Affinage

PARP1

Poly [ADP-ribose] polymerase 1 · UniProt P09874

Round 2 corrected
Length
1014 aa
Mass
113.1 kDa
Annotated
2026-04-29
130 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PARP1 is a nuclear poly(ADP-ribose) polymerase that senses DNA strand breaks and catalyzes the synthesis of poly(ADP-ribose) (PAR) chains from NAD+, coordinating DNA repair, chromatin remodeling, transcriptional regulation, and cell death signaling. DNA break recognition occurs through cooperative binding of the N-terminal zinc fingers (Zn1/Zn3) and WGR domain, which induces a collapsed multi-domain conformation that allosterically activates the C-terminal catalytic domain; automodification in cis then drives PARP1 release from DNA (PMID:22582261, PMID:26626479, PMID:36323657). PAR chains recruit repair effectors—XRCC1–DNA ligase III–DNA polymerase β for base excision and single-strand break repair, and PARP1 also operates in an alternative NHEJ pathway—while the accessory factor HPF1 redirects catalysis toward serine ADP-ribosylation of histones and PARP1 itself, modulating chromatin trapping and inhibitor sensitivity (PMID:9584196, PMID:15498778, PMID:27067600, PMID:34210965). Beyond repair, PARP1 maintains a transcriptionally permissive chromatin state by PARylating and excluding histone H1 and the demethylase KDM5B, acts as a histone chaperone upon automodification, is cleaved by caspase-3 during apoptosis, and when hyperactivated depletes NAD+ to trigger autophagy, parthanatos, and NLRP3 inflammasome assembly (PMID:20832725, PMID:25136112, PMID:7596430, PMID:19001878, PMID:35098371).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Identification of PARP1 as a caspase-3 substrate established that its proteolytic inactivation is a hallmark event during apoptosis, linking a DNA repair enzyme to programmed cell death.

    Evidence In vitro cleavage of purified PARP1 by purified caspase-3/apopain, confirmed by peptide inhibitor blockade and cell-free apoptotic extracts

    PMID:7596430 PMID:8642305

    Open questions at the time
    • Whether PARP1 cleavage is required for apoptosis or is a bystander event was not resolved
    • Caspase-3-independent cleavage pathways not explored
  2. 1998 High

    Discovery that XRCC1 physically associates with PARP1 through its BRCT domain and participates in a BER complex with DNA ligase III and DNA polymerase β established the molecular basis of PARP1's role in single-strand break repair.

    Evidence Yeast two-hybrid and co-immunoprecipitation in mammalian cells, followed by PARP1 KO MEF studies showing XRCC1 foci depend on PARP1

    PMID:14500814 PMID:9584196

    Open questions at the time
    • How PAR chain length controls XRCC1 recruitment kinetics was not determined
    • Structural basis of the XRCC1 BRCT–PAR interaction not resolved at this stage
  3. 2004 High

    Demonstration that PARP1, together with XRCC1–DNA ligase III, mediates an alternative (backup) NHEJ pathway revealed a second major DSB repair function independent of the canonical Ku/DNA-PKcs pathway.

    Evidence In vitro end-joining reconstitution with recombinant proteins, confirmed with PARP inhibitors and PARP1-deficient cells; genetic epistasis in DT40 cells showed Ku competition

    PMID:15498778 PMID:17088286

    Open questions at the time
    • Relative contribution of alt-NHEJ versus HR in different cell cycle phases not established
    • Whether PARP1 alt-NHEJ is error-prone in vivo not quantified
  4. 2006 High

    PARP1 was shown to be essential for topoisomerase IIβ-dependent transient DSB-mediated chromatin remodeling at gene promoters, establishing a direct role in transcriptional regulation beyond DNA repair.

    Evidence ChIP, in vivo promoter analysis, PARP1 enzymatic inhibition, and reconstituted transcription

    PMID:16794079

    Open questions at the time
    • Genome-wide scope of PARP1-dependent promoter remodeling not yet mapped
    • Whether PARylation of specific substrates or PARP1 structural presence drives transcription not separated
  5. 2010 High

    Genome-wide analysis showed PARP1 PARylates and excludes KDM5B from H3K4me3-marked promoters and displaces linker histone H1, establishing the molecular mechanism by which PARP1 maintains transcriptionally permissive chromatin.

    Evidence ChIP-seq, siRNA knockdown, PARP1 KO, histone modification and RNA Pol II profiling

    PMID:20832725

    Open questions at the time
    • Specificity determinants for which promoters require PARP1-dependent H1 exclusion not identified
    • Direct structural basis of KDM5B PARylation-mediated inhibition not resolved
  6. 2012 High

    The crystal structure of PARP1 domains on a DNA break revealed the allosteric activation mechanism: Zn1, Zn3, and WGR assemble on damage to induce a collapsed conformation that distorts the catalytic domain, favoring automodification in cis.

    Evidence X-ray crystallography of Zn1–Zn3–WGR-CAT bound to a DSB mimic, validated by mutagenesis and activity assays

    PMID:22582261

    Open questions at the time
    • How Zn2 and the BRCT domain contribute to activation on intact chromatin substrates not addressed
    • Full-length PARP1 structure on nucleosomal DNA not obtained
  7. 2012 High

    The PARP inhibitor trapping paradigm was established: PARPi cytotoxicity arises primarily from trapped PARP1–DNA complexes rather than from catalytic inhibition alone, and trapping potency varies among clinical inhibitors independently of catalytic IC50.

    Evidence Chromatin fractionation trapping assay and cytotoxicity analysis across 30 DT40 genetic backgrounds

    PMID:23118055

    Open questions at the time
    • Structural determinant of why different inhibitors trap with different potencies was unknown
    • Contribution of PARP2 trapping versus PARP1 trapping not fully deconvoluted
  8. 2014 High

    Automodification was shown to switch PARP1 from a chromatin compactor to a histone chaperone, providing a biochemical mechanism for PAR-dependent chromatin remodeling at damage sites.

    Evidence In vitro chromatin binding, nucleosome assembly, and histone sequestration assays comparing unmodified and automodified PARP1

    PMID:25136112

    Open questions at the time
    • In vivo evidence for PARP1 histone chaperone activity at specific loci not provided
    • How chaperone activity coordinates with other chromatin remodelers not addressed
  9. 2015 High

    NMR-based structural dynamics revealed a stepwise SSB sensing mechanism: zinc fingers detect break-induced DNA deformability via induced fit, progressing through an intermediate kinked state to full multi-domain assembly and catalytic activation.

    Evidence NMR, SAXS, and single-molecule smFRET with domain mutants and clinical inhibitor perturbation

    PMID:26626479 PMID:36323657

    Open questions at the time
    • Whether the same stepwise mechanism operates for all break geometries (gaps, DSBs, oxidized bases) not determined
    • Role of chromatin context in modulating the induced-fit pathway unexplored
  10. 2016 High

    Discovery of HPF1 as a PARP1 cofactor that redirects catalysis toward serine ADP-ribosylation of histones while limiting hyper-automodification resolved how PARP1 achieves substrate-specific modification at damage sites.

    Evidence Co-IP, MS, laser micro-irradiation, in vitro ADP-ribosylation; later MS-based site mapping (S499, S507, S519) with mutagenesis and HPF1/ARH3 KO PARPi sensitivity

    PMID:27067600 PMID:34210965

    Open questions at the time
    • Structural basis of HPF1-directed serine specificity not fully resolved at the time
    • How HPF1 stoichiometry is regulated at breaks remains unclear
  11. 2016 High

    c-Met phosphorylation of PARP1 at Y907 was found to increase enzymatic activity and reduce PARP inhibitor binding, identifying a receptor tyrosine kinase–mediated resistance mechanism.

    Evidence In vitro kinase assay, Y907 mutagenesis, PARP1 activity assay, xenograft tumor models

    PMID:26779812

    Open questions at the time
    • Whether other RTKs similarly modify PARP1 not explored
    • Structural mechanism by which pY907 reduces inhibitor binding not resolved
  12. 2020 High

    Allosteric modulation by PARPi was directly demonstrated: inhibitors differ in whether they promote PARP1 retention on or release from DNA, and medicinal chemistry converting a pro-release to a pro-retention compound increased cytotoxicity, establishing allostery as a druggable axis.

    Evidence Structural analysis, biochemical retention assays, single-molecule real-time retention assay, medicinal chemistry

    PMID:32241924 PMID:36070389

    Open questions at the time
    • Patient-level correlation between allosteric trapping mode and clinical efficacy not established
    • How chromatin environment modulates allosteric trapping not addressed
  13. 2020 High

    TRIP12 was identified as the E3 ubiquitin ligase controlling steady-state PARP1 levels via PAR-dependent binding (WWE domain) and HECT-mediated polyubiquitylation, linking PAR metabolism to proteasomal PARP1 turnover and PARPi sensitivity.

    Evidence Co-IP, domain mutant analysis, ubiquitylation assay, proteasome inhibitor, TRIP12 KO with PARP1 trapping readout

    PMID:32755579

    Open questions at the time
    • Whether other E3 ligases contribute to PARP1 turnover not explored
    • Regulation of TRIP12–PARP1 axis during the cell cycle not determined
  14. 2021 High

    PARP1 hyperactivation in nucleotide excision repair-deficient cells was shown to deplete NAD+, suppress SIRT1–PGC-1α signaling, and impair mitophagy, demonstrating that PARP1 activity level couples nuclear DNA damage to mitochondrial homeostasis.

    Evidence NAD+ measurements, mitophagy assays, PARP1 inhibition and NAD+ supplementation rescue in cells and C. elegans lifespan model

    PMID:24813611

    Open questions at the time
    • Direct measurement of compartmentalized NAD+ fluxes between nucleus and mitochondria at single-cell resolution not achieved
    • Whether this mechanism contributes to human premature aging syndromes in patients not demonstrated
  15. 2022 Medium

    PARP1 was found to PARylate NLRP3 and translocate to the cytosol to bridge NLRP3–TXNIP interaction, positioning PARP1 as a positive regulator of inflammasome assembly beyond its canonical nuclear functions.

    Evidence PARP1 KO macrophages, PARP1 inhibitor, subcellular fractionation, co-IP, IL-1β/caspase-1 activity

    PMID:35098371

    Open questions at the time
    • Mechanism of PARP1 cytosolic translocation not defined
    • Whether PARylation of NLRP3 is direct or mediated through intermediaries not fully resolved
    • Independent replication needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of PARP1 on nucleosomal DNA, how chromatin context modulates the allosteric trapping–release equilibrium in vivo, the quantitative contribution of compartmentalized NAD+ pools to PARP1 output, and the physiological significance of non-nuclear PARP1 functions such as inflammasome regulation.
  • Full-length PARP1–nucleosome structure not determined
  • In vivo single-molecule dynamics of PARP1 on chromatinized DNA not measured
  • Clinical predictors of allosteric trapping mode for PARPi therapy not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 9 GO:0140096 catalytic activity, acting on a protein 9 GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5 GO:0044183 protein folding chaperone 1
Localization
GO:0005634 nucleus 9 GO:0005694 chromosome 6 GO:0005654 nucleoplasm 4 GO:0005829 cytosol 1
Pathway
R-HSA-73894 DNA Repair 16 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 1 R-HSA-9612973 Autophagy 1
Partners
CTCFHPF1PARP2PARP3SIRT6TIMELESSTRIP12XRCC1
Complex memberships
HPF1–PARP1 complexPARP1–PARP2 heterodimerXRCC1–DNA ligase III–Polβ BER complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Caspase-3 (apopain/CPP32) cleaves PARP-1 during apoptosis, identifying PARP-1 as a key substrate of caspase-3 in the apoptotic pathway Protein purification, in vitro cleavage assay, peptide inhibitor studies Nature High 7596430
1996 Apopain/caspase-3 cleaves PARP-1 at a specific DEVD site, abolishing its DNA repair function as a fundamental mechanism of apoptotic cell death In vitro cleavage assay with recombinant apopain, cell-free apoptotic extracts, peptide inhibitors The Journal of experimental medicine High 8642305
1998 XRCC1 physically associates with PARP-1 via its central BRCT domain and negatively regulates PARP-1 activity following DNA damage; PARP-1 is a member of a BER multiprotein complex with XRCC1, DNA ligase III, and DNA polymerase β Yeast two-hybrid, co-immunoprecipitation in mammalian cells, overexpression activity assay Molecular and cellular biology High 9584196
2002 PARP-2 homo- and heterodimerizes with PARP-1; both interact with XRCC1, DNA polymerase β, and DNA ligase III, and PARP-2 participates in base excision repair alongside PARP-1 Co-immunoprecipitation, interaction domain mapping, gene-targeted knockout mice, DNA repair kinetics assay The Journal of biological chemistry High 11948190
2003 PARP-1 is required for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage; interaction is mediated by the XRCC1 BRCT I domain binding poly(ADP-ribose) Immunofluorescence, PARP-1 knockout MEFs, XRCC1 domain mutants, live-cell imaging Nucleic acids research High 14500814
2004 PARP-1, together with XRCC1–DNA ligase III, mediates an alternative (backup) NHEJ pathway for DNA double-strand break repair that is independent of DNA-PK/XRCC4/ligase IV In vitro synapsis and end-joining assay with nuclear extracts and recombinant proteins, PARP inhibitor cytotoxicity, repair kinetics in PARP-1-deficient cells The Journal of biological chemistry High 15498778
2006 PARP-1 is required for a topoisomerase IIβ-dependent, transient dsDNA break-initiated chromatin remodeling event at gene promoters, including histone H1-HMGB exchange, necessary for regulated transcription Chromatin immunoprecipitation, in vivo promoter analysis, PARP-1 enzymatic inhibition, reconstituted transcription Science High 16794079
2006 PARP-1 competes with Ku for binding to DNA double-strand break ends and operates in an alternative (backup) NHEJ pathway involving DNA ligase III; in irradiated cells Ku's higher affinity limits PARP-1 contribution unless classical NHEJ components are absent Genetic deletion of DT40 cell components, end-joining assays, PARP inhibitor sensitivity, chromatin fractionation Nucleic acids research High 17088286
2008 CTCF activates PARP-1 automodification even in the absence of nicked DNA in vitro; poly(ADP-ribosyl)ated PARP-1 inhibits DNMT1 activity non-covalently through ADP-ribose polymers, linking CTCF, PARylation, and DNA methylation patterning In vitro PARP-1 automodification assay with recombinant CTCF, DNMT1 activity assay, overexpression in mouse fibroblasts, methylation analysis The Journal of biological chemistry High 18539602
2008 PARP-1 poly(ADP-ribosyl)ates PPARγ under basal conditions in cardiac fibroblasts, preventing PPARγ DNA binding and suppressing adiponectin and AdipoR1 transcription Southwestern blot, EMSA, PARP-1 siRNA, PARP inhibitors (3-AB, PJ34), western blot Cardiovascular research Medium 18815186
2009 PARP-1 directly binds and poly(ADP-ribosyl)ates FOXO1, acting as a corepressor of FOXO1-mediated p27Kip1 gene expression; enzymatic activity is not required for repression; PARP-1 is recruited to the p27Kip1 promoter via FOXO1 binding Co-immunoprecipitation, ChIP, PARP-1 siRNA knockdown, reporter assays Biochemical and biophysical research communications Medium 19281796
2009 PARP-1 binds damaged DNA as a monomer; binding induces a conformational change around the zinc ribbon domain detectable by SAXS, resulting in robust catalytic activation; all three damage models (nick, blunt end, 3′ extension) bind PARP-1 with similar affinity Biochemical binding assays, thermodynamic measurements, small-angle X-ray scattering (SAXS) Journal of molecular biology High 19962992
2009 PARP-1 activation by DNA damage triggers autophagy through NAD+/ATP depletion and mTOR inhibition; PARP-1-deficient or -inhibited cells fail to induce autophagy after doxorubicin treatment Electron microscopy, GFP-LC3 transfection, autophagy gene expression, genetic KO (parp-1−/−), PARP inhibitor, mTOR activity assay Autophagy Medium 19001878
2010 PARP-1 prevents demethylation of H3K4me3 at regulated gene promoters by PARylating and excluding the histone demethylase KDM5B, and promotes exclusion of histone H1 to create a permissive chromatin environment for RNA Pol II loading ChIP-seq, siRNA knockdown, PARP-1 KO, RNA Pol II ChIP, histone modification profiling Molecular cell High 20832725
2010 PARP-3 interacts with PARP-1 via its N-terminal WGR domain and activates PARP-1 poly-ADP-ribosylation activity in the absence of DNA; PARP-3 is itself a mono-ADP-ribosylase In vitro ADP-ribosylation assay, co-immunoprecipitation, domain mapping, siRNA knockdown The Journal of biological chemistry High 20064938
2011 SIRT6 physically associates with PARP-1 and mono-ADP-ribosylates PARP-1 on lysine 521 under oxidative stress, thereby stimulating PARP-1 poly-ADP-ribosylase activity and enhancing DSB repair Co-immunoprecipitation, in vitro ADP-ribosylation assay, site-directed mutagenesis, SIRT6 KO cells, comet assay Science High 21680843
2012 PARP inhibitors trap PARP-1 and PARP-2 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 Chromatin fractionation (PARP-DNA complex trapping assay), cytotoxicity assays in 30 DT40 deletion cell lines, genetic epistasis Cancer research High 23118055
2012 Trp-tRNA synthetase (TrpRS) forms a nuclear complex with DNA-PKcs and PARP-1; IFN-γ-dependent PARylation of DNA-PKcs by this complex activates its kinase function and downstream p53 signaling Co-immunoprecipitation, Trp-AMP analog disruption of complex, in vitro PARylation assay, p53 signaling readout in vertebrate cells Nature chemical biology Medium 22504299
2012 Crystal structure of PARP-1 domains Zn1, Zn3, WGR-CAT in complex with a DNA double-strand break reveals that PARP-1 binds DNA as a monomer; interaction organizes domains into a collapsed conformation that introduces distortions in the catalytic domain, causing activation; domain contacts favor automodification in cis X-ray crystallography, in vitro activity assays, mutagenesis Science High 22582261
2014 Automodification of PARP-1 switches its function from chromatin architectural protein (high-affinity binding to intact chromatin) to histone chaperone capable of sequestering histones and assembling nucleosomes in vitro; automodification reduces affinity for intact chromatin but not for nucleosomes with exposed DNA ends In vitro chromatin binding assays, nucleosome assembly assay, histone sequestration assay, PARP-1 automodification in cells Proceedings of the National Academy of Sciences High 25136112
2014 PARP-1 hyperactivation in XPA-deficient cells reduces NAD+ and SIRT1-PGC-1α signaling, causing defective mitophagy; PARP-1 inhibition or NAD+ supplementation rescues mitochondrial defects and lifespan in xpa-1 nematodes NAD+ measurement, mitophagy assays (PINK1 cleavage, mitochondrial membrane potential), PARP-1 inhibition, NAD+ precursor supplementation, C. elegans lifespan assay, PARP-1 KO Cell High 24813611
2014 H2S sulfhydrates MEK1 at Cys341, leading to nuclear translocation of phospho-ERK1/2 which directly interacts with and activates PARP-1, which then recruits XRCC1 and DNA ligase III to DNA breaks for repair S-sulfhydration assay, co-immunoprecipitation, site-directed mutagenesis (MEK1 C341), subcellular fractionation, DNA damage assays EMBO reports Medium 24778456
2015 Crystal structure of Timeless PAB domain in complex with the PARP-1 catalytic domain reveals a specific PARP-1 interaction interface; Timeless accumulates at DNA damage sites in a PARP-1-dependent but PARylation-independent manner and promotes homologous recombination repair X-ray crystallography, co-immunoprecipitation, laser micro-irradiation live imaging, HR repair assay, PARP inhibitor trapping Molecular cell High 26344098
2015 NMR and structural studies reveal that two flexibly linked N-terminal zinc fingers of PARP-1 recognize SSBs through the extreme deformability of the broken DNA; multi-domain cooperative stepwise self-assembly allosterically activates the catalytic domain; automodification in cis releases PARP-1 as a monomer from DNA NMR, SAXS, structural ensemble calculations, biochemical activity assays, mutagenesis Molecular cell High 26626479
2016 HPF1/C4orf27 forms a robust complex with PARP-1 in cells, is recruited to DNA lesions in a PARP-1-dependent but catalytic-activity-independent manner; HPF1 promotes PARP-1-dependent trans ADP-ribosylation of histones and limits PARP-1 hyper-automodification Co-immunoprecipitation, mass spectrometry, laser micro-irradiation recruitment assay, in vitro ADP-ribosylation assay, HPF1 KO cells Molecular cell High 27067600
2016 c-Met receptor tyrosine kinase associates with and phosphorylates PARP-1 at Tyr907; PARP-1 pY907 increases PARP-1 enzymatic activity and reduces PARP inhibitor binding, causing resistance to PARP inhibition Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y907), PARP-1 activity assay, cell proliferation and xenograft tumor models Nature medicine High 26779812
2018 PARP-1 activity enhances E2F1 transcription factor activity to promote E2F1-dependent induction of homologous recombination repair factors; PARP-1 inhibition reduces HR factor availability and induces 'BRCA-ness' Transcriptional profiling, ChIP, PARP-1 inhibition, patient tissue PARP-1 activity assessment EMBO molecular medicine Medium 30467127
2018 PARP-1 can form a covalent DNA-protein crosslink (DPC) at apurinic/apyrimidinic sites via Schiff base formation with a lysine residue; repair requires proteasomal degradation of the crosslinked PARP-1 followed by a BER sub-pathway involving TDP1 Chromatin fractionation DPC assay, proteasome inhibitor (MG-132), alkylating agent cytotoxicity, in vitro BER reconstitution with model substrate DNA repair High 30466837
2019 PARP-1 activation recruits FUS to DNA damage sites via PAR binding; FUS assembles damaged DNA-rich compartments that are dissolved by PARG-mediated PAR hydrolysis, which initiates nucleocytoplasmic shuttling of FUS In vitro single-molecule reconstitution of PARP-1/PAR/DNA/FUS system, live-cell imaging, PARG treatment Cell reports High 31067465
2019 Unanchored tri-NEDD8 accumulates upon oxidative stress (via NEDP1 inhibition) and binds specifically to the second zinc finger domain of PARP-1, attenuating its activation and protecting cells from PARP-1-dependent cell death; acetylation of tri-NEDD8 is required for PARP-1 binding Co-immunoprecipitation, mass spectrometry, NEDP1 KO cells, PARP-1 activity assay, domain-specific binding assay The EMBO journal Medium 30804002
2020 Allosteric mechanism of PARP inhibitor action: some PARPi drive PARP-1 allostery toward retention on DNA breaks while others promote release; a pro-release compound was converted to a pro-retention compound, increasing cancer cell killing Structural analysis, biochemical PARP-1-DNA retention assays, cell cytotoxicity, medicinal chemistry Science High 32241924
2020 TRIP12 ubiquitin E3 ligase binds PARP-1 via its WWE (PAR-binding) domain and polyubiquitylates PARP-1 via its HECT domain, triggering proteasomal degradation and controlling steady-state PARP-1 levels; loss of TRIP12 elevates PARP-1 and increases PARPi-induced cytotoxic trapping Co-immunoprecipitation, domain mutant analysis, polyubiquitylation assay, proteasome inhibitor, TRIP12 KO with PARP-1 levels and trapping assay Cell reports High 32755579
2020 PARP1 exchanges rapidly at DNA damage sites even in the presence of clinical PARP inhibitors (as shown by FRAP), indicating persistent foci represent continuous recruitment of new PARP1 molecules due to impaired XRCC1-LIG3 repair, not physical stalling; residue H862 is identified as a key NAD+ interacting residue regulating PARP-1 exchange Quantitative live-cell imaging, FRAP, XRCC1 KO, NAD+ interacting residue mutagenesis (H862D, E988K) Nucleic acids research High 32890402
2020 SIRT3 accumulates in the nucleus under stress, physically interacts with PARP-1, and deacetylates PARP-1, reducing its activity and inhibiting cardiac hypertrophy Co-immunoprecipitation, SIRT3 overexpression (adenovirus), acetylation assay, cardiomyocyte hypertrophy model Aging Medium 32139662
2021 PARP-1 serine ADP-ribosylation (at residues S499, S507, S519) mediated by HPF1 counteracts PARP-1 trapping on chromatin by PARP inhibitors; loss of serine-ADPr regulators HPF1 or ARH3 sensitizes cells to PARPi Mass spectrometry (site identification), serine-to-alanine mutagenesis, HPF1/ARH3 KO cells, PARPi sensitivity assay, PARP-1 trapping assay Nature communications High 34210965
2021 Mitochondrial NAD+ supply controls nuclear PARP-1 (ARTD1) ADP-ribosylation activity; H2O2-induced oxidative stress reciprocally induces nuclear and reduces mitochondrial ADP-ribosylation; elevated mitochondrial ADP-ribosylation dampens nuclear PARP-1 activity and increases MMS-induced PARP-1 chromatin retention Immunofluorescence, western blot, mass spectrometry, mitochondrial uncoupler (FCCP), respiratory chain inhibition Molecular cell Medium 33450210
2021 PARP-1 binding of G-quadruplex DNA structures stimulates its enzymatic activity; loop features of G-quadruplexes (e.g., c-KIT promoter sequence) determine the degree of PARP-1 activation; oxidized G-quadruplexes also stimulate PARP-1 activity In vitro PARP-1 activity assay with G-quadruplex substrates, nanomolar affinity binding measurements, loop mutant G-quadruplexes Nucleic acids research High 33313902
2022 Single-molecule FRET reveals a two-step SSB sensing mechanism: PARP-1 N-terminal zinc fingers convert SSBs from unperturbed through an intermediate to a highly kinked DNA conformation via induced fit, driving multi-domain assembly; niraparib shifts equilibrium toward unkinked DNA while EB47 stabilizes the kinked state Single-molecule smFRET, structural ensemble calculations, PARP-1 domain mutants, clinical inhibitor comparison Nature communications High 36323657
2022 Single-molecule assay reveals a two-step mechanism of PARPi-induced PARP1 DNA retention: primary step is catalytic inhibition via NAD+ competition; secondary step is allosteric modulation; retention potency is predominantly determined by NAD+ competition Single-molecule real-time retention assay, NAD+ competition analysis, clinical PARPi panel Science advances High 36070389
2022 PARP-1 mediates association of DDX18 RNA helicase with R-loops in DNA lesion regions; DDX18 depletion causes R-loop accumulation, DNA replication defects, and genome instability rescued by RNase H1 overexpression Co-immunoprecipitation, R-loop immunofluorescence (S9.6 antibody), RPA32/RAD51 foci, DDX18 siRNA, RNase H1 overexpression rescue Cell reports Medium 35858569
2022 PARP-1 PARylates NLRP3 upon ATP stimulation and translocates to the cytosol, where it bridges NLRP3 and TXNIP to promote inflammasome assembly; PARP-1 positively regulates NLRP3 inflammasome activation through ROS production and PAR modification of NLRP3 PARP-1 KO macrophages (BMDM), PARP-1 inhibitor, cytosol/nuclear fractionation, co-immunoprecipitation, IL-1β/caspase-1 activity assay, ROS measurement Cellular and molecular life sciences Medium 35098371
2022 HMGB3 interacts with PARP-1 at DNA lesions and prevents PARP-1 trapping; loss of HMGB3 increases PARP-1 trapping and PARylation activity, sensitizing ovarian cancer cells to PARP inhibitors Co-immunoprecipitation (blocked by olaparib), PARP-1 trapping assay, PARylation assay, HMGB3 KD/overexpression, xenograft model Cell death & disease Medium 35332131

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 3743 7596430
2012 A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. The Journal of cell biology 1850 22412018
2012 Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer research 1766 23118055
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nature reviews. Molecular cell biology 1388 28676700
2010 Network organization of the human autophagy system. Nature 1286 20562859
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2005 Nucleolar proteome dynamics. Nature 934 15635413
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2017 PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression. Clinical cancer research : an official journal of the American Association for Cancer Research 823 28167507
1998 XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Molecular and cellular biology 786 9584196
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2006 A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science (New York, N.Y.) 734 16794079
2010 The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Molecular cell 727 20603072
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 SIRT6 promotes DNA repair under stress by activating PARP1. Science (New York, N.Y.) 692 21680843
2005 Poly(ADP-ribosyl)ation by PARP-1: 'PAR-laying' NAD+ into a nuclear signal. Genes & development 691 16140981
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic acids research 637 17088286
2002 Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. The Journal of biological chemistry 574 11948190
2010 An atlas of combinatorial transcriptional regulation in mouse and man. Cell 573 20211142
2014 Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 565 24813611
2012 Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1. Science (New York, N.Y.) 558 22582261
2004 Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. The Journal of biological chemistry 556 15498778
1996 Apopain/CPP32 cleaves proteins that are essential for cellular repair: a fundamental principle of apoptotic death. The Journal of experimental medicine 549 8642305
2003 A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic acids research 548 14500814
2010 The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes & development 541 20504901
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2008 Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation. Current opinion in cell biology 364 18450439
2003 PARP-1, a determinant of cell survival in response to DNA damage. Experimental hematology 313 12829019
2018 The comings and goings of PARP-1 in response to DNA damage. DNA repair 273 30177435
2015 Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1. Molecular cell 272 26626479
2010 PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway. Molecular cell 271 20832725
2020 Structural basis for allosteric PARP-1 retention on DNA breaks. Science (New York, N.Y.) 262 32241924
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2007 PARP-1 activation in the ERK signaling pathway. Trends in pharmacological sciences 115 17950909
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2004 PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation. International journal of radiation oncology, biology, physics 107 14751510
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2008 Integrin-linked kinase regulates E-cadherin expression through PARP-1. Developmental dynamics : an official publication of the American Association of Anatomists 66 18773488
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