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FLASH GENE

Symbol

PARP1

contributors: mct/ - updated : 11-12-2019

HGNC name	poly (ADP-ribose) polymerase 1
HGNC id	270

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	1q42.12      Physical location : 226.548.392 - 226.595.801
Synonym name	poly (ADP-ribose) polymerase family, member 1
	poly(ADP-ribose) synthetase
	poly(ADP-ribosyl) transferase
	poly(ADP-ribose) polymerase
	ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase)
	ADP-ribosyltransferase NAD(+)
Synonym symbol(s)	PARP, PPOL, ADPRT, ADPRT1, PARP-1, pADPRT-1, ARTD1
EC.number	2.4.2.30

DNA

TYPE	functioning gene
STRUCTURE	47.41 kb     23 Exon(s)

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D1S245 - D1S414 - D1S237 - D1S2827 - D1S229 - [D1S2860 - PARP1 - D1S549 - TGFB2 - D1S81 - HLX - D1S48 - D1S213 ] - D1S225 - D1S103 - qter
Text	[SLEB1 ]

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001618 23 - 4001 NP_001609 113 1014 - 1992 1505517

EXPRESSION

Type	ubiquitous

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine large intestine colon   highly Endocrine parathyroid       moderately Lymphoid/Immune lymph node       highly   tonsils       highly Nervous brain       moderately Reproductive male system testis     highly Respiratory respiratory tract trachea     highly Skin/Tegument skin       moderately Urinary bladder       moderately Visual eye       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     highly

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	embryonic tissue at an highly level

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	an automodification domain (AD) bears the major sites of automodification and contains a BRCT (BRCA1 C–terminus) fold
	one PARP alpha-helical domain
	one PARP catalytic domain, CAT, composed of two subdomains, the helical subdomain (HD) and the ART subdomain, which is conserved in other ADP-ribosyl transferases
	two zinc-binding domains, Zn1 and Zn2, enable PARP1 to recognize particular DNA structures
	a WGR, an essential domain of unknown function, a central component of the complex, interacting with Zn1, Zn3, CAT, and the DNA
	a domain C, essential for PARP1 activity, with a zinc-binding motif of three antiparallel beta-strands and four conserved cysteines positioned to coordinate the metal ligand, in addition to a helical region ; third zinc-binding domain, Zn3, has a distinct structure and function from that of Zn1 and Zn2

conjugated

RiboP , PhosphoP

mono polymer

homomer , heteromer , dimer , complex

HOMOLOGY

interspecies	homolog to rattus Parp1 (91.9 pc)
	homolog to murine Parp1 (92.6 pc)

Homologene

FAMILY

PARP family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,nucleus,chromatin/chromosome
	intracellular,nucleus,nucleolus
	intracellular,nuclear envelope
text	interacting with mitochondrial IMMT, leading to the mitochondrial localization of PARP1

basic FUNCTION	NAD+, ADP-ribosyltransferase, catalyzing the conversion of NAD to multibranched polymers containing up to 200 ADP-ribose residues
	zinc finger DNA-binding protein involved in DNA repair processes in eukaryotes
	catalyzes the synthesis of cellular poly(ADP-ribose) following DNA damage
	major acceptor for ADP-ribose polymers in an automodification reaction, while histone and other DNA-binding proteins (like HMG, topoisomearase I and II proteins) are also modified to a lesser extent, inducing changes in chromatin structure
	NAD(+)-dependent enzyme that plays a multifunctional role in DNA damage detection and repair and maintenance of genomic stability
	limitating of malignant transformation
	involved in necrotic cell death by ATP depletion
	involved in neuron survival in brain development
	together with XRCC1 and APTX, plays an essential role in single-strand DNA break repair
	with SET, may function by physically removing chromatin-bound DEK
	regulate the expression of surfactant protein B, a protein required for lung function
	acting as positive regulators of genomic stability in eukaryotic cells
	TERF2-associated poly(ADP-ribose)polymerase that protects eroded telomeres
	involved in crucial pathogenic events in Parkinson's disease
	plays a role in acute inflammatory diseases
	exerts a pivotal role in the basal repression of genes that are upregulated during TNFSF11-induced osteoclastogenesis
	required for atherogenesis by increasing adhesion molecules with endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability
	having an active role in sperm cell physiology in preventing apoptosis
	may have a role in preventing damage of mature sperm
	catalyzes poly(ADP-ribosyl)ation of the acceptor proteins using NAD (+) as a substrate
	may play a critical role in the regulation of BRCA2 transcription (binds to the BRCA2 promoter in a sequence-specific manner and negatively regulates BRCA2 expression)
	acting as a corepressor for FOXO1, which could play an important role in proper cell proliferation by regulating CDKN1B gene expression
	PARP1 and PARP2 are new participants of a spermatid-specific protein complex involved in genome reorganization throughout spermiogenesis
	may play a role in mitochondrial DNA damage signaling and/or repair
	positively regulates the transcription of MTUS1
	mediating the poly(ADP-ribosyl)ation of APLF and CHFR
	covalently ADP-ribosylates the amino-terminal histone tails of all core histones
	intramitochondrial PARP1 plays a role in mitochondrial DNA (mtDNA) damage signaling and/or repair
	modifies important regulatory lysines of the core histone tails, which are known to control chromatin structure and function
	can modify itself and other chromatin-associated proteins, thereby loosening chromatin to facilitate gene transcription
	negative regulator of CKB at the basal level and during TNFSF11-induced osteoclastogenesis
	negatively regulates the CKB expression at the basal level and TNFSF11 treatment induces degradation of PARP1 and thus increases the CKB expression
	roles of H2AFX and PARP1, PARP2 in the DNA damage response
	PARP1 and PARG regulates various cellular processes in response to genotoxic stress
	ADP-ribosylation of SMAD proteins by PARP1 is a key step in controlling the strength and duration of SMAD-mediated transcription
	serves potentially as a nuclear retention factor of KLF8
	involved in maintaining genomic stability as well as regulating DNA repair and transcriptional processes
	PARP1 and TET2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming
	enzymatic activities of NMNAT1 and PARP1 is linked to the regulation of a set of common target genes through functional interactions at target gene promoters
	mediates a protein feedback loop that regulates the pluripotency factor SOX2, suggesting a unique mechanism for maintenance of pluripotency
	implicated in the maintenance of silent rDNA chromatin during cell division
	function of PARP1 and ADP-ribosylation that serves to allow for the inheritance of silent chromatin structures, shedding light on how epigenetic marks are transmitted during each cell cycle
	PARP1) and PARP2 control cytosolic Ca(2+) shifts from extracellular and intracellular sources associated with autophagy or cell death
	role for PARP1, PARP2 in metabolic regulation by influencing mitochondrial function and oxidative metabolism
	is a regulator of polyadenylation during thermal stress
	PARP1 is a novel modulator of two UHRF1-regulated heterochromatin-associated events : the accumulation of H4K20me3 and the clearance of DNMT1
	RECQL helicases and PARP1 are involved in the control of DNA repair, telomere maintenance, and replicative stress
	having a modular domain architecture that couples DNA damage detection to poly(ADP-ribosyl)ation activity through a poorly understood mechanism
	PARP1 and poly(ADP-ribosyl)ation (PARylation) have been shown to be essential for the initial steps of cellular reprogramming
	PARP1 functions together with TIMELESS and TIPIN to protect the replisome in early S phase from transcription-replication conflicts

CELLULAR PROCESS	cell life, differentiation
	cell life, proliferation/growth
	cell life, cell death/apoptosis
	nucleotide, repair, base excision repair
	nucleotide, transcription, regulation
	protein, post translation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	constituent of the centromere abundantly present in the interphase nucleus
	component of the base excision repair complex, composed of XRCC1, PARP1, PARP2, POLB and LIG3
	forming homodimer or heterodimer with PARP2
	component of the SWAP complex, composed at least of NPM1, NCL, PARP1 and SWAP70
	GTF2I, PARP1, and SFPQ proteins, each previously implicated in gene regulation, forms a complex controlling transcription of DYX1C1
	roles in the regulation of chromatin structure and transcription

INTERACTION

DNA	binding mtDNA
	the interdomain contacts observed in the PARP1/DNA structure are critical for DNA-dependent activation of full-length PARP1

RNA

small molecule	metal binding, cofactor, nucleotide,
	Zn2+
	using NAD+ as a substrate

protein	physically and specifically associates with AURKB by its BRCT (BRCA-1 C-terminal) domain
	binding to the KIF4 proteins
	interacting with PARP3 and APTX
	interacting wth DEK and SET (constitute a network governing access to chromatin by the transcription machinery)
	NKX2-1 interacting proteins that influence its transcriptional activity
	associates with telomere repeat binding factor 2 (TERF2) and is capable of poly(ADP-ribosyl)ation of TERF2, which affects binding of TERF2 to telomeric DNA
	directly binds to and poly(ADP-ribosyl)ates FOXO1 protein (acts as a novel corepressor for FOXO1, which could be required for proper cell proliferation by regulating CDKN1B gene expression)
	. interacting with TIAM2, ZNF423, CHD1L
	interacting with POLA1, interaction functioning as part of the control of replication fork progression
	interacting with SMARCA1
	interaction with APTX, APEX1 (synergistic functions of aprataxin, PARP1 and APEX1 in the cellular response to DNA damage and the modulating function of aprataxin on base excision and long patch repair)
	PARP1 interaction with CENPB, CENPE, and CENPF during mitosis and apoptosis
	plays nonoverlapping functions with both histone H2AX and TP53BP1 in organismal development and DSB repair
	interacting with IMMT (promotes and is required for PARP1 mitochondrial localization)
	C12orf48 could directly interact with PARP1, and positively regulate the poly(ADP-ribosyl)ation activity of PARP1
	a SMAD-interacting partner (dissociates SMAD complexes from DNA by ADP-ribosylating SMAD3 and SMAD4, which attenuates SMAD-specific gene responses and TGFB-induced epithelial-mesenchymal transition)
	functional relationship between the DNA strand break-generating activity of TOP2B and the DNA strand break-dependent activation of PARP1 and PARP2 that in turn inhibit TOP2B
	interacting with KIAA0020 (specifically interacts with the catalytic domain of PARP1 and inhibits polyADP-ribosylation of PARP1)
	interaction of HES1 and PARP1 in B-ALL modulates the function of the HES1 transcriptional complex and signals through PARP1 to induce apoptosis
	PARP1 1s a novel KLF8-interacting protein, and interaction is critical for maintaining the proper subcellular localization, transcription-regulating function, and protein stability of KLF8 in the nucleus
	PARP1 interacting with the chromosome-targeting domain of the NCAPD2 subunit of condensin I
	strong interaction of TOP2B with XRCC6 as well as PARP1 suggesting that TOP2B is associated both in XRCC6 and PARP-dependent pathways in DSBs repair in primary neurons
	interaction between OGG1 and PARP1, a DNA-damage sensor protein involved in DNA repair and many other cellular processes
	regulates SOX2 protein activity (regulation of SOX2 activity by PARP1 is critical for efficient generation of induced pluripotent stem cells)
	PARP1 recruits NMNAT1 to promoters where it produces NAD(+) to support PARP1 catalytic activity, but also enhances the enzymatic activity of PARP1 independently of NAD(+) production
	PARP1 is a novel CHFR binding protein suggesting a functional interaction that regulates the early mitotic checkpoint and tumorigenesis (CHFR polyubiquitinates PARP1 and caused cell cycle arrest via PARP1 degradation)
	associates with BAZ2A, a subunit of the NoRC complex, via the noncoding pRNA and binds to silent rRNA genes after their replication in mid-late S phase
	regulatory role for HMGN1 in PARP1 activation
	interaction of HOXB7 with PARP1 that involves the homeodomain of HOXB7 and the first zinc finger domain of PARP1
	PARP1 regulates expression of SH3BP2
	plays a critical role in single-strand breaks (SSBs) repair (
	PARP1 is a novel DDB2-associated factor
	PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of CHD1L
	binds to and modifies Poly(A) polymerase (PAP) by poly(ADP-ribosyl)ation (PARylation) (PMUID: 23219533)
	binds to the C-terminal-100 amino acids of NEIL1 and NEIL1 binds to the BRCT domain of PARP1 (NEIL1 stimulates the poly(ADP-ribosyl)ation activity of PARP1)
	PARP1 stabilizes forks in the regressed state by limiting their restart by RECQL
	PRKAA2 exerts its anti-inflammatory effects through PARP1 and BCL6
	ETS1 activates, by direct interaction, the catalytic activity of PARP1 and is then poly(ADP-ribosyl)ated in a DNA-independent manner
	role for PARP1 in controlling the function of Tregs through modulation of the stable expression of FOXP3
	interaction of PARP1 with the E3 ubiquitin ligase UHRF1 that influences two UHRF1-regulated cellular processes
	DNA repair partners of TDP1 include PARP1, XRCC1, ligase III and PNKP from the base excision repair (BER) pathway
	cooperative function of RECQLs and PARP1 represents an important factor for maintaining genome integrity
	functional significance of PARP1 and TDP1 interaction in the process of DNA repair
	PARP1 and PAR (PolyADP ribose) actively, and in some instances differentially, regulate the activities and cellular localization of RECQL5 and WRN
	robust physical interaction between PARP1 and the replication fork protein TIMELESS, distinct from the known TIMELESS-TIPIN complex, which activates the intra-S phase checkpoint
	TIMELESS cooperateslikely in the PARP1-mediated DNA damage response (DDR)
	XRCC1 recruitment is promoted by PARP1, an enzyme that is activated following DNA damage and synthesizes ADP-ribose polymers that XRCC1 binds directly
	overlapping roles for PARP1 and PARP2 in the recruitment of endogenous XRCC1 and PNKP into oxidized chromatin
	epigenetic regulation of NOS2 by CASP1 involves cleavage of the chromatin regulator PARP1 and chromatin accessibility of the NFKB1 binding sites located at the NOS2 promoter
	PARP1 plays an additional DDB2-independent direct role in recruitment and stabilization of XPC at the UV-induced DNA lesions to promote nucleotide excision repair (GG-NER)
	SEPTIN4 is a novel PARP1 interacting protein and the interaction is enhanced under oxidative stress
	PARP1 is a crucial regulator of IRF1-mediated immune response

cell & other

REGULATION

activated by	single-strand DNA breaks
	DNA damage, and PARP1 and PARP2 inhibitors show promising activity in cancers with defective homologous recombination (HR) pathways for DSB repair

induced by

expression mainly dictated by Sp1

inhibited by

inhibition by TNKS1 overexpression, reducing genotoxin-induced death

Other	up-regulated by the dissociation of KIF4 proteins (KIF4A or KIF4B) from PARP1
	proteolytically cleaved by CASP3
	expression modulated by fibronectin during corneal wound healing
	phosphorylated by PRKDC or upon DNA damage
	poly ADP-ribosylated by PARP2
	regulated by RNF4 (mediates heat-shock-inducible ubiquitination of PARP1 and regulates the stability of PARP1)

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in NPM-ALK positive anaplastic large cells lymphoma constitutional     --over   early stage of diseased tricuspid valves exhibited higher mRNA levels for PARP1 compared to bicuspid valves

Susceptibility

to breast cancer to Parkinson disease (PD)

Variant & Polymorphism SNP	increasing the risk of breast cancer
	variations in the regulatory region of PARP1 gene might modify the risk for PD

Candidate gene	may participate in the pathophysiology of type I diabetes
	may be site of mutation in Fanconi anemia
Marker
Therapy target
	System Type Disorder Pubmed cancer     synthetic lethal therapeutic strategy for cancer treatment using PARP1 inhibitors cardiovascular atheroma   inhibition of PARP1 may represent a promising therapeutic target in atherosclerosis cancer     link between the PARP1 and G-quadruplex ligands and excellent efficacy of a multi-component strategy based on the use of PARP inhibitors in telomere-based therapy in cancer cancer     co-targeting PARP1 and KLF8 (or other potential PARP1-interacting KLFs) as a novel anti-cancer therapeutic strategy cancer     (PARP1) inhibitors are emerging as an important class of drugs for treating BRCA-deficient cancers cardiovascular valvulopathy   potential therapeutic target in aortic stenosis

ANIMAL & CELL MODELS