Affinage

PARP1

Poly [ADP-ribose] polymerase 1 · UniProt P09874

Length
1014 aa
Mass
113.1 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PARP1 is a nuclear ADP-ribosyltransferase that operates as a first-responder DNA damage sensor coupling break detection to poly(ADP-ribose) (PAR) synthesis, chromatin remodeling, and DNA repair pathway choice (PMID:23333033, PMID:19962992). Its N-terminal zinc fingers recognize strand breaks (nicks, blunt ends, 3' extensions) through sequence-independent contacts with exposed nucleotide bases, and break binding drives a multi-domain collapse onto the DNA that converts a relaxed substrate into a sharply kinked conformation by induced fit (PMID:23333033, PMID:36323657, PMID:19962992). This assembly cascade transmits an allosteric signal through interdomain contacts that unfolds the autoinhibitory helical subdomain (HD) of the catalytic domain, relieving competition for NAD+ binding and activating PAR synthesis (PMID:26626480, PMID:24189460). PARP1 also binds and is catalytically activated by specific G-quadruplex loop structures, extending its sensing role to non-B DNA (PMID:33313902). Through PARylation and protein interactions, PARP1 controls transcription by excluding linker histone H1 and inhibiting the demethylase KDM5B to open promoter chromatin for RNA Pol II loading (PMID:20832725), and it modifies sequence-specific factors including Smad3/4, PPARγ, FOXO1, and Sox2 to modulate their DNA binding and target gene programs (PMID:21095583, PMID:18815186, PMID:19281796, PMID:23939864). In genome maintenance, PARP1 competes with Ku at double-strand break ends to drive a DNA ligase III-dependent backup NHEJ pathway and supports homologous recombination through a direct, PARylation-independent interaction with Timeless (PMID:17088286, PMID:26344098). PARP1 activity and turnover are tightly regulated: HPF1 directs in trans histone ADP-ribosylation and serine auto-modification at S499/S507/S519 that limits PARP1 chromatin retention (PMID:27067600, PMID:34210965), while the TRIP12 E3 ligase ubiquitylates PARP1 via its PAR-binding WWE domain to trigger proteasomal degradation and limit trapping (PMID:32755579). Clinical PARP inhibitors trap PARP1 on DNA as cytotoxic complexes primarily by competing with NAD+, with allosteric effects that can increase or decrease retention depending on inhibitor chemistry (PMID:23118055, PMID:32241924, PMID:36070389, PMID:32890402).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2006 High

    Established that PARP-1 is not solely a single-strand break factor but competes with Ku for double-strand break ends to seed an alternative repair route, defining its role in DSB repair pathway choice.

    Evidence DNA end-binding competition assays and genetic deletion of classical NHEJ components with DSB repair kinetics

    PMID:17088286

    Open questions at the time
    • Did not define how the choice between classical and backup NHEJ is regulated in undamaged cells
    • Relative contribution of backup NHEJ versus HR in normal repair unclear
  2. 2009 High

    Resolved how PARP-1 physically engages damaged DNA, showing monomeric binding with comparable affinity for distinct break types and a zinc-ribbon conformational change linking damage detection to catalysis.

    Evidence Small-angle X-ray scattering with biochemical binding, activity, and thermodynamic assays

    PMID:19962992

    Open questions at the time
    • Low-resolution SAXS did not provide atomic detail of the activated state
    • Did not explain how the conformational change reaches the catalytic domain
  3. 2010 High

    Demonstrated that PARP-1 actively shapes chromatin and transcription, by excluding linker histone H1 and PARylating/inhibiting KDM5B to preserve H3K4me3 and license RNA Pol II loading.

    Evidence ChIP, RNA Pol II loading assays, KDM5B activity assays, and PARP-1 depletion

    PMID:20832725

    Open questions at the time
    • Did not establish how PARP-1 is targeted to specific promoters genome-wide
    • Generality across cell types not addressed
  4. 2010 High

    Extended PARP-1 substrate scope to signaling transcription factors, showing it PARylates Smad3/4 to dissociate them from DNA and attenuate TGF-β-driven EMT.

    Evidence Unbiased proteomic screen, Co-IP, in vitro ADP-ribosylation, DNA-binding and EMT assays

    PMID:21095583

    Open questions at the time
    • Did not map the modified residues on Smad proteins
    • In vivo relevance for fibrosis or development not tested
  5. 2013 High

    Provided the structural basis for damage sensing and activation, showing multiple domains collapse onto a break and zinc fingers read exposed bases sequence-independently to couple detection to PAR production.

    Evidence X-ray crystallography of essential PARP-1 domains bound to a DNA strand break with biochemical activity assays

    PMID:23333033

    Open questions at the time
    • Static structure did not capture the dynamics of activation
    • How the signal propagates to the catalytic domain not yet resolved at this stage
  6. 2013 Medium

    Showed mechanistically that interdomain contacts, not mere DNA binding, drive activation, separating catalytic activation from recruitment and transcriptional functions.

    Evidence Site-directed mutagenesis of domain-domain contacts with activity, recruitment, and reporter assays

    PMID:24189460

    Open questions at the time
    • Single lab
    • Did not identify the conformational intermediate linking contacts to catalysis
  7. 2015 High

    Identified the molecular switch of activation: DNA break detection unfolds the autoinhibitory helical domain (HD), which otherwise blocks productive NAD+ binding.

    Evidence HXMS, crystallography of HD deletion mutants, and biochemical activity assays

    PMID:26626480

    Open questions at the time
    • Did not quantify HD unfolding dynamics in real time
    • Coupling between HD unfolding and DNA conformation not yet measured
  8. 2015 High

    Defined a PARylation-independent protein interaction that channels PARP-1 into homologous recombination, via Timeless binding to the catalytic domain.

    Evidence Crystal structure of the Timeless PAB-PARP-1 catalytic domain complex with Co-IP, recruitment, and HR repair assays

    PMID:26344098

    Open questions at the time
    • Did not determine how Timeless promotes HR mechanistically downstream of recruitment
    • Selectivity for PARP-1 over other PARPs mechanism only partly explained
  9. 2016 High

    Discovered HPF1 as a partner that redirects PARP-1 activity in trans toward histones and restrains PARP-1 hyper-automodification.

    Evidence Reciprocal Co-IP, live-cell recruitment, in vitro ADP-ribosylation, and knockout cell biology

    PMID:27067600

    Open questions at the time
    • Did not yet identify the serine residues whose modification HPF1 enables
    • Functional consequence for trapping not addressed at this stage
  10. 2020 High

    Established that inhibitor chemistry, not just catalytic inhibition, controls PARP-1 retention, with pro-retention compounds enhancing cancer cell killing.

    Evidence Structural studies, biophysical binding, cell viability assays, and synthesis of a converted pro-retention probe

    PMID:32241924

    Open questions at the time
    • Did not quantify the relative weight of allostery versus NAD+ competition
    • Generalizability across all clinical inhibitors not established here
  11. 2020 High

    Identified TRIP12 as an E3 ligase that uses its PAR-binding WWE domain to target PARP1 for degradation, limiting cytotoxic trapping.

    Evidence Co-IP, domain mapping, ubiquitylation assays, proteasome inhibition, and TRIP12 knockout trapping measurements

    PMID:32755579

    Open questions at the time
    • Did not determine in vivo impact on PARPi therapeutic window
    • Whether TRIP12 acts selectively on trapped versus free PARP1 unclear
  12. 2020 High

    Reframed 'trapping' by showing PARP1 exchanges rapidly even under inhibitors and that NAD+ interaction governs exchange, with persistent foci reflecting ongoing recruitment due to delayed repair.

    Evidence Quantitative live-cell imaging, FRAP, PARP1 H862D/E988K mutants, and Xrcc1 knockout

    PMID:32890402

    Open questions at the time
    • Apparent tension with biochemical stable-complex trapping not fully reconciled
    • Did not test all clinical inhibitors for exchange behavior
  13. 2021 High

    Connected HPF1-dependent serine auto-modification at S499/S507/S519 to release from chromatin, defining a regulatory axis that tunes PARPi sensitivity.

    Evidence MS site mapping, site-directed mutagenesis, trapping assays, and HPF1/ARH3 knockouts

    PMID:34210965

    Open questions at the time
    • Did not establish dynamics of writing versus ARH3 erasing in real time
    • In vivo tumor relevance not tested
  14. 2022 High

    Captured the conformational dynamics of activation directly, showing zinc fingers kink DNA through an induced-fit cascade and that inhibitors shift the DNA conformational equilibrium.

    Evidence Single-molecule FRET and structural ensemble calculations with niraparib/EB47 comparison

    PMID:36323657

    Open questions at the time
    • Did not connect DNA kinking quantitatively to HD unfolding kinetics
    • Performed on defined substrates rather than chromatinized DNA
  15. 2022 High

    Dissected inhibitor-driven retention into a two-step mechanism dominated by NAD+ competition with secondary allostery that can raise or lower retention.

    Evidence Single-molecule assays monitoring PARP1-DNA retention in real time

    PMID:36070389

    Open questions at the time
    • Did not extend single-molecule retention measurements to the chromatin/cellular context
    • Relationship to clinical efficacy ranking not directly tested
  16. 2022 Medium

    Expanded PARP-1 substrate sensing to non-B DNA, showing it binds G-quadruplexes tightly but is catalytically stimulated only by specific loop features.

    Evidence In vitro binding affinity, activity assays with defined G4 structures, and loop deletion mutants

    PMID:33313902

    Open questions at the time
    • Single lab
    • Cellular consequences of G4-driven PARP-1 activation not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many context-specific PARP-1 partner and substrate relationships (e.g., metabolic, inflammatory, and transcription-factor regulation) are integrated and prioritized at a given locus or stress state remains unresolved.
  • No unified model links DNA-damage activation to the diverse non-repair signaling roles
  • Residue-level modification maps for most non-histone substrates are absent
  • Quantitative rules governing PARP-1 recruitment to specific genomic sites are undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0003677 DNA binding 4 GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 3 GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-73894 DNA Repair 4 R-HSA-4839726 Chromatin organization 3 R-HSA-392499 Metabolism of proteins 2
Partners
HPF1KDM5BNLRP3SMAD3SMAD4TIMELESSTRIP12XRCC1
Complex memberships
NLRP3 inflammasomePARP1-HPF1 complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 PARP inhibitors trap PARP1 and PARP2 as stable complexes at damaged DNA sites; trapped PARP-DNA complexes are more cytotoxic than unrepaired SSBs caused by PARP inactivation alone. Trapping potency differs markedly among inhibitors (niraparib > olaparib >> veliparib) independent of catalytic inhibitory potency. Biochemical trapping assays, genetically altered DT40 cell lines with deletions in specific DNA repair genes, cytotoxicity measurements Cancer research High 23118055
2015 PARP-1 activation requires local unfolding of the helical subdomain (HD) of its catalytic domain. The HD acts as an autoinhibitory domain that blocks productive NAD+ binding; DNA break detection causes HD unfolding to relieve this autoinhibition. Hydrogen/deuterium exchange-mass spectrometry (HXMS), crystallographic analysis of HD deletion mutants, biochemical activity assays Molecular cell High 26626480
2020 Structurally distinct PARP inhibitors drive PARP-1 allostery in opposite directions: some promote PARP-1 release from a DNA break (pro-release), while others retain PARP-1 on a DNA break (pro-retention). Converting a pro-release compound to a pro-retention compound increased cancer cell killing. Structural studies, biophysical binding assays, cell viability assays, synthesis of novel PARPi compound Science (New York, N.Y.) High 32241924
2016 HPF1 (C4orf27) forms a robust complex with PARP-1 in cells, is recruited to DNA lesions in a PARP-1-dependent but catalysis-independent manner, promotes PARP-1-dependent in trans ADP-ribosylation of histones, and limits DNA damage-induced hyper-automodification of PARP-1. Co-immunoprecipitation, live-cell recruitment assays, in vitro ADP-ribosylation assays, knockdown/knockout cell biology Molecular cell High 27067600
2021 Serine ADP-ribosylation at PARP1 residues S499, S507, and S519 (dependent on HPF1) counteracts PARP1 trapping on chromatin; loss of HPF1 or ARH3 increases PARPi-induced PARP1 trapping and sensitizes cells to PARP inhibitors. Mass spectrometry mapping of modification sites, site-directed mutagenesis, PARP1 trapping assays, genetic knockouts Nature communications High 34210965
2013 Crystal structure of essential PARP-1 domains in complex with a DNA strand break revealed that multiple PARP-1 domains collapse onto damaged DNA through interdomain contacts, and that PARP-1 uses zinc fingers to detect DNA breaks through sequence-independent interaction with exposed nucleotide bases, coupling damage detection to elevated PAR production. X-ray crystallography, biochemical activity assays Current opinion in structural biology High 23333033
2010 PARP-1 regulates chromatin structure and transcription by PARylating and inhibiting/excluding the histone demethylase KDM5B to prevent demethylation of H3K4me3, and by promoting exclusion of linker histone H1 to open promoter chromatin, creating a permissive environment for RNA Pol II loading. ChIP, RNA Pol II loading assays, PARP-1 depletion, KDM5B activity assays, histone modification analysis Molecular cell High 20832725
2006 PARP-1 binds to DNA DSB ends in direct competition with Ku and operates in an alternative backup NHEJ pathway together with DNA ligase III, distinct from the classical NHEJ pathway using DNA-PKcs/Ku/Ligase IV/XRCC4. When Ku and classical NHEJ components are absent, PARP-1 is recruited for DSB repair. DNA end-binding competition assays, genetic deletion of NHEJ components, DSB repair kinetics, PARP inhibitor treatment Nucleic acids research High 17088286
2010 PARP-1 ADP-ribosylates Smad3 and Smad4 (identified as PARP-1-interacting partners by unbiased proteomic screen), dissociating Smad complexes from DNA and thereby attenuating Smad-mediated transcription and TGF-β-induced epithelial-mesenchymal transition. Unbiased proteomic screen, Co-IP, in vitro ADP-ribosylation assay, DNA-binding assays, EMT assays Molecular cell High 21095583
2014 PARP1 (ARTD1) activation leads to PAR synthesis that suppresses glycolysis independently of NAD+ depletion; PAR binds directly to hexokinase 1 (HK1), suppressing HK1 activity and blocking glycolysis and ATP production after DNA damage. Real-time metabolic measurements (Seahorse), proteomics-based PAR interactome after DNA damage, HK1 activity assays, direct NAD+ depletion comparison Cell reports High 25220464
2015 Timeless physically interacts with PARP-1 via its PAB (PARP-1-binding domain) independently of poly(ADP-ribosylation), specifically with PARP-1 but not PARP-2 or PARP-3; Timeless recruitment to DNA damage requires PARP-1 but not PARylation; Timeless-PARP-1 interaction is required for efficient homologous recombination repair. Crystal structure of Timeless PAB-PARP-1 catalytic domain complex, Co-IP, laser-induced DNA damage recruitment assays, HR repair assays, PARP inhibitor trapping experiments Molecular cell High 26344098
2020 TRIP12 ubiquitin E3 ligase binds PARP1 via its central PAR-binding WWE domain and uses its HECT domain to catalyze polyubiquitylation of PARP1, triggering proteasomal degradation and limiting PARPi-induced cytotoxic PARP1 trapping. Co-IP, domain mapping, ubiquitylation assays, proteasome inhibitor experiments, TRIP12 knockout cells, PARP1 trapping measurements Cell reports High 32755579
2022 Single-molecule FRET and structural ensemble calculations revealed that PARP-1 N-terminal zinc fingers convert DNA SSBs from a largely unperturbed conformation via an intermediate to a highly kinked DNA conformation through an induced-fit mechanism via a multi-domain assembly cascade; niraparib shifts equilibrium towards unkinked DNA conformation, while EB47 stabilizes the kinked state. Single-molecule FRET (smFRET), structural ensemble calculations, PARP inhibitor comparison Nature communications High 36323657
2022 PARPi modulate PARP1-DNA retention through a two-step mechanism: primary step of catalytic inhibition via NAD+ binding competition, followed by allosteric modulation; retention potency is predominantly determined by NAD+ competition, while allosteric effects can either increase or decrease retention. Single-molecule assays monitoring PARP1 retention on DNA in real time Science advances High 36070389
2020 Clinical PARP inhibitors do not physically stall PARP1 at DNA damage sites; instead, PARP1 exchanges rapidly even in the presence of PARPi. Persistent PARP1 foci represent continued recruitment of different PARP1 molecules due to delayed repair from attenuated XRCC1-LIG3 recruitment. PARP1-H862D (NAD+ interacting residue mutant, not PARylation-deficient E988K) forms stable foci, identifying NAD+ interaction as key to PARP1 exchange. Quantitative live-cell imaging, FRAP, PARP1 mutant analysis (H862D, E988K), Xrcc1 knockout Nucleic acids research High 32890402
2009 PARP-1 binds damaged DNA (nick, blunt end, 3' extension) as a monomer with similar affinity for all three, and undergoes a conformational change at the zinc ribbon domain upon DNA binding that leads to catalytic activation; the N-terminal half is extended and flexible in solution but compacts around damaged DNA. Small-angle X-ray scattering, biochemical binding and activity assays, thermodynamic measurements Journal of molecular biology High 19962992
2014 PARP-1 poly(ADP-ribosyl)ates GAPDH in ischemic renal proximal tubules, inhibiting GAPDH enzymatic activity and blocking glycolysis, thereby exacerbating ATP depletion and necrotic cell death. In vitro and in vivo hypoxia models, PARP-1 inhibitor treatment, GAPDH activity assays, detection of poly(ADP-ribosyl)ated GAPDH, ATP measurements Journal of the American Society of Nephrology : JASN Medium 19056868
2007 PARP-1 is directly activated by phosphorylated ERK2 through a physical interaction independent of DNA damage and DNA binding; this ERK2-induced PARP-1 activation amplifies ERK signaling, enhancing Elk1 phosphorylation, core histone acetylation, and c-fos expression. Co-immunoprecipitation, in vitro kinase/activation assays, reporter assays for Elk1 and c-fos, histone acetylation measurements Trends in pharmacological sciences Medium 17950910
2014 H2S induces S-sulfhydration of MEK1 at cysteine 341, leading to phosphorylation of ERK1/2 and its nuclear translocation where ERK directly interacts with and activates PARP-1; activated PARP-1 then recruits XRCC1 and DNA ligase III to DNA breaks for repair. S-sulfhydration assay, site-directed mutagenesis (MEK1 C341), Co-IP of ERK-PARP-1, DNA repair foci assays EMBO reports Medium 24778456
2008 PARP-1 poly(ADP-ribosyl)ates PPARγ in cardiac fibroblasts under basal conditions, preventing PPARγ DNA binding and suppressing PPARγ-target genes including adiponectin; PARP-1 inhibition enhances PPARγ DNA binding and transactivation. Co-immunoprecipitation, EMSA, Southwestern blot, PARP-1 siRNA/inhibitor, RT-PCR/Western blot Cardiovascular research Medium 18815186
2009 PARP-1 directly binds and poly(ADP-ribosyl)ates FOXO1, acting as a corepressor on the p27(Kip1) promoter through FOXO1 interaction; PARP-1 represses FOXO1-mediated p27 expression and the repressive effect does not require PARylation enzymatic activity. Co-IP, in vitro PARylation assay, ChIP, luciferase reporter assay, PARP-1 knockdown Biochemical and biophysical research communications Medium 19281796
2013 DNA-PK activation is required upstream of PARP-1 recruitment to chromatin and PARP-1 activation in cisplatin-damaged cells; inhibition of DNA-PK prevents PARP-1 activation and its chromatin recruitment, and both DNA-PK and PARP-1 are required for DNA damage-induced inhibition of rRNA synthesis. In situ run-on rRNA synthesis assay, DNA-PK and PARP-1 inhibitors, chromatin fractionation, cell cycle analysis Nucleic acids research Medium 23775790
2013 PARP-1 allosteric regulation via interdomain contacts is required for DNA-damage-dependent catalytic activation; disruption of domain-domain contacts by mutagenesis prevents DNA-damage-dependent catalytic activation without affecting PARP-1 recruitment to DNA damage or transcriptional regulation. Site-directed mutagenesis of domain-domain contact residues, PARP-1 activity assays, live-cell recruitment assays, transcriptional reporter assays Cancer research Medium 24189460
2014 MacroH2A1.1 recruits PARP-1 to promote CBP-mediated acetylation of histone H2B at K12 and K120, which regulates gene expression; this regulation is lost in cancer cells. RNA-seq, Co-IP, ChIP-seq, histone modification analysis in primary human cells vs cancer cells Nature structural & molecular biology Medium 25306110
2013 PARP-1 ADP-ribosylates Sox2 during somatic cell reprogramming, promoting Sox2 binding to the Fgf4 enhancer and activating Fgf4 expression; loss of PARP-1 or its catalytic activity reduces reprogramming efficiency, which is rescued by exogenous Fgf4. PARP-1 knockout fibroblasts, PARP inhibitor treatment, in vitro PARylation of Sox2, ChIP at Fgf4 enhancer, Fgf4 rescue experiment Stem cells (Dayton, Ohio) Medium 23939864
2018 PARP-1 forms covalent DNA-protein crosslinks (DPCs) at apurinic/apyrimidinic (AP) sites via Schiff base formation between a PARP-1 lysine side chain and the C1' of the AP site; repair of PARP-1 DPCs involves proteasomal degradation of PARP-1 followed by tyrosyl-DNA phosphodiesterase 1 (TDP1) processing of the remaining adduct, completed by the BER machinery. In vitro DPC formation assay, proteasome inhibitor experiments, model DNA substrate repair assays, TDP1 activity assay DNA repair Medium 30466837
2017 MEIS transcription factors associate with chromatin-bound PBX1 at target promoters, recruit PARP1/ARTD1, and initiate PARP1-mediated eviction of linker histone H1 to open chromatin during neuronal differentiation. ChIP, Co-IP, live-cell imaging, PARP1 knockdown, differentiation assays The Journal of cell biology Medium 28739678
2022 PARP-1 mediates the association of DDX18, a putative RNA helicase, with R-loop structures; DDX18 depletion causes aberrant R-loop accumulation and DNA replication defects that are rescued by RNase H1 overexpression, placing PARP-1 in a pathway regulating R-loop homeostasis. Co-IP, R-loop detection assays (S9.6 antibody), DDX18 knockdown, RNase H1 rescue, γH2AX and RPA32/RAD51 foci Cell reports Medium 35858569
2022 PARP-1 PARylates NLRP3 upon ATP stimulation, translocating to the cytosol; PARP-1 bridges NLRP3 and TXNIP to facilitate NLRP3 inflammasome complex assembly and IL-1β production in macrophages. PARP-1 knockout BMDMs, PARP-1 inhibitor, Co-IP of NLRP3-PARP-1-TXNIP, cytosol/nuclear fractionation, IL-1β ELISA Cellular and molecular life sciences : CMLS Medium 35098371
2008 Integrin-linked kinase (ILK) regulates E-cadherin expression through PARP-1; PARP-1 binds to the Snail promoter ILK Responsive Element (SIRE) in an ILK-dependent manner, promoting Snail and ZEB1 expression and repressing E-cadherin. EMSA/Southwestern blot (SIRE-binding), PARP-1 siRNA, ILK silencing, ChIP-like promoter binding assay Developmental dynamics Low 18773488
2019 PARP-1 promotes NF-κB nuclear translocation and binding to NF-κB response sequences in macrophages, driving CCL2 production and NK cell recruitment to viral infection sites; peritoneal macrophages are the main source of PARP-1-dependent CCL2. PARP-1 knockout mice, vaccinia virus infection model, NF-κB nuclear translocation assay, CCL2 ELISA, CCR2-blocking experiments JCI insight Medium 31217354
2013 PARP-1 interacts with and regulates HIF-2α protein levels and HIF-2-dependent gene expression (ANGPTL4, erythropoietin); PARP-1 forms a complex with HIF-2α that is sensitive to PARP inhibition and appears to protect HIF-2α from VHL-dependent degradation. Co-IP, PARP-1 knockdown/inhibition, HIF-2α mRNA and protein analysis, PARP-1 knockout mice (EPO levels, red cell counts) Oncogene Medium 23455322
2020 SIRT3 interacts with PARP-1 in the nucleus of cardiomyocytes under stress, deacetylates PARP-1, and thereby reduces PARP-1 activity and cardiac hypertrophic gene expression. Co-immunoprecipitation, adenoviral SIRT3 overexpression, PARP-1 acetylation assay, isoproterenol/phenylephrine hypertrophy models Aging Low 32139662
2017 PARP-1 enzymatic activity promotes E2F1 transcription factor activity and E2F1-mediated induction of homologous recombination DNA repair factors; PARP-1 inhibition reduces HR factor availability, inducing 'BRCA-ness'. Transcriptional profiling, E2F1 reporter assays, HR factor protein measurements, PARP inhibitor treatment EMBO molecular medicine Medium 30467127
2015 LRP1 directly interacts with PARP-1 in human retinal microvascular endothelial cells; this interaction decreases under hypoxia, and LRP1 knockdown increases PARP-1 activity with subsequent phosphorylation of retinoblastoma protein and CDK2, promoting cell cycle progression and angiogenesis. Co-IP, LRP1 knockdown, PARP-1 activity assay, Ki67 staining, pRb/CDK2 western blot, oxygen-induced retinopathy model Arteriosclerosis, thrombosis, and vascular biology Low 26634655
2021 Mitochondrial NAD+ controls nuclear ARTD1 (PARP1)-induced ADP-ribosylation; H2O2-induced oxidative stress reciprocally induces nuclear and reduces mitochondrial ADP-ribosylation, demonstrating a NAD+-mediated mitochondrial-nuclear crosstalk that modulates PARP1 chromatin retention and PARPi efficacy. Immunofluorescence, western blot, mass spectrometry, respiratory chain inhibition, FCCP uncoupler, MMS-induced PARP1 retention assays Molecular cell Medium 33450210
2021 PARP-1 binds G-quadruplex structures with nanomolar affinity, but only specific G-quadruplex loop features (as found in the c-KIT promoter sequence) stimulate PARP-1 catalytic activity; oxidized G-quadruplexes also stimulate PARP-1 activity through their loop structures. In vitro binding affinity measurements, PARP-1 enzymatic activity assays with various G4 structures, loop deletion mutants Nucleic acids research Medium 33313902
2017 MKP-1 suppresses JNK1/2 activity, thereby reducing PARP-1 ubiquitination and maintaining PARP-1 protein levels; silencing MKP-1 promotes JNK1/2-dependent PARP-1 ubiquitination and proteasomal degradation, reducing cisplatin resistance. MKP-1 knockdown/overexpression, JNK1/2 silencing, PARP-1 ubiquitination assay, PARP-1 protein level measurement Oncogene Low 28650468

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer research 1796 23118055
2005 Poly(ADP-ribosyl)ation by PARP-1: 'PAR-laying' NAD+ into a nuclear signal. Genes & development 692 16140981
2006 PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic acids research 640 17088286
2012 On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes & development 621 22391446
2004 Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends in pharmacological sciences 398 15120492
2008 Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation. Current opinion in cell biology 365 18450439
2003 PARP-1, a determinant of cell survival in response to DNA damage. Experimental hematology 313 12829019
2015 PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain. Molecular cell 294 26626480
2018 The comings and goings of PARP-1 in response to DNA damage. DNA repair 276 30177435
2010 PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway. Molecular cell 272 20832725
2020 Structural basis for allosteric PARP-1 retention on DNA breaks. Science (New York, N.Y.) 266 32241924
2016 HPF1/C4orf27 Is a PARP-1-Interacting Protein that Regulates PARP-1 ADP-Ribosylation Activity. Molecular cell 263 27067600
2007 Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovascular drug reviews 256 17919258
2012 The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. Cell metabolism 255 22921416
2013 PARP-1 and gene regulation: progress and puzzles. Molecular aspects of medicine 222 23357755
2019 PARP-1 and its associated nucleases in DNA damage response. DNA repair 204 31302005
2013 Beyond DNA Repair: Additional Functions of PARP-1 in Cancer. Frontiers in oncology 201 24350055
2018 PARP1 Trapping by PARP Inhibitors Drives Cytotoxicity in Both Cancer Cells and Healthy Bone Marrow. Molecular cancer research : MCR 199 30429212
2004 PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development. DNA repair 190 15279798
2015 PARP-1 involvement in neurodegeneration: A focus on Alzheimer's and Parkinson's diseases. Mechanisms of ageing and development 185 25881554
2014 ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD+ depletion. Cell reports 185 25220464
2013 PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis. Current opinion in structural biology 173 23333033
2011 Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases. The American journal of pathology 170 21356345
2013 Beyond DNA repair, the immunological role of PARP-1 and its siblings. Immunology 157 23489378
2008 Epigenetics: poly(ADP-ribosyl)ation of PARP-1 regulates genomic methylation patterns. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 136 19001527
2007 Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis. European journal of cancer (Oxford, England : 1990) 132 17714938
2007 Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage. Current opinion in pharmacology 129 18032109
2014 S-sulfhydration of MEK1 leads to PARP-1 activation and DNA damage repair. EMBO reports 128 24778456
2010 Investigation of PARP-1, PARP-2, and PARG interactomes by affinity-purification mass spectrometry. Proteome science 124 20388209
2011 PARP-1 and PARP-2: New players in tumour development. American journal of cancer research 122 21968702
2007 Modulation of transcription by PARP-1: consequences in carcinogenesis and inflammation. Current medicinal chemistry 121 17504138
2010 PARP-1 attenuates Smad-mediated transcription. Molecular cell 120 21095583
2007 PARP-1 activation in the ERK signaling pathway. Trends in pharmacological sciences 116 17950909
2017 PARP1 Trapping and DNA Replication Stress Enhance Radiosensitization with Combined WEE1 and PARP Inhibitors. Molecular cancer research : MCR 109 29133592
2004 PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation. International journal of radiation oncology, biology, physics 108 14751510
2014 ARTD1 (PARP1) activation and NAD(+) in DNA repair and cell death. DNA repair 107 25283336
2015 Timeless Interacts with PARP-1 to Promote Homologous Recombination Repair. Molecular cell 106 26344098
2020 The Ubiquitin Ligase TRIP12 Limits PARP1 Trapping and Constrains PARP Inhibitor Efficiency. Cell reports 105 32755579
2021 Rapid Detection and Signaling of DNA Damage by PARP-1. Trends in biochemical sciences 104 33674152
2010 Poly(ADP-ribose) polymerase-1 (PARP-1) and its therapeutic implications. Vascular pharmacology 101 20633699
2021 PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling. International journal of molecular sciences 99 34066057
2014 MacroH2A1.1 and PARP-1 cooperate to regulate transcription by promoting CBP-mediated H2B acetylation. Nature structural & molecular biology 98 25306110
2003 Are poly(ADP-ribosyl)ation by PARP-1 and deacetylation by Sir2 linked? BioEssays : news and reviews in molecular, cellular and developmental biology 96 12879452
2013 PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis? Cancers 94 24202328
2021 Serine-linked PARP1 auto-modification controls PARP inhibitor response. Nature communications 85 34210965
2021 Emerging role of PARP-1 and PARthanatos in ischemic stroke. Journal of neurochemistry 79 34241907
2017 PARP1 in Carcinomas and PARP1 Inhibitors as Antineoplastic Drugs. International journal of molecular sciences 74 28991194
2020 Clinical PARP inhibitors do not abrogate PARP1 exchange at DNA damage sites in vivo. Nucleic acids research 73 32890402
2015 Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma. PloS one 72 26505995
2008 PARP-1 inhibits glycolysis in ischemic kidneys. Journal of the American Society of Nephrology : JASN 68 19056868
2008 Integrin-linked kinase regulates E-cadherin expression through PARP-1. Developmental dynamics : an official publication of the American Association of Anatomists 66 18773488
2015 Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Future oncology (London, England) 65 25757679
2018 PARP-1 regulates DNA repair factor availability. EMBO molecular medicine 64 30467127
2023 PARP1 roles in DNA repair and DNA replication: The basi(c)s of PARP inhibitor efficacy and resistance. Seminars in oncology 60 37714792
2012 Increased PARP-1 association with DNA in alkylation damaged, PARP-inhibited mouse fibroblasts. Molecular cancer research : MCR 59 22246237
2009 Regulation of FOXO1-mediated transcription and cell proliferation by PARP-1. Biochemical and biophysical research communications 59 19281796
2020 Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies. Cancers 57 32046278
2009 Structural and biophysical studies of human PARP-1 in complex with damaged DNA. Journal of molecular biology 57 19962992
2013 Targeting PARP-1 allosteric regulation offers therapeutic potential against cancer. Cancer research 53 24189460
2008 PARP-1 suppresses adiponectin expression through poly(ADP-ribosyl)ation of PPAR gamma in cardiac fibroblasts. Cardiovascular research 53 18815186
2021 Mitochondrial NAD+ Controls Nuclear ARTD1-Induced ADP-Ribosylation. Molecular cell 52 33450210
2021 G-Quadruplex loops regulate PARP-1 enzymatic activation. Nucleic acids research 50 33313902
2014 PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced nonapoptotic cell death. Toxicological sciences : an official journal of the Society of Toxicology 50 24752504
2022 DDX18 prevents R-loop-induced DNA damage and genome instability via PARP-1. Cell reports 49 35858569
2014 PARP-1 expression is increased in colon adenoma and carcinoma and correlates with OGG1. PloS one 49 25526641
2013 Interaction between PARP-1 and HIF-2α in the hypoxic response. Oncogene 48 23455322
2020 The Multifactorial Role of PARP-1 in Tumor Microenvironment. Cancers 47 32245040
2009 PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol. Biochemical pharmacology 47 19426673
2008 Poly(ADP-ribose)polymerase-1 (PARP-1) in carcinogenesis: potential role of PARP inhibitors in cancer treatment. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 46 18558578
2013 DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1. Nucleic acids research 45 23775790
2022 A two-step mechanism governing PARP1-DNA retention by PARP inhibitors. Science advances 43 36070389
2020 Role of PARP-1 in mitochondrial homeostasis. Biochimica et biophysica acta. General subjects 43 32553688
2011 ADP-ribosylation of histones by ARTD1: an additional module of the histone code? FEBS letters 43 21420964
2022 SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage. Molecular cell 42 35104452
2018 Repair pathway for PARP-1 DNA-protein crosslinks. DNA repair 42 30466837
2011 Association between PARP-1 V762A polymorphism and cancer susceptibility: a meta-analysis. Genetic epidemiology 42 22127734
2022 PARP-1 regulates inflammasome activity by poly-ADP-ribosylation of NLRP3 and interaction with TXNIP in primary macrophages. Cellular and molecular life sciences : CMLS 40 35098371
2022 HMGB3 promotes PARP inhibitor resistance through interacting with PARP1 in ovarian cancer. Cell death & disease 40 35332131
2015 LRP1 Regulates Retinal Angiogenesis by Inhibiting PARP-1 Activity and Endothelial Cell Proliferation. Arteriosclerosis, thrombosis, and vascular biology 40 26634655
2021 Deficiency of PARP-1 and PARP-2 in the mouse uterus results in decidualization failure and pregnancy loss. Proceedings of the National Academy of Sciences of the United States of America 39 34580230
2020 Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1). Journal of enzyme inhibition and medicinal chemistry 39 32779949
2012 Salidroside stimulates DNA repair enzyme Parp-1 activity in mouse HSC maintenance. Blood 38 22427203
2019 PARP-1 activity (PAR) determines the sensitivity of cervical cancer to olaparib. Gynecologic oncology 34 31434613
2022 Structural dynamics of DNA strand break sensing by PARP-1 at a single-molecule level. Nature communications 33 36323657
2016 Iodinated benzimidazole PARP radiotracer for evaluating PARP1/2 expression in vitro and in vivo. Nuclear medicine and biology 33 27689533
2020 SIRT3 inhibits cardiac hypertrophy by regulating PARP-1 activity. Aging 32 32139662
2015 Role of PARP-1 in prostate cancer. American journal of clinical and experimental urology 32 26069882
2023 PARP-1: a critical regulator in radioprotection and radiotherapy-mechanisms, challenges, and therapeutic opportunities. Frontiers in pharmacology 31 37351512
2022 Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice. Blood 31 34359075
2019 Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515. ACS medicinal chemistry letters 31 30996792
2015 Minocycline inhibits PARP‑1 expression and decreases apoptosis in diabetic retinopathy. Molecular medicine reports 31 26165350
2013 Artd1/Parp1 regulates reprogramming by transcriptional regulation of Fgf4 via Sox2 ADP-ribosylation. Stem cells (Dayton, Ohio) 29 23939864
2006 Players in the PARP-1 cell-death pathway: JNK1 joins the cast. Trends in biochemical sciences 29 16679020
2021 Molecular Imaging: PARP-1 and Beyond. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 28 33579802
2020 Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine. International journal of molecular sciences 27 32245127
2011 Impact of PARP-1 and DNA-PK expression on survival in patients with glioblastoma multiforme. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 26 21775006
2019 PARP-1 controls NK cell recruitment to the site of viral infection. JCI insight 25 31217354
2017 Platinum(IV) prodrugs multiply targeting genomic DNA, histone deacetylases and PARP-1. European journal of medicinal chemistry 25 29031068
2017 MKP-1 suppresses PARP-1 degradation to mediate cisplatin resistance. Oncogene 24 28650468
2017 MEIS homeodomain proteins facilitate PARP1/ARTD1-mediated eviction of histone H1. The Journal of cell biology 24 28739678

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