| 1999 |
PARP-2 is a damaged DNA-binding protein that catalyzes poly(ADP-ribose) polymer formation in a DNA-dependent manner and undergoes automodification; it is localized in the nucleus and accounts for residual poly(ADP-ribose) synthesis in PARP-1-deficient cells. |
Recombinant protein purification, in vitro DNA-binding assay, in vitro PAR synthesis assay, nuclear localization by cell fractionation/immunofluorescence |
The Journal of biological chemistry |
High |
10364231
|
| 2002 |
PARP-2 homo- and heterodimerizes with PARP-1 (with interacting interfaces mapped and being sites of reciprocal ADP-ribosylation), and physically interacts with BER proteins XRCC1, DNA polymerase β, and DNA ligase III. XRCC1 negatively regulates PARP-2 activity while serving as a polymer acceptor. PARP-2-deficient cells show delayed DNA strand-break resealing after alkylating agent treatment, confirming a role in BER. |
Co-immunoprecipitation, in vitro pulldown, PARP activity assays, gene knockout mouse model (MNU treatment), comet assay |
The Journal of biological chemistry |
High |
11948190
|
| 2003 |
PARP-2-deficient mice are sensitive to ionizing radiation; PARP-2-/- MEFs show post-replicative genomic instability, G2/M accumulation, chromosome mis-segregation with kinetochore defects after alkylating agent treatment. Combined PARP-1/PARP-2 double knockout is lethal at gastrulation, demonstrating overlapping essential functions. Female-specific lethality in PARP-1+/-PARP-2-/- mice is linked to X chromosome instability. |
Gene knockout mouse models, metaphase chromosome analysis, flow cytometry, irradiation survival assays |
The EMBO journal |
High |
12727891
|
| 2004 |
PARP-2 physically binds to the telomere-protective protein TRF2 via the N-terminal domain of PARP-2 and the myb domain of TRF2. PARP activity covalently heteromodifies TRF2's dimerization domain and non-covalently modifies its myb domain via PAR binding, negatively regulating TRF2 DNA-binding activity. PARP-2-/- cells display spontaneously increased chromosome/chromatid breaks and telomere ends lacking TTAGGG repeats. |
Co-immunoprecipitation, in vitro pulldown, colocalization studies, ADP-ribosylation assays, telomere FISH on PARP-2-/- cells |
Molecular and cellular biology |
High |
14749375
|
| 2005 |
PARP-2 accumulates in the nucleolus and partially colocalizes with nucleophosmin/B23. PARP-2 interacts with B23 through its N-terminal DNA-binding domain via a constitutive association that does not depend on PARP activity or ribosomal transcription. A nuclear localization signal and nucleolar localization signal were identified in the N-terminal domain. PARP-1 and PARP-2 are delocalized from the nucleolus upon RNA polymerase I inhibition. |
Immunofluorescence, co-immunoprecipitation, NLS/NoLS mutagenesis, RNA pol I inhibition experiments, PARP-1/2-deficient MEFs |
Journal of cell science |
High |
15615785
|
| 2006 |
PARP-2 interacts with thyroid transcription factor-1 (TTF-1) via the E (catalytic) domain of PARP-2 and the C-terminal domain of TTF-1; both PARP-2 and PARP-1 enhance the activity of the surfactant protein-B (Sftpb) gene promoter in vitro. PARP-2 is selectively expressed in fetal mouse lung epithelial cells. |
Co-immunoprecipitation with mass spectrometry identification, GST pulldown domain mapping, luciferase reporter assay, immunohistochemistry |
The Journal of biological chemistry |
Medium |
16461352
|
| 2008 |
PARP-2 binds TIF1β with high affinity both directly and through HP1α; Parp-2 and its activity are required for relocation of TIF1β to heterochromatic foci during primitive endodermal differentiation. Both PARP-1 and PARP-2 selectively poly(ADP-ribosyl)ate HP1α. PARP-2 binds HP1β but not HP1γ, whereas PARP-1 binds weakly to TIF1β and HP1β only. |
Co-immunoprecipitation, pulldown assays, in vitro ADP-ribosylation, shRNA knockdown, immunofluorescence colocalization, differentiation assays |
FASEB journal |
Medium |
18676401
|
| 2008 |
Lysines 36 and 37 in the nuclear localization signal of PARP-2 are acetylated by histone acetyltransferases PCAF and GCN5L in vitro and in vivo. Acetylation at these residues reduces PARP-2 DNA-binding activity and enzymatic ADP-ribosylation activity, and reduces auto-mono-ADP-ribosylation. |
In vitro acetyltransferase assay, site-directed mutagenesis (K36A, K37A), DNA-binding assay, auto-ADP-ribosylation assay, in vivo co-immunoprecipitation |
The international journal of biochemistry & cell biology |
High |
18436469
|
| 2009 |
During immunoglobulin class switch recombination, Parp2 actively suppresses IgH/c-myc translocations, functioning as a translocation suppressor. Parp1 facilitates alternative (microhomology-mediated) end-joining. Neither Parp1 nor Parp2 is required for CSR per se, but Parp enzymatic activity is induced in an AID-dependent manner during CSR. |
Parp1/Parp2 knockout mouse B cells, CSR assays, translocation frequency analysis by PCR/Southern blot, ADP-ribose detection |
The Journal of experimental medicine |
High |
19364882
|
| 2009 |
Parp2 is required for spermiogenesis; Parp2 interacts with transition protein TP2 and chaperone HSPA2 (Parp2-TP2 interaction partially mediated by poly(ADP-ribosyl)ation). Only Parp1 poly(ADP-ribosyl)ates HSPA2. A Parp1/Parp2/TP2/HSPA2 spermatid-specific complex was identified. Parp2 deficiency causes loss of TP2-expressing spermatids, defective chromatin condensation, and abnormal manchette microtubule formation. |
In vitro protein-protein interaction assays, ADP-ribosylation assays, immunohistochemistry, electron microscopy on Parp2-/- mouse testes |
Experimental cell research |
High |
19607827
|
| 2010 |
Crystal structures of the catalytic domain of human PARP2 in complex with inhibitors 3-aminobenzamide and ABT-888 were determined, revealing structural features of the NAD+ binding site and enabling comparison with PARP1 for selective inhibitor design. |
X-ray crystallography |
Biochemistry |
High |
20092359
|
| 2011 |
PARP-2 acts as a direct transcriptional repressor of the SIRT1 promoter. PARP-2 deficiency increases SIRT1 expression and activity in myotubes (not via changes in NAD+ levels), promotes energy expenditure, increases mitochondrial content, and protects against diet-induced obesity in mice; however, PARP-2-/- mice are glucose intolerant due to defective pancreatic β-cell function. |
PARP-2 knockout mouse model, siRNA knockdown in myotubes, SIRT1 promoter reporter assay, ChIP, metabolic phenotyping, NAD+ measurements |
Cell metabolism |
High |
21459329
|
| 2011 |
PARP1 and PARP2 modulate topoisomerase II beta (TOP2B) activity during spermiogenesis: PARP1 and PARP2 activity strongly inhibits TOP2B in vitro, and this inhibition is counteracted by PAR glycohydrolase activity. Genetic and pharmacological PARP inhibition both increase TOP2B covalent DNA binding in vivo in spermatids. |
In vitro TOP2B activity assay with purified PARP1/PARP2, pharmacological PARP inhibition in mice, genetic PARP knockout mice, TOP2B-DNA complex assay in spermatids |
Biology of reproduction |
High |
21228215
|
| 2012 |
PARP inhibitors trap PARP1 and PARP2 at damaged DNA, forming cytotoxic PARP-DNA complexes. The trapping potency differs among inhibitors (niraparib > olaparib >> veliparib) and does not correlate with catalytic inhibitory potency. Homologous recombination, post-replication repair, Fanconi anemia pathway, polymerase β, and FEN1 are critical for repairing trapped PARP-DNA complexes. |
Cellular PARP trapping assay, clonogenic survival, 30 genetically defined DT40 cell lines with specific DNA repair gene deletions |
Cancer research |
High |
23118055
|
| 2013 |
PARP-2 interacts with AP site-containing DNA via Schiff base formation through its N-terminal domain. PARP-2, like PARP-1, inhibits APE1 activity by binding to AP sites, but unlike PARP-1, this inhibitory effect is not regulated by PAR synthesis. PARP-2 DNA binding is not modulated by autoPARylation. |
EMSA, cross-linking assays, APE1 activity assay in presence of PARP-2 |
Biochimie |
Medium |
25724268
|
| 2013 |
PARP-2 interacts with and inhibits both DNA polymerase β and FEN1 in vitro. Unlike PARP-1, poly(ADP-ribosyl)ation by PARP-2 does not restore DNA pol β or FEN1 activity. PARP-2 can also modulate the poly(ADP-ribosyl)ation activity of PARP-1, decreasing it. PARP-2 shows highest affinity for flap-containing DNA but is most efficiently activated by 5'-overhang DNA. |
EMSA for DNA binding (Kd measurements), in vitro BER enzyme activity assays (pol β, FEN1), PAR synthesis assays |
Biochimie |
Medium |
23357680
|
| 2013 |
PARP-2 is a direct transcriptional suppressor of the SREBP1 promoter in a manner dependent on its enzymatic activity. PARP-2 deletion increases hepatic SREBP1 expression, inducing downstream lipogenic genes and resulting in higher hepatic cholesterol content and decreased serum HDL levels in mice. |
PARP-2 knockout mice, siRNA knockdown in HepG2 cells, promoter reporter assay, gene expression analysis, lipid measurements |
Biochimica et biophysica acta |
Medium |
24365238
|
| 2014 |
PARP-2 (and PARP-3) are selectively activated by DNA breaks harboring a 5' phosphate group, suggesting activation by specific DNA repair intermediates competent for ligation. The WGR domain is the central regulatory domain of PARP-2, not the N-terminal region (NTR). PARP-1, PARP-2, and PARP-3 share an allosteric activation mechanism involving local destabilization of the catalytic domain upon DNA binding. |
Biochemical activation assays with defined DNA substrates, domain deletion/mutagenesis analysis, in vitro PAR synthesis assays |
Nucleic acids research |
High |
24928857
|
| 2014 |
ARTD2/PARP2 is activated by RNA in addition to DNA. RNA binding is mediated by the N-terminal SAP domain. In cells, this RNA-stimulated ARTD2 activation contributes to increased PAR formation under combined genotoxic + RNA-accumulating conditions, predominantly through ARTD2 rather than ARTD1. |
In vitro PAR synthesis assay with RNA substrates, domain deletion analysis (SAP domain), siRNA knockdown in cells, Actinomycin D co-treatment experiments |
Nucleic acids research |
Medium |
24510188
|
| 2014 |
PARP-2 deletion in mice causes chronic anemia due to shortened erythrocyte lifespan and impaired erythroid progenitor differentiation. PARP-2 deficiency triggers replicative stress in erythroblasts (γ-H2AX accumulation in S-phase, CHK1/RPA phosphorylation, micronuclei), activating p53-dependent DNA damage response, G2/M arrest, and apoptosis. Loss of pro-apoptotic Puma restores hematocrit; loss of p21 causes perinatal death by exacerbating erythropoiesis defects. |
PARP-2 knockout mice, flow cytometry, γ-H2AX staining, CHK1/RPA phosphorylation assays, genetic epistasis with Puma and p21 knockout |
Cell death and differentiation |
High |
25501596
|
| 2014 |
miR-149 directly inhibits PARP-2 expression, increasing cellular NAD+ and SIRT1 activity, which promotes mitochondrial biogenesis via PGC-1α activation. PARP-2 knockdown in skeletal muscle myotubes recapitulates miR-149 overexpression effects on SIRT1/PGC-1α pathway. |
miR-149 overexpression in myotubes, PARP-2 knockdown, NAD+ measurement, SIRT1 activity assay, PGC-1α and mitochondrial marker analysis |
Diabetes |
Medium |
24757201
|
| 2015 |
All three domains of PARP-2 (NTR, WGR, CAT) collectively contribute to DNA damage interaction. The NTR is natively disordered and is required for activation on specific DNA damage types but is not essential for PARP-2 localization to DNA damage sites. The WGR and CAT domains together recruit PARP-2 to DNA breaks. |
Biophysical analyses (SAXS/SEC-MALS indicating NTR disorder), structural studies, DNA-binding assays, live-cell laser micro-irradiation localization with domain deletion mutants, in vitro PAR synthesis assays |
Nucleic acids research |
High |
26704974
|
| 2015 |
PARP2 preferentially and specifically recognizes single DNA nicks (low binding to undamaged DNA or DSBs), and activation by SSBs drives synthesis of highly branched PAR. PARP1 has broader affinity (nicks and DSBs). PARP2 in dimeric form is more effective at PAR synthesis than monomer, opposite to PARP1. PARP2 suppresses PAR synthesis by PARP1 after SSB formation. |
Single-molecule AFM imaging, fluorescence titration, PAR synthesis biochemical assay with defined DNA substrates |
Nucleic acids research |
High |
26673720
|
| 2016 |
The WGR domain of PARP2 is the key domain for DNA break detection; crystal structures of the ARTD2 WGR domain bound to DSB-mimicking DNA reveal end-to-end DNA interaction mode, how PARP2 recognizes nicked DNA and the 5'-phosphate group, and how it mediates DNA end joining in vitro. Mutagenesis of the WGR-DNA interface confirms WGR is critical for DNA binding and catalytic activation. |
X-ray crystallography, site-directed mutagenesis, in vitro activity assays, DNA-binding assays, stoichiometry measurements |
Nucleic acids research |
High |
30321391
|
| 2016 |
PARP-2 contains transcriptional repression activity independent of its enzymatic activity, recruiting HDAC5, HDAC7, and histone methyltransferase G9a to promoters of cell cycle-related genes and generating repressive chromatin marks (histone deacetylation and methylation). |
PARP-2 catalytic mutant overexpression, co-immunoprecipitation of HDAC5/7 and G9a, ChIP at target gene promoters, reporter assays |
Biochemical and biophysical research communications |
Medium |
23291187
|
| 2017 |
PARP2 stabilizes replication forks that encounter BER intermediates through Fbh1-dependent regulation of Rad51. PARP2 is dispensable for tolerance to SSBs alone or for homologous recombination dysfunction, but is redundant with PARP1 in BER. Combined PARP1+PARP2 disruption causes defective BER, elevated replication-associated DNA damage, inability to stabilize Rad51 at damaged replication forks, and uncontrolled DNA resection. |
PARP1/PARP2 single and double knockouts, replication fork stability assays, Rad51 focus analysis, Fbh1 genetic epistasis, DNA resection assays |
Nature communications |
High |
29467415
|
| 2017 |
PARP2 controls DSB repair pathway choice independently of its PAR synthesis activity by limiting accumulation of the resection barrier 53BP1 at DNA damage sites, thereby promoting CtIP-dependent DNA end-resection and channeling repair toward HR, SSA, and alternative end-joining rather than canonical NHEJ. |
PARP2 knockout and catalytic mutant cells, 53BP1 focus analysis, CtIP-dependent resection assay, HR/SSA/A-EJ/C-EJ reporter assays |
Nucleic acids research |
High |
29036662
|
| 2018 |
PARP2 is preferentially activated by PAR itself (not just DNA breaks), and this PAR-dependent activation leads PARP2 to preferentially catalyze branched PAR chain synthesis. The N-terminus of PARP2 directly binds PAR to promote enzymatic activity toward branched chain synthesis. The PBZ domain of APLF specifically recognizes branched PAR chains to regulate chromatin remodeling in the DNA damage response. |
In vitro PAR synthesis assay with pre-formed PAR as activator, N-terminus deletion/mutation, PAR structure analysis, APLF-PBZ pulldown with branched PAR |
Nature communications |
High |
30104678
|
| 2018 |
PARP2 and PARP3 can PARylate and MARylate (respectively) 5'- and 3'-terminal phosphate residues at double- and single-strand break termini of DNA molecules in vitro, demonstrating that PARPs can directly ADP-ribosylate DNA ends in addition to protein substrates. |
In vitro ADP-ribosylation assay with defined DNA substrates, PAR/MAR detection methods, cell-free extracts, anti-PAR antibody on purified genomic DNA from bleomycin-treated cells |
Nucleic acids research |
High |
29361132
|
| 2019 |
PARP-2, but not PARP-1, is a critical component of the androgen receptor (AR) transcriptional machinery in prostate cancer cells through direct interaction with the pioneer factor FOXA1, facilitating AR recruitment to genome-wide prostate-specific enhancer regions. Selective PARP-2 targeting blocks PARP-2-FOXA1 interaction, attenuating AR-mediated gene expression and inhibiting PCa growth. |
Co-immunoprecipitation of PARP-2 with FOXA1, ChIP-seq for AR and PARP-2, siRNA/pharmacological PARP-2 knockdown, gene expression analysis, cell proliferation assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
31266892
|
| 2020 |
Cryo-EM structure of human PARP2-HPF1 bound to a nucleosome shows PARP2-HPF1 bridges two nucleosomes with broken DNA aligned for ligation. DNA break bridging induces conformational changes in PARP2 that signal DNA break recognition to the catalytic domain, licensing HPF1 binding and PARP2 activation. HPF1 switches PARP2 amino acid specificity from aspartate/glutamate to serine. Active PARP2 cycles through conformational states to exchange NAD+ and substrate. |
Cryo-electron microscopy structural determination of PARP2-HPF1-nucleosome complex |
Nature |
High |
32939087 33141820
|
| 2020 |
The chromatin remodeler ALC1 (CHD1L) is strictly required for PARP2 release from DNA damage sites. Catalytic inactivation of ALC1 quantitatively traps PARP2 but not PARP1. PARP inhibitors robustly trap PARP2 at DNA lesions, impacting cellular DNA damage responses. |
Live-cell imaging of PARP2 foci, ALC1 catalytic mutant cell lines, PARP inhibitor treatment, PARP2 vs PARP1 differential analysis |
Molecular cell |
High |
33275888
|
| 2020 |
PARP2 deficiency in myeloid cells increases immature myeloid cell populations in bone marrow and impairs CCL3 chemokine expression by enhancing transcriptional repression by β-catenin, creating an immune-suppressive microenvironment that promotes breast cancer bone metastasis. |
Myeloid-specific PARP2 knockout mice, osteoclast differentiation assays, bone marrow cell population analysis, β-catenin ChIP, CCL3 expression analysis, T cell population analysis |
Nature communications |
Medium |
32221289
|
| 2021 |
Crystal structure of PARP2 in complex with activating 5'-phosphorylated DNA shows the WGR domain bridges the dsDNA gap and joins DNA ends; DNA binding causes major conformational changes including reorganization of helical fragments in the regulatory domain, relieving autoinhibition. The activated conformation allows NAD+ binding and HPF1 association (which switches residue specificity from glutamate to serine). |
X-ray crystallography, comparison with PARP1 crystal structures, in vitro activity assays with HPF1 |
Nature communications |
High |
34108479
|
| 2021 |
HPF1 has a dual function with PARP2: it can both stimulate DNA-dependent and DNA-independent autoPARylation of PARP2 (and histone heteroPARylation) at defined HPF1/NAD+ concentrations, and suppress PARylation activity (promoting NAD+ hydrolysis) at higher concentrations. PARP2 is more efficiently stimulated by HPF1 in automodification and is more active in histone heteroPARylation than automodification. |
In vitro PARylation assays with purified PARP2, HPF1, and nucleosomes; NAD+ hydrolase assay; comparison with PARP1 |
Communications biology |
High |
34732825
|
| 2021 |
PARP-1 and PARP-2 deficiency in the uterus leads to pregnancy loss due to decidualization failure. Absence of PARP-1 and PARP-2 increases p53 signaling and senescent decidual cells. Embryo attachment and luminal epithelium removal are unaffected; the defect is specifically at decidualization. |
Uterine-specific PARP-1/PARP-2 conditional knockout mice, histology, p53 signaling analysis, senescence markers, embryo attachment assay |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
34580230
|
| 2021 |
PARP2 predominantly functions in single-strand break repair at actively transcribed DNA regions; this function is bypassed when transcription is inhibited. CSB chromatin remodeler recruits XRCC1 and HPF1 downstream of PARP1 and PARP2, and CSB regulates SSBR mediated by both PARP1 and PARP2. |
Chromatin co-fractionation, alkaline comet assay for SSBR kinetics, transcription inhibition experiments, PARP1/PARP2-deficient cells |
Nucleic acids research |
Medium |
37326017
|
| 2022 |
PARP inhibitors trap PARP2 by switching its recruitment mode from predominantly PARP1- and PAR-dependent rapid exchange to WGR domain-mediated stalling on DNA. In PARP1-deficient cells, residual PARP2 foci are DNA-dependent and require the WGR domain (R140 critical) and catalytic domain (H415). PARP2 trapping by inhibitors is independent of auto-PARylation. |
Live-cell imaging in PARP1-deficient cells, WGR (R140A) and catalytic (H415A) domain PARP2 mutants, PARP inhibitor treatment (niraparib, talazoparib, olaparib) |
Nucleic acids research |
High |
35349716
|
| 2023 |
Certain clinical PARP inhibitors exert an allosteric effect on PARP2 that increases its retention on DNA breaks through communication between the catalytic and DNA-binding regions; this is distinct from PARP1 where no clinical PARPi exhibits allosteric retention. AZD5305 exhibits a clear reverse allosteric effect on PARP2. |
Biochemical PARP2 DNA retention assay, PARP2 allosteric mutant mimicking inhibitor-bound state, live-cell imaging of PARP2 at damage sites |
Science advances |
High |
36961901
|
| 2023 |
PARP2 forms a remarkably stable mechanical bridge (rupture force ~85 pN) across blunt-end 5'-phosphorylated DSBs and restores torsional continuity. PARP2 switches between bridging and end-binding modes depending on DNA overhang type. In contrast, PARP1 does not form bridging interactions across blunt or short overhang DSBs and competes away PARP2 bridge formation. |
Single-molecule magnetic tweezers force spectroscopy, defined DSB substrates with various overhangs |
Proceedings of the National Academy of Sciences of the United States of America |
High |
37216533
|
| 2024 |
DNA replication specifically activates PARP2 robustly; PARP2 is selectively recruited and activated by 5'-phosphorylated nicks (5'p-nicks) between Okazaki fragments. Catalytically inactive PARP2 (E534A), but not absent PARP2, impedes Ligase 1- and Ligase 3-mediated ligation, causing dose-dependent replication fork collapse. This PARylation-dependent structural function at nicks is essential for erythropoiesis and explains PARPi-induced anemia. |
Parp2 E534A knock-in mice, comparison with Parp2-/- and Lig1-/- mice, Okazaki fragment ligation assay, replication fork analysis, Tp53/Chk2 genetic epistasis, selective PARP2 recruitment to 5'p-nicks |
Molecular cell |
High |
39383878
|
| 2024 |
PARP2 promotes replication stress-induced telomere fragility via the break-induced replication (BIR) pathway by orchestrating DNA end resection, strand invasion, and BIR-dependent mitotic DNA synthesis through POLD3 recruitment and activity. |
PARP2 knockout cells, BIR reporter assay, POLD3 recruitment analysis, telomere fragility assay (FISH), BLM helicase depletion model, oxidative lesion induction |
Nature communications |
Medium |
38565848
|