Affinage

APEX1

DNA repair nuclease/redox regulator APEX1 · UniProt P27695

Round 2 corrected
Length
318 aa
Mass
35.6 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APEX1 is a bifunctional nuclear protein that serves as the major mammalian apurinic/apyrimidinic (AP) endonuclease essential for base excision repair (BER) and as a redox regulator of transcription factor activity. Its C-terminal endonuclease domain, with catalytic residue Asp-210, cleaves AP sites via a DNA-kinking mechanism that flips the abasic nucleotide into an active-site pocket; this repair activity—not the redox function—is essential for cell viability, and its loss causes abasic-site accumulation, genomic instability, and apoptosis, including failure of T effector cell generation (PMID:10667800, PMID:10871340, PMID:15694346, PMID:39739423). The N-terminal redox domain, dependent on Cys-65, activates transcription factors including AP-1, NF-κB, p53, HIF-1α, Pax-8, and NRF2 through a thioredoxin-mediated reduction cascade, and p300-dependent acetylation drives APEX1 nuclear translocation to promote NF-κB-dependent inflammatory gene expression and atherogenesis (PMID:1380454, PMID:9108029, PMID:33887608, PMID:34810252). XRCC1 physically interacts with APEX1's N-terminal region and stimulates its endonuclease and 3′-phosphodiesterase activities, coordinating sequential BER steps (PMID:11707423).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1991 High

    Cloning of the human APEX1 cDNA established it as the major nuclear AP endonuclease, resolving the molecular identity of the enzyme responsible for abasic-site repair in human cells.

    Evidence cDNA cloning and functional complementation in AP endonuclease-deficient E. coli

    PMID:1722334

    Open questions at the time
    • No structural information on the enzyme
    • Redox function not yet recognized
  2. 1992 High

    Discovery that the same gene product (Ref-1) mediates both AP endonuclease repair and redox-dependent activation of AP-1, NF-κB, and other transcription factors revealed APEX1 as a bifunctional protein with separable activities.

    Evidence Protein purification from HeLa nuclear extracts with EMSA, immunodepletion, and AP endonuclease assay

    PMID:1380454

    Open questions at the time
    • Structural basis for separation of domains unknown
    • Identity of the redox-active residue(s) unresolved
  3. 1997 High

    Mapping the two-domain architecture (C-terminal endonuclease, N-terminal redox with essential Cys-65) and establishing a thioredoxin → Ref-1 → AP-1/p53 redox cascade defined the molecular logic of APEX1's transcription-factor activation.

    Evidence Domain deletion/mutagenesis, in vitro cross-linking, mammalian two-hybrid (TRX–Ref-1 interaction), EMSA for p53 activation

    PMID:9108029 PMID:9119221 PMID:9406232

    Open questions at the time
    • Whether TRX directly reduces Cys-65 or acts indirectly was unresolved
    • Structural basis of redox domain activity unknown
  4. 1998 High

    APEX1 expression was shown to be selectively induced by reactive oxygen species, with ROS-treated cells acquiring resistance to further oxidative challenge, establishing APEX1 as a component of the adaptive oxidative stress response.

    Evidence Northern/Western blot, immunofluorescence for nuclear translocation, cytotoxicity assays in HeLa and WI-38 cells

    PMID:9560228

    Open questions at the time
    • Transcriptional regulators driving APEX1 induction undefined
    • Whether redox and repair functions both contribute to adaptive resistance was unclear
  5. 2000 High

    Co-crystal structures of APE1 bound to abasic DNA revealed a DNA-kinking, base-flipping catalytic mechanism and active-site geometry supporting metal-dependent phosphodiester hydrolysis, while mutagenesis of Asp-210 proved it is essential for catalysis but not substrate binding.

    Evidence X-ray crystallography (three co-crystal structures with Mn²⁺), alanine-scanning mutagenesis with enzyme kinetics

    PMID:10667800 PMID:10871340

    Open questions at the time
    • Product release mechanism and hand-off to downstream BER factors not fully resolved
    • No co-structure with XRCC1 or polymerase β
  6. 2001 High

    Identification of a direct physical and functional interaction between XRCC1 and APE1 demonstrated that BER is coordinated through scaffold-mediated stimulation of AP-site incision, linking the incision and gap-filling steps.

    Evidence Co-immunoprecipitation, in vitro enzymatic stimulation, XRCC1-mutant cell rescue

    PMID:11707423

    Open questions at the time
    • Structural basis of the XRCC1–APE1 interface (N-terminal 35 residues) unresolved
    • Whether other BER scaffold proteins modulate APE1 similarly was unknown
  7. 2005 High

    Functional complementation of APEX1 knockdown by yeast Apn1 (which lacks redox activity) proved that the AP endonuclease—not the redox—function is the essential activity required for cell viability.

    Evidence RNAi knockdown in multiple human cell lines with heterologous Apn1 rescue, apoptosis assays, DNA damage quantification

    PMID:15694346

    Open questions at the time
    • Whether redox function becomes essential under specific physiological stresses was untested
    • Tissue-specific requirements not addressed
  8. 2005 Medium

    APEX1 was shown to participate in hypoxia-responsive transcriptional complexes (with HIF-1α, STAT3, CBP/p300) on the VEGF promoter and to regulate nuclear import/export via N-terminal signals and karyopherin interactions, expanding its roles beyond BER.

    Evidence ChIP on VEGF promoter, co-IP, dominant-negative STAT3/HIF-1α; EGFP-fusion live-cell imaging with deletion mutagenesis and importin pull-down

    PMID:15735682 PMID:15942031

    Open questions at the time
    • Whether APEX1 redox activity is required on the VEGF promoter specifically was not tested with separation-of-function mutants
    • Nuclear export signal identity not mapped to specific residues
  9. 2021 High

    Identification of p300-dependent acetylation as the trigger for APEX1 nuclear translocation under oscillatory shear stress, driving NF-κB-dependent inflammation and atherogenesis in vivo, connected the protein's post-translational regulation to cardiovascular disease.

    Evidence Co-IP (p300–APEX1), acetylation assays, endothelial-specific conditional KO mouse with carotid ligation model

    PMID:34810252

    Open questions at the time
    • Specific acetylation sites on APEX1 mediating nuclear translocation not fully mapped
    • Whether acetylation affects endonuclease catalytic activity directly was not tested
  10. 2021 High

    Separation-of-function mutagenesis (C65A) and pharmacological redox inhibition demonstrated that APEX1 activates NRF2 through a redox-dependent mechanism requiring GSK-3β inactivation, identifying a new downstream cytoprotective pathway.

    Evidence siRNA knockdown with WT vs. C65A reconstitution, E3330 redox inhibitor, ARE-luciferase reporter, Western blot in esophageal adenocarcinoma cells

    PMID:33887608

    Open questions at the time
    • Whether APEX1 directly reduces a specific cysteine on GSK-3β or acts indirectly is unclear
    • Relevance beyond Barrett's esophagus/adenocarcinoma model not tested
  11. 2024 High

    Conditional T cell-specific Apex1 deletion proved that endonuclease activity (not redox function) is required for T effector cell generation, as abasic-site accumulation during proliferation causes genomic instability and apoptosis, and chemical APE1 inhibitors blocked autoimmune disease.

    Evidence Conditional KO in T cells, domain-separation mutagenesis, abasic-site quantification, autoimmune disease models, chemical inhibitor treatment

    PMID:39739423

    Open questions at the time
    • Whether the redox function contributes to T cell differentiation or cytokine signaling independently was not fully excluded
    • Long-term immunological consequences of APE1 inhibition unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the N-terminal redox domain's mechanism (no high-resolution structure of the reduced/oxidized Cys-65 region exists), how APEX1's repair and redox functions are coordinately regulated by post-translational modifications in different cellular contexts, and whether selective pharmacological targeting of one function spares the other in vivo.
  • No crystal structure of redox-active N-terminal domain in reduced vs. oxidized states
  • Comprehensive acetylation/phosphorylation site map with functional assignments lacking
  • Therapeutic index of endonuclease-selective vs. redox-selective inhibitors not established in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 6 GO:0016491 oxidoreductase activity 5 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 3
Pathway
R-HSA-73894 DNA Repair 7 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1
Partners
EP300HIF1ANFE2L2NFKB1PAX8TP53TXNXRCC1
Complex memberships
BER complex (with XRCC1)SET complex (with SET, pp32, HMG-2, NM23-H1)

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The human APE/APEX1 cDNA was cloned and shown to encode the major nuclear AP endonuclease. The predicted protein is a member of a conserved DNA repair enzyme family (including bacterial ExoA and ExoIII, and Drosophila Rrp1). Expressed human Ape protein conferred resistance to methyl methanesulfonate in AP endonuclease-deficient E. coli, establishing enzymatic function in vivo. cDNA cloning, functional complementation in endonuclease-deficient bacteria, protein purification Proceedings of the National Academy of Sciences of the United States of America High 1722334
1992 Ref-1 (APEX1) was identified as a bifunctional protein: its gene product both stimulates DNA binding activity of Fos-Jun heterodimers, Jun-Jun homodimers, NF-κB, Myb, and ATF/CREB transcription factors via a redox mechanism, and possesses AP endonuclease DNA repair activity. Immunodepletion showed Ref-1 is the major AP-1 redox activity in HeLa nuclear extracts. The redox and DNA repair activities are biochemically separable. Protein purification, in vitro DNA-binding (EMSA), immunodepletion of nuclear extracts, AP endonuclease assay The EMBO journal High 1380454
1994 Ref-1 (APEX1) was identified as an nCaRE (negative calcium-responsive element) binding protein that mediates Ca2+-dependent transcriptional repression of the PTH gene. Anti-Ref-1 antibody eliminated the nCaRE-protein complex. Antisense Ref-1 expression experiments in cultured cells demonstrated that Ref-1-DNA interaction leads to Ca2+-dependent transcriptional suppression, establishing a transcriptional repressor activity for APEX1. Southwestern cloning, gel shift assay with antibody supershift, antisense expression vector experiments The Journal of biological chemistry Medium 7961715
1997 Ref-1 (APEX1) was identified as a potent activator of p53 DNA-binding activity by both redox-dependent and redox-independent mechanisms. Ref-1 was purified from HeLa nuclear extracts based on its ability to stimulate latent p53 DNA binding. Oxidized p53 (full-length and truncated p53Δ30) is stimulated by Ref-1; in the presence of reducing agent, Ref-1 potently stimulates full-length but not p53Δ30, indicating both redox and non-redox modes. Ref-1 also stimulates p53 transactivation in vivo. Protein purification from HeLa extracts, EMSA, in vitro transcription assay, in vivo transactivation assay Genes & development High 9119221
1997 AP-1 transcriptional activity is regulated by a direct molecular cascade: thioredoxin (TRX) translocates to the nucleus upon phorbol ester stimulation and directly associates with Ref-1 (APEX1), requiring TRX catalytic cysteine residues. Co-overexpression of TRX and Ref-1 in COS-7 cells potentiated AP-1 activity only after nuclear TRX translocation. Direct TRX–Ref-1 association was confirmed by in vitro diamide-induced cross-linking and in vivo mammalian two-hybrid assay. In vitro cross-linking, mammalian two-hybrid assay, co-overexpression in COS-7 cells, site-directed mutagenesis of TRX cysteines Proceedings of the National Academy of Sciences of the United States of America High 9108029
1997 APEX1 (HAP1/Ref-1) is the major human AP endonuclease. Its repair function resides in the C-terminal region while redox activation of transcription factors involves the N-terminal ~6 kDa fragment, with Cys-65 being essential for redox activity. Active-site residues were defined through structural and mutagenesis studies, establishing the two-domain functional architecture. Active-site mutagenesis, domain deletion analysis, enzymatic assays Oncology research Medium 9406232
1998 Ref-1 (APEX1) controls Pax-8 paired domain DNA-binding activity via redox regulation in vitro. In co-transfection experiments, Ref-1 increased Pax-8 transactivation of the thyroglobulin promoter. Immunoreactivity data indicated that Ref-1 levels in thyroid cell nuclear extracts correlate with amounts of reduced Pax-8, suggesting that redox regulation of the Pax-8 paired domain occurs in vivo. In vitro DNA-binding assay, co-transfection, immunoreactivity analysis of nuclear extracts Biochemical and biophysical research communications Medium 9813166
1998 APEX1 (APE-1) gene expression is selectively induced by sublethal levels of reactive oxygen species (ROS) and ROS generators including ionizing radiation, but not by UV or alkylating agents. Increased APE mRNA and protein were accompanied by nuclear translocation of the endonuclease. ROS-treated cells showed increased resistance to cytotoxic ROS generators but not UV, suggesting an adaptive response mediated by enhanced APE-1 repair activity. Northern/Western blot, immunofluorescence for nuclear translocation, cytotoxicity assays in HeLa and WI-38 cells Proceedings of the National Academy of Sciences of the United States of America High 9560228
1999 Overexpression of HAP1/APEX1 in CHO cells sensitized them to bioreductive drugs (mitomycin C, porfiromycin, daunorubicin, aziridinyl benzoquinone) but not to methylmethanesulfonate, bleomycin, or H2O2. A mutant HAP1 with intact AP-endonuclease activity but deleted redox function abolished sensitization to bioreductive drugs, demonstrating that the redox function specifically mediates activation of these compounds. Stable transfection, cytotoxicity assays, site-directed mutagenesis separating repair from redox domains Carcinogenesis High 10190555
1999 TRX potentiates Ref-1 (APEX1)-mediated activation of p53 DNA binding and p53-dependent p21 transactivation. Transdominant-negative TRX mutant suppressed both TRX and Ref-1 effects on p53. Cisplatin-induced p53 activation and p21 transactivation were inhibited by dominant-negative TRX, and cisplatin stimulated TRX nuclear translocation, establishing a redox cascade: TRX → Ref-1 → p53 → p21. EMSA, luciferase transactivation assay, Western blot, dominant-negative mutant overexpression, immunofluorescence The Journal of biological chemistry High 10585464
2000 Three co-crystal structures of human APE1 bound to abasic DNA showed that APE1 uses a rigid, pre-formed positively charged surface to kink DNA and engulf the AP-DNA strand. APE1 inserts loops into both DNA major and minor grooves and binds a flipped-out AP site in a base-excluding pocket. Active-site geometry with Mn2+ supports a catalytic mechanism. Alanine substitutions of DNA-helix-penetrating residues showed APE1 is structurally optimized to retain the cleaved product, suggesting coordination of glycosylase displacement and product hand-off. X-ray crystallography (co-crystal structures), active-site mutagenesis (alanine substitutions), enzymatic assays Nature High 10667800
2000 Substitution of Asp-210 in HAP1 (APEX1) by Asn or Ala eliminates AP endonuclease activity; substitution by Glu reduces specific activity ~500-fold with a 3000-fold reduced kcat but unchanged Km, demonstrating Asp-210 is required for catalysis but not substrate recognition. Mutant proteins retained efficient binding to AP-site-containing oligonucleotides and pBQ-adducted substrates, and the D210 substitution mutants formed stable HAP1-substrate complexes that normally exist only transiently. Site-directed mutagenesis, in vitro AP endonuclease assay, enzyme kinetics (Km, kcat), electrophoretic mobility shift assay Nucleic acids research High 10871340
2001 XRCC1 physically interacts with APE1 (HAP1/APEX1) and stimulates its AP endonuclease and 3'-phosphodiesterase activities. APE1 lacking its first 35 amino acids is catalytically competent but loses XRCC1 affinity and is not stimulated by XRCC1. XRCC1-mutant cell lines show diminished AP-site repair capacity that is rescued by XRCC1 reconstitution, establishing XRCC1 as a scaffold/modulator that coordinates AP-site incision and repair synthesis steps. Co-immunoprecipitation, in vitro enzymatic stimulation assay, cell-line mutants, domain deletion analysis The EMBO journal High 11707423
2002 Selenomethionine (SeMet) activates p53 via a redox mechanism requiring Ref-1 (APEX1). A dominant-negative Ref-1 blocked SeMet-dependent p53 oxidation/reduction. A peptide containing only p53 Cys275 and Cys277 showed a SeMet-induced response, identifying these cysteines as key mediators. SeMet induced sequence-specific p53 DNA binding, transactivation, and preferentially activated the DNA repair branch of the p53 pathway in mouse embryo fibroblasts. Redox assay for p53, dominant-negative Ref-1, peptide substrate assay, EMSA, MEF p53-null comparison Proceedings of the National Academy of Sciences of the United States of America Medium 12357032
2003 APE/Ref-1 (APEX1) negatively regulates the activity of the Ras-related GTPase Rac1. The protein is involved in repair of oxidative/alkylating DNA damage and in redox-dependent and -independent transcriptional regulation of AP-1, NF-κB, HIF-1, and p53. APEX1 expression is inducible by oxidative stress and its overexpression protects cells against ROS-induced genotoxicity, while downregulation sensitizes cells, establishing its role in the adaptive cellular response to oxidative stress. Transfection with truncated proteins separating repair vs. redox activities, cytotoxicity assays, Rac1 activity assays Toxicology Medium 14599768
2003 Ape1 (APEX1) is part of a GzmA-activated SET complex (together with pp32, SET, HMG-2) localized to the ER. GzmA cleaves SET, releasing its inhibition of NM23-H1 (GAAD), enabling NM23-H1 to nick chromosomal DNA during caspase-independent apoptosis. Ape1 is a constituent of this ER-associated complex implicated in CTL-mediated apoptosis. Biochemical co-purification, co-immunoprecipitation, RNAi silencing of NM23-H1, immunofluorescence, GzmA cleavage assays Cell Medium 12628186
2004 MUTYH prevents mAPEX1 from incising the AP site generated at A:8-oxoG positions after adenine excision. Recombinant mMUTYH efficiently blocked mAPEX1 incision of the AP site it generated opposite 8-oxoG, but not AP sites generated by uracil DNA glycosylase. MUTYH mutants R361A and G365D (C-terminal domain) failed to protect the AP site from APEX1 incision, demonstrating the C-terminal domain of MUTYH is required to prevent inappropriate processing by APEX1. In vitro reconstitution with recombinant proteins, site-directed mutagenesis of MUTYH, cell-free extract assays from thymocytes, EMSA Nucleic acids research High 15199168
2005 APEX1 nuclear localization requires its N-terminal 20 amino acids. The first 7 residues and residues 8–13 (E12/D13) can independently promote nuclear import. APEX1 interacts with karyopherin alpha 1 and 2 (nuclear importins) in a manner requiring these N-terminal residues. Treatment with the nuclear export inhibitor leptomycin B revealed a previously unidentified nuclear export signal, indicating APEX1 subcellular distribution is regulated by both nuclear import and export. EGFP fusion live-cell imaging, deletion mutagenesis, far-western analysis, immuno-pull-down, leptomycin B treatment Nucleic acids research High 15942031
2005 Strong RNAi-mediated knockdown of Ape1 (APEX1) in multiple human cell types stopped cell proliferation and activated apoptosis, correlated with accumulation of abasic DNA damage. These effects were rescued by yeast Apn1, which shares AP endonuclease activity but lacks Ref1 redox function and human Ape1 protein interactions. This genetic epistasis demonstrates that AP endonuclease activity—not redox regulation—is the essential vital function of APEX1. RNAi knockdown, expression of heterologous Apn1 for functional complementation, flow cytometry (apoptosis), DNA damage assays Molecular cell High 15694346
2005 Ref-1 (APEX1), p53, and Brca1 form a protein complex in response to selenomethionine treatment. SeMet induced Ref-1 and p53 proteins, Brca1 and Ref-1 were shown to interact concurrently with p53, and Brca1-null mouse fibroblasts lost SeMet-mediated DNA damage protection, establishing that Brca1 is required alongside Ref-1 for selenium-driven DNA repair activation via the p53 pathway. Co-immunoprecipitation, Brca1-null MEF comparison, UV-damage protection assays Anticancer research Medium 16619485
2005 8-OxoA in tandem with an AP site on the same DNA strand inhibits HAP1 (APEX1) incision of the AP site when 8-oxoA is 3' to the AP site and separated by up to two bases, but not in the 5' orientation or at greater distances. This demonstrates that APEX1 activity can be impaired by adjacent oxidative base lesions in clustered DNA damage. In vitro incision assay with synthetic oligonucleotides containing defined tandem lesions, comparison with E. coli glycosylases Fpg and Nth Radiation research Medium 15606310
2005 HIF-1α, STAT3, CBP/p300, and Ref-1/APE (APEX1) form a transcriptional complex on the VEGF promoter under hypoxia-mimicking conditions. Src activation is required for this complex formation. Both STAT3 and HIF-1α must bind the VEGF promoter simultaneously for maximum VEGF transcription. Ref-1/APE is a component of this promoter complex, indicating its role in hypoxia-driven oncogenic transcription. ChIP, co-immunoprecipitation, dominant-negative transfection of STAT3 and HIF-1α, Src inducible expression system Oncogene Medium 15735682
2007 In ischemia-preconditioned myocardium, Ref-1 (APEX1) undergoes nuclear translocation and physically associates with NF-κB and Nrf2 in the nucleus (confirmed by co-immunoprecipitation). This Ref-1 activation generates a survival signal evidenced by increased Akt phosphorylation, which is abolished by antisense Ref-1. Trx-1 association with NF-κB is also increased in adapted heart in a Ref-1-dependent manner. Confocal microscopy confirmed 3D nuclear colocalization of Ref-1 with NF-κB. Antisense Ref-1 treatment, co-immunoprecipitation of nuclear extracts, confocal microscopy, Western blot for Akt phosphorylation Free radical biology & medicine Medium 17602955
2013 APEX1 overexpression or knockdown in human colon cancer cells profoundly altered malignant properties (proliferation, anchorage-independent growth, migration, invasion, angiogenesis in vitro; tumor formation and metastasis in xenograft models). These oncogenic effects were mediated by APEX1-driven upregulation of Jagged1, a Notch ligand. APEX1 expression positively correlated with Jagged1 in colon cancer cell lines and patient tissues, identifying APEX1 as an upstream activator of Jagged1/Notch signaling. Stable overexpression/knockdown, anchorage-independent growth assay, transwell invasion/migration, xenograft mouse model, co-expression analysis in patient tissue The Journal of clinical investigation Medium 23863623
2019 AP endonuclease 1 (Apex1) in zebrafish is required for normal brain development. Apex1 knockdown increased ROS, 8-oxoguanine, and abasic sites, reduced Ogg1, Polb, and Ogg1 protein levels, and caused maldistribution/loss of four brain transcription factors (fezf2, otx2, egr2a, pax2a) independently of p53. Conversely, H2O2 exposure increased Apex1 and other BER components. Apex1 also regulates Creb1 transcription factor expression, linking oxidative stress, BER, and brain transcriptional programs. Morpholino knockdown in zebrafish, ROS/8-oxoguanine/abasic site quantification, immunofluorescence, Western blot Cell death & disease Medium 31024003
2019 P53 negatively regulates APE1/Ref-1 (APEX1) in lung microvascular endothelial cells, and APE1/Ref-1 disrupts endothelial barrier function. Pharmacologic and genetic P53 modulators were used to demonstrate this negative regulatory relationship, with real-time permeability measurements confirming that APE1/Ref-1 activity promotes endothelial permeability. Pharmacologic P53 modulation, genetic P53 manipulation, real-time endothelial permeability measurements Immunobiology Low 31023490
2021 Oscillatory shear (OS) promotes APEX1 nuclear translocation via p300 acetyltransferase-mediated acetylation of APEX1. OS promotes binding of p300 to APEX1, leading to its acetylation and nuclear translocation. Knockdown of APEX1 reversed OS-induced proinflammatory (NF-κB-dependent) phenotype. Endothelial-specific APEX1 deletion in mice ameliorated atherogenesis. Physical interaction between vitexin (a flavonoid) and APEX1 was experimentally verified and vitexin inhibited APEX1 nuclear translocation and atherogenesis. siRNA knockdown, endothelial-specific conditional knockout mouse model, co-immunoprecipitation (p300-APEX1), acetylation assays, confocal microscopy, carotid partial ligation model Proceedings of the National Academy of Sciences of the United States of America High 34810252
2021 APEX1 regulates HIF-1α and downstream cellular functions (ROS production, carbonic anhydrase 9-mediated intracellular pH, migration, angiogenesis) in hypoxic lung cancer cells. APEX1 physically interacts with HIF-1α (verified experimentally), and this interaction is inhibited by cephalomannine (CPM) in vitro and in vivo. APEX1/HIF-1α pathway inhibition by CPM suppressed hypoxia-driven malignant properties. Co-immunoprecipitation (APEX1–HIF-1α), siRNA knockdown, xenograft mouse model, ROS/pH/migration/angiogenesis functional assays Cell death & disease Medium 33990544
2021 APE1/REF1 (APEX1) activates NRF2 in a redox-dependent manner in Barrett's-related esophageal adenocarcinoma. Acidic bile salts (ABS) induced concordant increases in APE1 and NRF2. APE1 knockdown reduced NRF2 protein stability, nuclear localization, and transcription activation. Reconstitution with wild-type but not redox-deficient C65A APE1 mutant, or treatment with redox inhibitor E3330, demonstrated redox-dependence. Mechanistically, APE1 redox function was required for phosphorylation and inactivation of GSK-3β, thereby preventing NRF2 degradation. siRNA knockdown with WT and C65A mutant reconstitution, pharmacological redox inhibitor (E3330), ARE luciferase reporter, Western blot, nuclear fractionation Redox biology High 33887608
2021 APEX1 deletion in SGC-7901 gastric cancer cells (via CRISPR/Cas9) attenuated cell growth, metastatic properties, and doxorubicin resistance. miR-27a-5p was validated as targeting APEX1 and suppressing APEX1-dependent gastric cancer progression and drug resistance via RAS/MEK/FOS and PTEN/AKT/SMAD2 pathways. APEX1 promotes doxorubicin resistance by altering MAPK and AKT pathway regulation. CRISPR/Cas9 APEX1 deletion, miRNA-target validation, Western blot for pathway proteins, functional assays (proliferation, invasion, drug sensitivity) International journal of pharmaceutics Medium 33675923
2024 Conditional deletion of Apex1 specifically in T cells caused accumulation of baseless DNA sites (abasic sites) in proliferating T cells, leading to genomic instability and apoptotic cell death. Apex1-deleted T cells failed to acquire effector features after activation and could not mediate autoimmune diseases or allergic tissue damage. Mutagenesis pinpointed the endonuclease domain (not the redox domain) as essential for T effector cell generation. Chemical inhibitors of Apex1 base repair activity similarly abrogated autoimmune disease induction. Conditional T cell-specific knockout, abasic site quantification, mutagenesis of endonuclease vs. redox domains, autoimmune disease mouse models, chemical inhibitor treatment The Journal of clinical investigation High 39739423

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
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
2011 Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 1055 21496894
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
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
1992 Redox activation of Fos-Jun DNA binding activity is mediated by a DNA repair enzyme. The EMBO journal 849 1380454
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1997 AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proceedings of the National Academy of Sciences of the United States of America 698 9108029
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
2000 DNA-bound structures and mutants reveal abasic DNA binding by APE1 and DNA repair coordination [corrected]. Nature 640 10667800
2013 Great ape genetic diversity and population history. Nature 586 23823723
2010 An atlas of combinatorial transcriptional regulation in mouse and man. Cell 573 20211142
1991 Cloning and expression of APE, the cDNA encoding the major human apurinic endonuclease: definition of a family of DNA repair enzymes. Proceedings of the National Academy of Sciences of the United States of America 479 1722334
2003 Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 439 12628186
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. American journal of epidemiology 431 16221808
1997 Identification of redox/repair protein Ref-1 as a potent activator of p53. Genes & development 423 9119221
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2001 XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein-protein interactions. The EMBO journal 392 11707423
2017 Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nature biotechnology 378 28319085
2005 Akt/PKB regulates actin organization and cell motility via Girdin/APE. Developmental cell 378 16139227
1998 Activation of apurinic/apyrimidinic endonuclease in human cells by reactive oxygen species and its correlation with their adaptive response to genotoxicity of free radicals. Proceedings of the National Academy of Sciences of the United States of America 359 9560228
1999 Thioredoxin-dependent redox regulation of p53-mediated p21 activation. The Journal of biological chemistry 356 10585464
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2005 Polymorphisms of DNA repair genes and risk of non-small cell lung cancer. Carcinogenesis 333 16195237
2005 HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 329 15735682
2004 Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5alpha. Proceedings of the National Academy of Sciences of the United States of America 319 15249685
2014 The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. The Journal of neuroscience : the official journal of the Society for Neuroscience 300 24453320
2004 The human and African green monkey TRIM5alpha genes encode Ref1 and Lv1 retroviral restriction factor activities. Proceedings of the National Academy of Sciences of the United States of America 291 15249687
1989 Functional dissection and sequence of yeast HAP1 activator. Cell 279 2643482
1997 Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Human molecular genetics 275 9361024
2005 A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells. Molecular cell 234 15694346
2002 Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. Proceedings of the National Academy of Sciences of the United States of America 215 12357032
2013 Dual regulation of cytosolic ascorbate peroxidase (APX) by tyrosine nitration and S-nitrosylation. Journal of experimental botany 212 24288182
2010 Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron 211 20152113
2003 Restriction of multiple divergent retroviruses by Lv1 and Ref1. The EMBO journal 204 12554640
1994 The maternal genes apx-1 and glp-1 and establishment of dorsal-ventral polarity in the early C. elegans embryo. Cell 204 8156602
2022 ApE, A Plasmid Editor: A Freely Available DNA Manipulation and Visualization Program. Frontiers in bioinformatics 186 36304290
1999 Molecular mechanism of heme signaling in yeast: the transcriptional activator Hap1 serves as the key mediator. Cellular and molecular life sciences : CMLS 166 11212295
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1994 A redox factor protein, ref1, is involved in negative gene regulation by extracellular calcium. The Journal of biological chemistry 121 7961715
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1992 HAP1 and ROX1 form a regulatory pathway in the repression of HEM13 transcription in Saccharomyces cerevisiae. Molecular and cellular biology 105 1588959
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2021 Vitexin inhibits APEX1 to counteract the flow-induced endothelial inflammation. Proceedings of the National Academy of Sciences of the United States of America 40 34810252
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2004 MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or reaction product with its C-terminal domain. Nucleic acids research 33 15199168
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2022 Nitric Oxide (NO) Differentially Modulates the Ascorbate Peroxidase (APX) Isozymes of Sweet Pepper (Capsicum annuum L.) Fruits. Antioxidants (Basel, Switzerland) 31 35453450
2021 Activation of NRF2 by APE1/REF1 is redox-dependent in Barrett's related esophageal adenocarcinoma cells. Redox biology 30 33887608
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2007 Complex determinants within the Moloney murine leukemia virus capsid modulate susceptibility of the virus to Fv1 and Ref1-mediated restriction. Virology 26 17343889
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2017 DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome. Proceedings of the National Academy of Sciences of the United States of America 25 28137862
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2021 Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours. British journal of cancer 20 33658640
2021 The APEX1/miRNA-27a-5p axis plays key roles in progression, metastasis and targeted chemotherapy of gastric cancer. International journal of pharmaceutics 20 33675923
2019 Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies. Acta neuropathologica communications 20 31036086
2016 Association between Single-Nucleotide Polymorphisms of the hOGG1,NEIL1,APEX1, FEN1,LIG1, and LIG3 Genes and Alzheimer's Disease Risk. Neuropsychobiology 20 27010693
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2019 Serum Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) Level as a Potential Biomarker of Cholangiocarcinoma. Biomolecules 19 31454981