediate around 3.5% of all transcribed RNAs covering a broad range of functions from inflammation to metabolism (Ke, Zhang, Lv, Zeng, & Ba, 2019; Kraus, 2008). PARP1 can also enhance the accessibility of promoters via histone and nucleosome replacements and can enhance transcription by replacing negative transcriptional cofactors with positive ones (Kraus & Hottiger, 2013; Muthurajan et al., 2014).
Recent findings described new roles of PARP1 in the regulation of RNA binding proteins, rRNA synthesis, ribosome biogenesis, and mRNA regulation (Ke et al., 2019; Ryu, Kim, & Kraus, 2015). Accordingly, PARP1 can regulate gene expression at the post-transcriptional level.
Cell death and PARP1
As mentioned before, PARP1 is known to be cleaved and inactivated by active caspases 3 and 7 and this cleavage is accepted as a 'hallmark of apoptosis' (Castri et al., 2014; Desroches & Denault, 2019). The cleavage causes the formation of 24 kDa and 89 kDa fragments. Depending on the intensity and type of stimuli resulting in the cleavage, two main consequences have been reported: (1) reduced PARylation during DNA repair processes; (2) the modification of PARP1 transcriptional activity (Castri et al., 2014).
Recent studies indicate that PARP1 hyperactivation, ie. excessive PARylation by PARP1, can lead 'parthanatos', a form of necrotic cell death which PAR induces the nuclear translocation of apoptosis-inducing factor ( AIFM1) from mitochondria to initiate chromatinolysis and cell death independently of caspase activation. For a long time, it has been thought that the cell death caused by excessive activation of PARP occurs via the catalytic consumption of NAD+ followed by ATP reduction and bioenergetic collapse. However, Andrabi et al. showed that not the decreased NAD+, but PAR-dependent inhibition of hexokinase activity leads to defects in glycolysis and therefore causes the bioenergetic collapse. On the other hand, PARP1 activity is kept at much lower levels during normal unstressed cellular conditions (Andrabi et al., 2014; Dawicki-McKenna et al., 2015; Gupte, Liu, & Kraus, 2017).
 
  Figure 4. Multifaceted nature of PARP-1: PARP1 functions in DNA repair, chromatin modification, inflammation, transcriptional regulation, and cell death. DBS: Double Strand Break; BER: Base Excision Repair; SSB: Single Strand Break; SPR: Short-Patch Repair; LPR: Long-Patch Repair. The figure is modified from (Swindall, Stanley, & Yang, 2013).
 
  Figure 5. The Role of PARP1 in human organs. The figure is modified from (Bai, 2015).

Mutations

Note A list of PARP1 mutations in cancer can be found in: COSMIC, the Catalogue of Somatic Mutations in Cancer, https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=PARP1
Germinal Parp1-/- mice are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities (Tha Jackson Laboratory; www.jax.org/strain/002779).
Somatic Lys933Asn and Lys945Asn mutations were found to be significantly correlated with colorectal cancer (CRC) in the Saudi population. Since these mutations were identified to be localized in PARP1 catalytic domain (CD), mutations of these lysine residues were suggested to affect the PARP1 catalytic activity (Alshammari, Shalaby, Alanazi, & Saeed, 2014). In addition, Val762Ala polymorphism in the CD has been reported as the most common variant of PARP1 associated with an increased risk of many tumors (Toss & Laura, 2013).
Using genome-wide and high-density CRISPR-Cas9 'tag-mutate-enrich' mutagenesis screens, Pettitt et al. identified PARP1 mutant alleles that cause in vitro and in vivo PARP inhibitor resistance. The results reveal that point mutations in the ZnF domains were sufficient for the inhibitor resistance (Pettitt et al., 2018).
Polymorphisms: In addition to mutations, through modulation of PARP1 expression level and enzyme activity, PARP1 gene polymorphisms can affect the outcome and response to therapy of cancer. For example, PARP1 SNP rs1805407, found in perfect linkage disequilibrium with two PARP1 promoter SNPs (rs2077197 and rs6665208), was shown to be associated with higher PARP1 expression (Abecassis et al., 2019). In another study, expression quantitative trait locus (eQTL) analysis in melanocytic cell types revealed that presence of the 1q42.1 melanoma risk allele (rs3219090[G]) is correlated with higher PARP1 levels. Furthermore, a proteomic screen identified that RECQL helicase binds to the insertion allele of PARP1 (indel SNP rs144361550) in melanoma cells and primary human melanocytes (J. Choi et al., 2017). In another study, using a new data integrative approach applied on multi-modal -omics, and clinical data, Abecassis et al. demonstrated that response to chemotherapy is directly linked to the gene expression, four methylation variables and PARP1 SNP rs1805407 in a cohort of metastatic melanoma patients (Abecassis et al., 2019). According to the results of another genotyping study, Val762Ala, Asp81Asp, and Lys352Lys polymorphisms and the haplotype-ACAAC in PARP1 are associated with reduced risk of non-Hodgkin lymphoma in Korean males (Jin et al., 2010). In a case-control study conducted in the Hexi area of China, PARP1 2819G allele was shown to be associated with an increased risk of gastric cancer (He, Liu, Shan, Zhu, & Li, 2012).
In addition, PAR metabolism is also involved in malignancies. For instance, PARylation of proteins in peripheral blood leukocytes was shown to be reduced by more than 50% in head, neck, breast and cervical cancers (Lakadong, Kataki, & Sharan, 2010).

Implicated in

Note PARP1 has been implicated in several human pathologies (Figure 5). Defects in PARP1 function have been shown to be associated with several diseases, such as conditions or diseases related with chronic inflammation, neurodegenerative disorders, cardiovascular diseases, and cancer.
  
Entity Cardiovascular diseases
Note Myocardial infarction (MI) is a common cardiovascular disease characterized by the induction of inflammation and apoptosis of cardiomyocytes because of the diminished levels of oxygen and nutrients in the myocardial tissue. In a rat model of MI, Wang et al. suggested that oxidative DNA damage caused by the generation of reactive species during the onset of MI can cause excessive activation of PARP1 followed by an imbalance of cell survival mechanisms that contribute to the death of cardiomyocytes. The authors showed that inhibition of iNOS (Inducible nitric oxide synthase), an important member of inflammatory cytokines regulated by PARP1 via the NF- kB pathway, or inhibition of PARP1 was able to reduce the level of apoptosis caused by the ischemic myocardial damage (J. Wang et al., 2015).
More recently, it has been shown that PARP1 can affect cardiac functions also via autophagy activation. Therefore, inhibition of PARP1 was suggested to be protective against cardiac ischemia injury by repressing autophagy (C. Wang, Xu, Zhang, Zhang, & Huang, 2018).
  
  
Entity Diabetes and Obesity
Note PARP1 has been suggested to play an important role in adipogenesis and cellular metabolism (Erener, Hesse, Kostadinova, & Hottiger, 2011; Jokinen, Pirnes-Karhu, Pietiläinen, & Pirinen, 2017; Luo et al., 2017). In their in vivo study, Devalaraja-Narashimha and Padanilam showed that knock out of Parp reversed resistance to diet-induced obesity by decreasing energy expenditure in mice (Devalaraja-Narashimha & Padanilam, 2010).
  
  
Entity Central Nervous System Disorders
Note PARP1 activation is known to be associated with the pathogenesis of several central nervous system disorders, including ischemia, neuroinflammation, and neurodegenerative diseases such as Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) (Martire, Mosca, & d'Erme, 2015; Palazzo, Mikolcevic, Mikoc, & Ahel, 2019). Neurological disorders can be characterized by aggregation of cytotoxic proteins, enhanced levels of oxidative stress followed by DNA damage, PARP1 activation, and excess of cellular levels of PAR (Palazzo et al., 2019). For instance, in PD, intracellular monomericSNCA (alpha-synuclein) forms higher-ordered protein aggregates which can spread from cell to cell. These α-synuclein aggregates can activate nitric oxide synthase which enhances the production of NOS. NOS can cause DNA damage and activation of PARP1 and nuclear production of PAR. PAR is transported into the cytosol where it interacts with α-synuclein and further accelerates fibrillization and misfolding of this cytotoxic protein α-synuclein in a pathogenic loop. Ultimately, accumulation of pathologic α-synuclein results in cell death via parthanatos and neuronal dysfunction (Kam et al., 2018).
A growing number of evidence shows that mitochondrial function is strictly controlled by PARP1 which is responsible for about more than 90% of PARylation in the brain (Pieper et al., 2000). In addition to oxidative stress which is able to activate PARP1, recent studies claim that PARP1 is a critical component of a molecular interactions network responsible in the nervous system disorders related to mitochondrial function. It was suggested that deleterious consequences of PARP1 activation on mitochondrial function are caused by its interaction with SIRT1 (Sirtuin 1). In addition, the interaction of PARP1 with promoters of nuclear genes encoding for mitochondrial transcription factors and mtDNA repair proteins were identified (Czapski et al., 2018).
  
  
Entity Viral Infections
Note A broad range of DNA and RNA viruses are known to activate DNA repair pathways in the absence of host DNA damage. PARP1 is known to be recruited to the Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus genomes and it prevents viral replication by modifying viral proteins involved in genome replication and partitioning. On the other hand, hepatitis B virus was found to require PARP1 for efficient transcription. Additionally, PARP1 inhibits the expression of retrotransposons in Drosophila and retroviruses in avian cells (Gutierrez, Valdes, Serguera, & Llano, 2016). It has been reported that efficient HIV-1 (Human Immunodeficiency Virus-1) integration and transcriptional activation also require PARP1 activity (Ha et al., 2001; Yu, Liu, Yang, & Zhou, 2018). Recently, PARP1 was shown as a cofactor in the activity of the influenza A virus polymerase (Westera et al., 2019). In another study, Shou et al. showed that PARP1 functions as a regulator of NF-kB by promoting its nuclear translocation and by facilitating its binding to the NF-kB response sequences in macrophages upon vaccinia virus infection; therefore PARP1 can provide viral control through natural killer (NK) cell recruitment to the site of infection (Shou, Fu, Huang, & Yang, 2019)
  
  
Entity Gastric cancer
Note Depending on the survival analysis, upregulation of PARP1 expression was shown to be correlated with poor overall survival rates of gastric cancer patients (Afzal et al., 2019). Enhanced PARP1 expression was found to be significantly associated with Helicobacter pylori infection, decreased differentiation, increased depth of invasion, presence of lymphatic invasion and lymph node metastasis, and advanced tumor-node-metastasis stage (Y. Liu et al., 2016).
  
  
Entity Lung cancer
Note In lung adenocarcinoma patients, PARP1 was claimed to enhance tumor metastasis through supporting several metastatic features, including anoikis resistance, invasion, extravasation and self-renewal (E. B. Choi et al., 2016).
  
  
Entity Ovarian cancer and Breast cancer
Note Breast Cancer Susceptibility Genes BRCA1 and BRCA2 are tumor suppressors that function in the repair DSBs via the homologous recombination (HR) repair pathway. In BRCA mutant tumor cells, PARP inhibition was shown to induce 'synthetic lethality' resulting in profound tumor cell cytotoxicity without harming normal cells (Jiang, Li, Li, Bai, & Zhang, 2019).
In addition to malignant tissues of BRCA-mutant, triple-negative, and receptor-positive breast carcinoma, PARP1 is overexpressed significantly in uterine carcinoma and ovarian carcinoma. As in breast carcinoma, ovarian cancer cells show high sensitivity to drugs designed for PARP1 inhibition (Iqbal et al., 2012; Thompson & Easton, 2003; L. Wang et al., 2017).
  
  
Entity Pancreatic cancer
Note BRCA2 mutation carriers have a more than 3 fold risk of developing pancreatic cancer and women with BRCA 1/2 mutation were shown to have an approximate 2.5 fold increase in the incidence of pancreatic cancer (Breast Cancer Linkage Consortium, 1999; Iqbal et al., 2012; Thompson & Easton, 2003). In the context of familial pancreatic cancer, studies have shown that pedigrees with germline mutations in BRCA1 and BRCA2 have an increased lifetime risk of pancreatic cancer. A germline mutation in one of these genes represents the earliest risk factor in many familial pancreatic cancer kindreds. In patients with sporadic pancreatic cancer, BRCA1/2 were also found to be mutated in the most advanced pancreatic intraepithelial neoplasia lesions (Greer & Whitcomb, 2007). In BRCA1/2 mutated tumors, which homologous recombination ca not be utilized to repair DSBs, inhibitors of PARP are suggested to target tumor cells to terminate their BER rescue pathway thus leading to accumulation of DNA damage, genomic instability and eventually cell death (Fogelman et al., 2011; Yuan, Liao, Hsueh, & Mirshahidi, 2011).
  
  
Entity Non-Hodgkin's lymphoma
Note PARP1 expression is known to be enhanced in non-Hodgkin's lymphoma (Ossovskaya et al., 2010). Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma. Expression of LIM-domain only 2 ( LMO2) is one of the best prognostic markers of longer survival following therapy. Very recently, LMO2 expression was found to lead dysfunction in homolog recombination (HR) and tumor cell sensitization to genotoxic agents and PARP1/2 inhibitors were shown to enhance this effect further. Therefore, Parvin et al. suggested that the utilization of PARP inhibitors in combination with immunochemotherapy in LMO2-expressing tumors such as DLBCL, follicular lymphoma, and T-ALL (Parvin et al., 2019).
BCL6 is one of the therapeutic targets in lymphoma. As a transcription factor, BCL6 is expressed in germinal centre B cells and it is fundamental for the formation of germinal centres and the production of high-affinity antibodies. On the other hand, during terminal differentiation to plasma cells, BCL6 has to be transcriptionally downregulated. BCL6 is known to be highly expressed in B cell non-Hodgkin's lymphoma and in a subset of cases of diffuse large cell lymphoma. PARP1 was shown to bind in a sequence-specific manner at the BCL6 locus and contributes to the regulation of BCL6 transcription (Ambrose, Papadopoulou, Beswick, & Wagner, 2007).
  
  
Entity Melanoma
Note Melanoma is characterized by defects in repair and cell cycle regulation. Malfunctioning in nucleotide excision repair is thought to play an important role in melanoma. Since BRCA2 mutations are known to be associated with melanoma, PARP inhibitors were introduced into melanoma therapy. However, use of PARP inhibitors in melanoma therapy ended with controversial clinical observations. In an in vitro melanoma model, Cseh et al. showed that pharmacologic PARP inhibition triggers mitochondrial events known to be associated with cell survival, but also enhances the cytotoxic effects of cytostatic compounds (Cseh et al., 2019). These findings may explain the controversial results about the use of PARP inhibitors in the treatment of malignancies.
  
  
Entity Colorectal cancer
Note Colitis is the inflammation of the inner lining of the colon caused by several inflammatory factors like infection, ischaemia, and allergic reactions. Chronic inflammatory disorders, including inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are thought to result from a dysregulated mucosal immune response to commensal gut microbiota in genetically susceptible individuals. Colorectal cancer (CRC) is well known to be associated with long-standing and extensive colitis (Palazzo et al., 2019). PARP1 is overexpressed in human CRC and elevated PARP1 expression is correlated with disease progression. Although PARP1 has been reported to support the focal inflammation during the tumor progression, protective effects of PARP1 against DNA alkylation and oxidation damage during the initial steps of CRC have also been shown. Mechanistically, the pro-inflammatory functions of PARP1 were shown to be related with the modulation of NF-kB activity and stimulation of IL6-STAT3-cyclin D1 axis (Dörsam et al., 2018).
  
  
Entity Prostate cancer
Note n vivo and in vitro studies showed that PARP1 can modulate androgen receptor ( AR) functions by recruiting to the AR function sites, and therefore by promoting AR occupancy and AR functions (Schiewer et al., 2012). Silencing of PARP1 was reported to downregulate epithelial-mesenchymal transition (EMT) markers, inhibit PI3K, suppress the expression of EGFR and p-GSK3B (Ser9) in in vivo and in vitro prostate cancer models (Y. Lai et al., 2018).
  

To be noted

The design of PARP1 inhibitors and clinical trials of PARP1 inhibitors in cancer have been receiving considerable attention.

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Citation

This paper should be referenced as such :
Sinem Tunçer, Kubra Kavak
PARP1 (poly(ADP-ribose) polymerase 1)
Atlas Genet Cytogenet Oncol Haematol. 2020;24(8):300-312.
Free journal version : [ pdf ]   [ DOI ]


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ]
  t(3;5)(q26;q31) H2AFY/MECOM
t(12;12)(p13;q13) ETV6/BAZ2A


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Pancreatic tumors: an overview
PARP1/MIXL1 (1q42)


External links

Nomenclature
HGNC (Hugo)PARP1   270
Cards
AtlasPARP1ID585ch1q42
Entrez_Gene (NCBI)PARP1  142  poly(ADP-ribose) polymerase 1
AliasesADPRT; ADPRT; ADPRT1; ARTD1; 
PARP; PARP-1; PPOL; pADPRT-1
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Ensembl hg19 (Hinxton)ENSG00000143799 [Gene_View]
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ICGC DataPortalENSG00000143799
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Genomic and cartography
GoldenPath hg38 (UCSC)PARP1  -     chr1:226360691-226408093 -  1q42.12   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PARP1  -     1q42.12   [Description]    (hg19-Feb_2009)
GoldenPathPARP1 - 1q42.12 [CytoView hg19]  PARP1 - 1q42.12 [CytoView hg38]
ImmunoBaseENSG00000143799
genome Data Viewer NCBIPARP1 [Mapview hg19]  
OMIM173870   
Gene and transcription
Genbank (Entrez)AF401218 AK125650 AK225654 AK303340 AK312339
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RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PARP1
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Gene Expression Viewer (FireBrowse)PARP1 [ Firebrowse - Broad ]
GenevisibleExpression of PARP1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)142
GTEX Portal (Tissue expression)PARP1
Human Protein AtlasENSG00000143799-PARP1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP09874   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP09874  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP09874
Splice isoforms : SwissVarP09874
PhosPhoSitePlusP09874
Domaine pattern : Prosite (Expaxy)BRCT (PS50172)    PARP_ALPHA_HD (PS51060)    PARP_CATALYTIC (PS51059)    PARP_ZN_FINGER_1 (PS00347)    PARP_ZN_FINGER_2 (PS50064)   
Domains : Interpro (EBI)BRCT_dom    BRCT_dom_sf    PADR1    PADR1_dom_sf    PARP    Poly(ADP-ribose)pol_cat_dom    Poly(ADP-ribose)pol_reg_dom    Poly(ADP-ribose)pol_reg_dom_sf    WGR_dom_sf    WGR_domain    Znf_PARP    Znf_PARP_sf   
Domain families : Pfam (Sanger)BRCT (PF00533)    PADR1 (PF08063)    PARP (PF00644)    PARP_reg (PF02877)    WGR (PF05406)    zf-PARP (PF00645)   
Domain families : Pfam (NCBI)pfam00533    pfam08063    pfam00644    pfam02877    pfam05406    pfam00645   
Domain families : Smart (EMBL)BRCT (SM00292)  PADR1 (SM01335)  WGR (SM00773)  zf-PARP (SM01336)  
Conserved Domain (NCBI)PARP1
DMDM Disease mutations142
Blocks (Seattle)PARP1
PDB (RSDB)1UK0    1UK1    1WOK    2COK    2CR9    2CS2    2DMJ    2JVN    2L30    2L31    2N8A    2RCW    2RD6    2RIQ    3GJW    3GN7    3L3L    3L3M    3OD8    3ODA    3ODC    3ODE    4AV1    4DQY    4GV7    4HHY    4HHZ    4L6S    4OPX    4OQA    4OQB    4PJT    4R5W    4R6E    4RV6    4UND    4UXB    4XHU    4ZZZ    5A00    5DS3    5HA9    5KPN    5KPO    5KPP    5KPQ    5WRQ    5WRY    5WRZ    5WS0    5WS1    5WTC    5XSR    5XST    5XSU    6BHV    6GHK    6NRF    6NRG    6NRH    6NRI    6NRJ   
PDB Europe1UK0    1UK1    1WOK    2COK    2CR9    2CS2    2DMJ    2JVN    2L30    2L31    2N8A    2RCW    2RD6    2RIQ    3GJW    3GN7    3L3L    3L3M    3OD8    3ODA    3ODC    3ODE    4AV1    4DQY    4GV7    4HHY    4HHZ    4L6S    4OPX    4OQA    4OQB    4PJT    4R5W    4R6E    4RV6    4UND    4UXB    4XHU    4ZZZ    5A00    5DS3    5HA9    5KPN    5KPO    5KPP    5KPQ    5WRQ    5WRY    5WRZ    5WS0    5WS1    5WTC    5XSR    5XST    5XSU    6BHV    6GHK    6NRF    6NRG    6NRH    6NRI    6NRJ   
PDB (PDBSum)1UK0    1UK1    1WOK    2COK    2CR9    2CS2    2DMJ    2JVN    2L30    2L31    2N8A    2RCW    2RD6    2RIQ    3GJW    3GN7    3L3L    3L3M    3OD8    3ODA    3ODC    3ODE    4AV1    4DQY    4GV7    4HHY    4HHZ    4L6S    4OPX    4OQA    4OQB    4PJT    4R5W    4R6E    4RV6    4UND    4UXB    4XHU    4ZZZ    5A00    5DS3    5HA9    5KPN    5KPO    5KPP    5KPQ    5WRQ    5WRY    5WRZ    5WS0    5WS1    5WTC    5XSR    5XST    5XSU    6BHV    6GHK    6NRF    6NRG    6NRH    6NRI    6NRJ   
PDB (IMB)1UK0    1UK1    1WOK    2COK    2CR9    2CS2    2DMJ    2JVN    2L30    2L31    2N8A    2RCW    2RD6    2RIQ    3GJW    3GN7    3L3L    3L3M    3OD8    3ODA    3ODC    3ODE    4AV1    4DQY    4GV7    4HHY    4HHZ    4L6S    4OPX    4OQA    4OQB    4PJT    4R5W    4R6E    4RV6    4UND    4UXB    4XHU    4ZZZ    5A00    5DS3    5HA9    5KPN    5KPO    5KPP    5KPQ    5WRQ    5WRY    5WRZ    5WS0    5WS1    5WTC    5XSR    5XST    5XSU    6BHV    6GHK    6NRF    6NRG    6NRH    6NRI    6NRJ   
Structural Biology KnowledgeBase1UK0    1UK1    1WOK    2COK    2CR9    2CS2    2DMJ    2JVN    2L30    2L31    2N8A    2RCW    2RD6    2RIQ    3GJW    3GN7    3L3L    3L3M    3OD8    3ODA    3ODC    3ODE    4AV1    4DQY    4GV7    4HHY    4HHZ    4L6S    4OPX    4OQA    4OQB    4PJT    4R5W    4R6E    4RV6    4UND    4UXB    4XHU    4ZZZ    5A00    5DS3    5HA9    5KPN    5KPO    5KPP    5KPQ    5WRQ    5WRY    5WRZ    5WS0    5WS1    5WTC    5XSR    5XST    5XSU    6BHV    6GHK    6NRF    6NRG    6NRH    6NRI    6NRJ   
SCOP (Structural Classification of Proteins)1UK0    1UK1    1WOK    2COK    2CR9    2CS2    2DMJ    2JVN    2L30    2L31    2N8A    2RCW    2RD6    2RIQ    3GJW    3GN7    3L3L    3L3M    3OD8    3ODA    3ODC    3ODE    4AV1    4DQY    4GV7    4HHY    4HHZ    4L6S    4OPX    4OQA    4OQB    4PJT    4R5W    4R6E    4RV6    4UND    4UXB    4XHU    4ZZZ    5A00    5DS3    5HA9    5KPN    5KPO    5KPP    5KPQ    5WRQ    5WRY    5WRZ    5WS0    5WS1    5WTC    5XSR    5XST    5XSU    6BHV    6GHK    6NRF    6NRG    6NRH    6NRI    6NRJ   
CATH (Classification of proteins structures)1UK0    1UK1    1WOK    2COK    2CR9    2CS2    2DMJ    2JVN    2L30    2L31    2N8A    2RCW    2RD6    2RIQ    3GJW    3GN7    3L3L    3L3M    3OD8    3ODA    3ODC    3ODE    4AV1    4DQY    4GV7    4HHY    4HHZ    4L6S    4OPX    4OQA    4OQB    4PJT    4R5W    4R6E    4RV6    4UND    4UXB    4XHU    4ZZZ    5A00    5DS3    5HA9    5KPN    5KPO    5KPP    5KPQ    5WRQ    5WRY    5WRZ    5WS0    5WS1    5WTC    5XSR    5XST    5XSU    6BHV    6GHK    6NRF    6NRG    6NRH    6NRI    6NRJ   
SuperfamilyP09874
Human Protein Atlas [tissue]ENSG00000143799-PARP1 [tissue]
Peptide AtlasP09874
HPRD01435
IPIIPI00449049   IPI00981395   IPI00940720   IPI00478427   IPI00477173   
Protein Interaction databases
DIP (DOE-UCLA)P09874
IntAct (EBI)P09874
BioGRIDPARP1
STRING (EMBL)PARP1
ZODIACPARP1
Ontologies - Pathways
QuickGOP09874
Ontology : AmiGOnegative regulation of transcription by RNA polymerase II  nucleotide-excision repair, DNA damage recognition  nucleotide-excision repair, DNA duplex unwinding  telomere maintenance  double-strand break repair via homologous recombination  nuclear chromosome, telomeric region  RNA polymerase II regulatory region sequence-specific DNA binding  DNA-binding transcription activator activity, RNA polymerase II-specific  DNA binding  RNA binding  NAD+ ADP-ribosyltransferase activity  NAD+ ADP-ribosyltransferase activity  NAD+ ADP-ribosyltransferase activity  NAD+ ADP-ribosyltransferase activity  protein binding  nucleus  nucleus  nuclear envelope  nucleoplasm  nucleoplasm  transcription factor complex  nucleolus  nucleolus  mitochondrion  DNA repair  nucleotide-excision repair, preincision complex stabilization  nucleotide-excision repair, preincision complex assembly  nucleotide-excision repair, DNA incision, 3'-to lesion  nucleotide-excision repair, DNA incision, 5'-to lesion  double-strand break repair  double-strand break repair  transcription by RNA polymerase II  protein ADP-ribosylation  protein ADP-ribosylation  apoptotic process  cellular response to DNA damage stimulus  mitochondrion organization  transforming growth factor beta receptor signaling pathway  transcription factor binding  zinc ion binding  response to gamma radiation  positive regulation of cardiac muscle hypertrophy  regulation of SMAD protein complex assembly  membrane  protein autoprocessing  nuclear body  peptidyl-serine ADP-ribosylation  peptidyl-glutamic acid poly-ADP-ribosylation  enzyme binding  protein kinase binding  signal transduction involved in regulation of gene expression  macrophage differentiation  estrogen receptor binding  DNA ADP-ribosylation  mitochondrial DNA metabolic process  cellular response to insulin stimulus  protein-containing complex  protein-DNA complex  positive regulation of intracellular estrogen receptor signaling pathway  nucleotide-excision repair, DNA incision  cellular response to oxidative stress  cellular response to UV  site of double-strand break  protein modification process  DNA damage response, detection of DNA damage  identical protein binding  histone deacetylase binding  mitochondrial DNA repair  regulation of DNA methylation  positive regulation of transcription by RNA polymerase II  protein N-terminus binding  regulation of catalytic activity  NAD binding  positive regulation of mitochondrial depolarization  positive regulation of SMAD protein signal transduction  protein poly-ADP-ribosylation  protein poly-ADP-ribosylation  protein auto-ADP-ribosylation  R-SMAD binding  global genome nucleotide-excision repair  cellular response to zinc ion  site of DNA damage  positive regulation of protein localization to nucleus  positive regulation of neuron death  regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway  positive regulation of single strand break repair  regulation of cellular protein localization  response to aldosterone  negative regulation of telomere maintenance via telomere lengthening  cellular response to amyloid-beta  positive regulation of myofibroblast differentiation  positive regulation of double-strand break repair via homologous recombination  protein ADP-ribosylase activity  protein ADP-ribosylase activity  ATP generation from poly-ADP-D-ribose  positive regulation of transcription regulatory region DNA binding  negative regulation of ATP biosynthetic process  
Ontology : EGO-EBInegative regulation of transcription by RNA polymerase II  nucleotide-excision repair, DNA damage recognition  nucleotide-excision repair, DNA duplex unwinding  telomere maintenance  double-strand break repair via homologous recombination  nuclear chromosome, telomeric region  RNA polymerase II regulatory region sequence-specific DNA binding  DNA-binding transcription activator activity, RNA polymerase II-specific  DNA binding  RNA binding  NAD+ ADP-ribosyltransferase activity  NAD+ ADP-ribosyltransferase activity  NAD+ ADP-ribosyltransferase activity  NAD+ ADP-ribosyltransferase activity  protein binding  nucleus  nucleus  nuclear envelope  nucleoplasm  nucleoplasm  transcription factor complex  nucleolus  nucleolus  mitochondrion  DNA repair  nucleotide-excision repair, preincision complex stabilization  nucleotide-excision repair, preincision complex assembly  nucleotide-excision repair, DNA incision, 3'-to lesion  nucleotide-excision repair, DNA incision, 5'-to lesion  double-strand break repair  double-strand break repair  transcription by RNA polymerase II  protein ADP-ribosylation  protein ADP-ribosylation  apoptotic process  cellular response to DNA damage stimulus  mitochondrion organization  transforming growth factor beta receptor signaling pathway  transcription factor binding  zinc ion binding  response to gamma radiation  positive regulation of cardiac muscle hypertrophy  regulation of SMAD protein complex assembly  membrane  protein autoprocessing  nuclear body  peptidyl-serine ADP-ribosylation  peptidyl-glutamic acid poly-ADP-ribosylation  enzyme binding  protein kinase binding  signal transduction involved in regulation of gene expression  macrophage differentiation  estrogen receptor binding  DNA ADP-ribosylation  mitochondrial DNA metabolic process  cellular response to insulin stimulus  protein-containing complex  protein-DNA complex  positive regulation of intracellular estrogen receptor signaling pathway  nucleotide-excision repair, DNA incision  cellular response to oxidative stress  cellular response to UV  site of double-strand break  protein modification process  DNA damage response, detection of DNA damage  identical protein binding  histone deacetylase binding  mitochondrial DNA repair  regulation of DNA methylation  positive regulation of transcription by RNA polymerase II  protein N-terminus binding  regulation of catalytic activity  NAD binding  positive regulation of mitochondrial depolarization  positive regulation of SMAD protein signal transduction  protein poly-ADP-ribosylation  protein poly-ADP-ribosylation  protein auto-ADP-ribosylation  R-SMAD binding  global genome nucleotide-excision repair  cellular response to zinc ion  site of DNA damage  positive regulation of protein localization to nucleus  positive regulation of neuron death  regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway  positive regulation of single strand break repair  regulation of cellular protein localization  response to aldosterone  negative regulation of telomere maintenance via telomere lengthening  cellular response to amyloid-beta  positive regulation of myofibroblast differentiation  positive regulation of double-strand break repair via homologous recombination  protein ADP-ribosylase activity  protein ADP-ribosylase activity  ATP generation from poly-ADP-D-ribose  positive regulation of transcription regulatory region DNA binding  negative regulation of ATP biosynthetic process  
Pathways : KEGGBase excision repair    NF-kappa B signaling pathway   
REACTOMEP09874 [protein]
REACTOME PathwaysR-HSA-5696400 [pathway]   
NDEx NetworkPARP1
Atlas of Cancer Signalling NetworkPARP1
Wikipedia pathwaysPARP1
Orthology - Evolution
OrthoDB142
GeneTree (enSembl)ENSG00000143799
Phylogenetic Trees/Animal Genes : TreeFamPARP1
HOGENOMP09874
Homologs : HomoloGenePARP1
Homology/Alignments : Family Browser (UCSC)PARP1
Gene fusions - Rearrangements
Fusion : MitelmanPARP1/MIXL1 [1q42.12/1q42.12]  
Fusion : FusionGDB2.4.2.30   
Fusion : Fusion_HubACBD3--PARP1    CBS--PARP1    DENND1B--PARP1    FRS2--PARP1    H3F3A--PARP1    HNRNPU--PARP1    IGKC--PARP1    MACROD1--PARP1    MDK--PARP1    MIXL1--PARP1    MYLK--PARP1    PARP1--APE1    PARP1--BACH1    PARP1--DENND1B    PARP1--FUS   
PARP1--INTS3    PARP1--KCNIP2    PARP1--NMNAT2    PARP1--PARP1    PARP1--POMT1    PARP1--PPP2R5A    PARP1--SON    PARP1--ZNF490    PARVG--PARP1    PECAM1--PARP1    RCC2--PARP1    RP5-857K21.7--PARP1    SPON2--PARP1    SRP68--PARP1    VWA2--PARP1   
ZC3H11A--PARP1   
Fusion : QuiverPARP1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPARP1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PARP1
dbVarPARP1
ClinVarPARP1
MonarchPARP1
1000_GenomesPARP1 
Exome Variant ServerPARP1
GNOMAD BrowserENSG00000143799
Varsome BrowserPARP1
Genetic variants : HAPMAP142
Genomic Variants (DGV)PARP1 [DGVbeta]
DECIPHERPARP1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPARP1 
Mutations
ICGC Data PortalPARP1 
TCGA Data PortalPARP1 
Broad Tumor PortalPARP1
OASIS PortalPARP1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPARP1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DPARP1
Mutations and Diseases : HGMDPARP1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PARP1
DgiDB (Drug Gene Interaction Database)PARP1
DoCM (Curated mutations)PARP1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PARP1 (select a term)
intoGenPARP1
OncoKBPARP1
NCG6 (London) select PARP1
Cancer3DPARP1(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM173870   
Orphanet
DisGeNETPARP1
MedgenPARP1
Genetic Testing Registry PARP1
NextProtP09874 [Medical]
TSGene142
GENETestsPARP1
Target ValidationPARP1
Huge Navigator PARP1 [HugePedia]
snp3D : Map Gene to Disease142
BioCentury BCIQPARP1
ClinGenPARP1
Clinical trials, drugs, therapy
Protein Interactions : CTD142
Pharm GKB GenePA32
Pharm GKB PathwaysPA166115250   
Clinical trialPARP1
Miscellaneous
canSAR (ICR)PARP1 (select the gene name)
HarmonizomePARP1
DataMed IndexPARP1
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePARP1
EVEXPARP1
GoPubMedPARP1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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