PARP1 (poly(ADP-ribose) polymerase 1)

Alias_names	PPOL
	ADPRT
	"ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase)
	poly (ADP-ribose) polymerase family, member 1"
Alias_symbol (synonym)	PARP
Other alias	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
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)

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 Species Gene Symbol Identity (%) DNA vs. P.troglodytes PARP1 99,2 vs. M.mulatta PARP1 97,7 vs. C.lupus PARP1 88,4 vs. B.taurus PARP1 88,4 vs. M.musculus Parp1 86,5 vs. R.norvegicus Parp1 86,1 vs. G.gallus PARP1 75,2 vs. X.tropicalis parp1 72 vs. D.rerio parp1 69,5 vs. D.melanogaster Parp 49,5 vs. A.gambiae AgaP_AGAP003230 53,1 vs. C.elegans pme-1 48,2 vs. A.thaliana PARP1 50,2 vs. O.sativa Os07g0413700 51,7
	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) PARP1-201 ENST00000366790.3 570 - - Protein coding PARP1-202 ENST00000366792.3 553 - - Protein coding PARP1-203 ENST00000366794.10 3978 CCDS1554 NM_001618.4 Protein coding PARP1-204 ENST00000463968.5 830 - - lncRNA PARP1-205 ENST00000468608.1 438 - - lncRNA PARP1-206 ENST00000469663.1 542 - - lncRNA PARP1-207 ENST00000490921.5 3165 - - lncRNA PARP1-208 ENST00000491816.1 416 - - lncRNA PARP1-209 ENST00000498787.1 628 - - lncRNA PARP1-210 ENST00000629232.1 477 - - 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 ID Description Location (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 1 Chr 13, NC_000013.11 (110936624..110940232) ADPRTP1, PPOLP1

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) Name Transcript ID Protein Charge Isoelectric Point Molecular Weight CCDS UniProt RefSeq PARP1-201 ENST00000366790.3 155aa 10,0 9,4862  17,324.99 g/mol - Q5VX85 - PARP1-202 ENST00000366792.3 108aa 3,0 7,7272  12,234.02 g/mol - Q5VX84 - PARP1-203 ENST00000366794.10 1014aa 31,5 9,3322 113,083.79 g/mol  CCDS1554 A0A024R3T8 P09874 NM_001618.4 PARP1-210 ENST00000629232.1 108aa 3,0 7,7272 12,234.02 g/mol  - Q5VX84 - Table 5. Pairwise alignment of PARP1 protein sequences (in distance from human) (HomoloGene:1222, NCBI) Gene Species Gene Symbol Identity (%) PROTEIN vs. P.troglodytes PARP1 99 vs. M.mulatta PARP1 98,2 vs. C.lupus PARP1 94,1 vs. B.taurus PARP1 90,4 vs. M.musculus Parp1 92,2 vs. R.norvegicus Parp1 91,6 vs. G.gallus PARP1 79,5 vs. X.tropicalis parp1 75,7 vs. D.rerio parp1 72,1 vs. D.melanogaster Parp 43,8 vs. A.gambiae AgaP_AGAP003230 46,5 vs. C.elegans pme-1 41,1 vs. A.thaliana PARP1 42,3 vs. O.sativa Os07g0413700 42,7
	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).

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