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FLASH GENE
Symbol PARP1 contributors: mct/ - updated : 11-12-2019
HGNC name poly (ADP-ribose) polymerase 1
HGNC id 270
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)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein 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
    SystemTypeDisorderPubmed
    cancer  
    synthetic lethal therapeutic strategy for cancer treatment using PARP1 inhibitors
    cardiovascularatheroma 
    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
    cardiovascularvalvulopathy 
    potential therapeutic target in aortic stenosis
    ANIMAL & CELL MODELS