Affinage

APEX1

DNA repair nuclease/redox regulator APEX1 · UniProt P27695

Length
318 aa
Mass
35.6 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APE1/Ref-1 is a multifunctional enzyme that couples DNA base excision repair (BER) to redox-dependent regulation of transcription, with its two activities encoded by separable domains: a non-conserved N-terminal domain mediates cysteine-dependent reductive activation of transcription factors, while conserved C-terminal sequences carry out DNA repair (PMID:7506414). The DNA repair arm performs AP endonuclease incision 5' to abasic sites through a metal- and nucleophile-dependent mechanism, using arginine clamps for product release and molding mismatched bases into Watson-Crick-like geometry to discriminate clustered lesions (PMID:26458045); the same active site also supports 3' mismatch/damage removal by a non-base-flipping, DNA-bending mechanism and exonucleolytic cleavage governed by an induced space-filling RM bridge (PMID:29374164, PMID:33504804), and operates on nucleosomal substrates by sculpting and bending DNA to reach solvent-exposed abasic sites (PMID:36104361). This repair function is the essential cellular activity of APE1, as a repair-only heterologous AP endonuclease rescues the proliferation arrest and apoptosis caused by APE1 depletion (PMID:16199212), and it acts through BER partners XRCC1 and DNA polymerase β (PMID:27050370) while initiating SSB end resection via its exonuclease activity in concert with APE2 and PCNA (PMID:31828326). In parallel, the redox function reductively activates transcription factors including p53, Pax-8, AP-1 and STAT3, with p53 stimulated by both redox-dependent and redox-independent mechanisms via direct physical association (PMID:9119221, PMID:10523305, PMID:23094050), and negatively regulates NRF2 independently of repair (PMID:25492865). APE1 has additional RNA-directed roles, possessing 3' RNA phosphatase and 3'-5' exoribonuclease activities at its shared catalytic site (PMID:25498387) and degrading abasic mitochondrial mRNA to sustain mitochondrial translation and respiration (PMID:34224750). Beyond catalysis, an extreme N-terminal motif drives nucleolar condensate assembly that recruits and activates the ATR-Chk1 DNA damage response independently of nuclease and redox functions (PMID:36200829). APE1 localization and secretion are tuned by p300-mediated acetylation, which drives nuclear translocation and NF-κB-dependent inflammatory signaling (PMID:34810252); in vivo, endogenous APE1 protects against ischemic brain injury (PMID:27274063), restrains cellular senescence and premature aging (PMID:29750271), and is required for T effector cell generation and class switch recombination (PMID:18025127, PMID:39739423).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1994 High

    Established that APE1/Ref-1's redox and DNA repair activities are mechanistically and structurally separable, defining the gene as a bifunctional protein rather than a single-activity enzyme.

    Evidence Deletion mutagenesis, cysteine alkylation/oxidation, and crosslinking in vitro

    PMID:7506414

    Open questions at the time
    • Did not resolve atomic basis of either activity
    • Cysteine identity mediating redox activity not pinpointed
  2. 1997 High

    Showed APE1/Ref-1 activates p53 by both redox-dependent and redox-independent routes, broadening its transcriptional regulatory scope beyond simple cysteine reduction.

    Evidence Purified Ref-1 with in vitro DNA-binding and in vivo transactivation assays

    PMID:9119221

    Open questions at the time
    • Structural basis of redox-independent p53 stimulation not defined
    • Physiological stimulus context unaddressed
  3. 1999 High

    Demonstrated a direct physical APE1-p53 interaction that is functionally required for p53 transactivation of target genes and apoptosis, linking redox regulation to a defined transcriptional program.

    Evidence Reciprocal Co-IP and antisense knockdown with promoter-reporter and endogenous gene readouts

    PMID:10523305

    Open questions at the time
    • Interaction interface not mapped
    • Did not separate repair from redox contribution to p53 effects
  4. 1998 Medium

    Extended the redox-coactivator role to Pax-8, showing APE1/Ref-1 reductively activates a tissue-specific transcription factor.

    Evidence In vitro DNA-binding and co-transfection reporter assays in thyroid cells

    PMID:9813166

    Open questions at the time
    • Single-lab cell-based evidence
    • Direct interaction not demonstrated by reciprocal methods
  5. 2006 Medium

    Identified ERp57 as an APE1 partner and component of a reductive activation system, providing a source of reducing equivalents for transcription factor activation under oxidative stress.

    Evidence Co-IP in three cell lines plus DNA-binding and oxidative-stress survival assays

    PMID:16962936

    Open questions at the time
    • Single lab
    • Stoichiometry and direct electron-transfer mechanism unresolved
  6. 2009 High

    Resolved which APE1 activity is essential by complementation, proving the AP endonuclease repair function—not redox—is required for cell viability.

    Evidence siRNA depletion rescued by repair-only S. cerevisiae Apn1, with abasic site quantification

    PMID:16199212

    Open questions at the time
    • Does not address non-essential but physiologically important redox/RNA roles
    • Cell-line context only
  7. 2014 High

    Revealed that APE1's DNA nuclease active site also performs 3' RNA phosphatase and exoribonuclease chemistry, and that common population variants impair this RNA activity.

    Evidence In vitro RNA substrate assays with systematic active-site mutagenesis and variant characterization

    PMID:25498387

    Open questions at the time
    • Cellular RNA substrates not identified in this study
    • Functional consequence of variant RNA defects in vivo unknown
  8. 2014 Medium

    Defined a redox-specific role for APE1 in negatively regulating the NRF2 antioxidant program, cleanly separated from repair and independent of ROS.

    Evidence Genetic and small-molecule (E3330) repression with NRF2 reporter/target assays

    PMID:25492865

    Open questions at the time
    • Direct molecular target of redox action on NRF2 pathway not identified
    • Single lab
  9. 2012 Medium

    Added STAT3 to the set of transcription factors whose DNA binding requires APE1 redox function, reinforcing redox control of oncogenic signaling.

    Evidence Redox-specific mutagenesis, knockdown, and E3330 inhibition with DNA-binding/reporter assays

    PMID:23094050

    Open questions at the time
    • Direct STAT3-APE1 contact not structurally defined
    • Single lab
  10. 2015 High

    Provided the first high-resolution structural basis for AP-site incision, defining the metal/nucleophile site, arginine product-release clamps, and the mechanism of clustered lesion discrimination.

    Evidence Multiple X-ray structures of APE1-DNA complexes with kinetic validation

    PMID:26458045

    Open questions at the time
    • Did not capture exonuclease or RNA substrate states
    • Nucleosomal context not addressed
  11. 2016 High

    Demonstrated an endogenous neuroprotective role for APE1 in vivo, linking its repair function to limiting AP-site accumulation and prodeath signaling after stroke.

    Evidence Tamoxifen-inducible conditional Apex1 knockout in a focal cerebral ischemia model

    PMID:27274063

    Open questions at the time
    • Did not isolate repair vs redox contributions to neuroprotection
    • Cell-type-specific source of protection not fully resolved
  12. 2016 Medium

    Connected disease-associated APE1 variants to defective partner engagement, showing reduced AP endonuclease activity and impaired XRCC1/Pol β association drive genomic stress and growth defects.

    Evidence shRNA-variant complementation with Co-IP and γH2AX/PAR readouts

    PMID:27050370

    Open questions at the time
    • Whether interaction loss is cause or consequence of activity loss unclear
    • Single lab
  13. 2017 Medium

    Implicated APE1 in double-strand break repair pathway choice, favoring BRCA1-mediated HR over error-prone NHEJ and influencing chemoresistance.

    Evidence Knockdown/overexpression with HR/NHEJ reporters and Co-IP with Chk2 and HR proteins

    PMID:28852018

    Open questions at the time
    • Mechanism by which APE1 biases pathway choice not defined
    • Single lab
  14. 2018 High

    Defined the structural mechanism for 3' mismatch/damage removal, showing APE1 places the 3' group intra-helically without base flipping, aided by DNA nicks and bending.

    Evidence Multiple high-resolution APE1-DNA crystal structures with biochemical assays

    PMID:29374164

    Open questions at the time
    • Cellular pathway recruiting this proofreading activity not established
    • Single lab
  15. 2018 High

    Established APE1 as a guardian against senescence and aging, with deficiency causing telomere-associated DNA damage and premature aging features rescuable by telomerase.

    Evidence shRNA in primary fibroblasts plus conditional Apex1 knockout mice with telomere FISH

    PMID:29750271

    Open questions at the time
    • Mechanistic link between APE1 loss and telomere-specific damage incomplete
    • Repair vs other activities not dissected
  16. 2020 Medium

    Showed APE1 senses single-strand breaks and initiates 3'-5' end resection via its exonuclease activity, defining a role in SSB repair and signaling beyond simple incision.

    Evidence Xenopus egg extract and in vitro reconstitution with exonuclease mutant and Co-IP of APE2/PCNA

    PMID:31828326

    Open questions at the time
    • Relative contribution of APE1 vs APE2 resection in human cells unclear
    • Single lab
  17. 2021 High

    Provided a unifying structural model—an induced RM space-filling bridge—explaining how APE1 selects substrates for both endonucleolytic and exonucleolytic cleavage by sterics rather than base identity.

    Evidence X-ray structures of APE1-dsDNA end-binding complexes with activity and binding assays

    PMID:33504804

    Open questions at the time
    • Single lab
    • In-cell relevance of end-binding mode not tested
  18. 2021 Medium

    Uncovered a mitochondrial RNA surveillance function, showing APE1 degrades abasic mitochondrial mRNA to maintain mitochondrial translation and respiration.

    Evidence APE1 depletion with endoribonuclease assays, Seahorse respiration, and translation readouts

    PMID:34224750

    Open questions at the time
    • Full set of mitochondrial RNA substrates not catalogued
    • Single lab
  19. 2021 Medium

    Revealed a non-catalytic scaffolding function: APE1 forms nucleolar condensates that recruit and directly activate the ATR-Chk1 DDR pathway, independent of nuclease and redox activities.

    Evidence Condensate assays, in vitro ATR kinase assay, Co-IP with ATR/TopBP1/ETAA1, and W119R mutagenesis

    PMID:36200829

    Open questions at the time
    • Physiological trigger for nucleolar condensation unclear
    • Single lab
  20. 2022 High

    Extended AP-site incision to chromatin, showing APE1 cleaves solvent-exposed nucleosomal abasic sites via a DNA-sculpting/bending mechanism while occluded sites are protected.

    Evidence Cryo-EM of an APE1-nucleosome complex with kinetic cleavage assays

    PMID:36104361

    Open questions at the time
    • How occluded sites are eventually repaired not resolved
    • Role of chromatin remodelers not addressed
  21. 2021 Medium

    Linked acetylation-controlled APE1 trafficking to vascular inflammation, with p300-driven acetylation promoting nuclear translocation and NF-κB-dependent atherogenesis.

    Evidence Co-IP of p300/APEX1, endothelial-specific Apex1 deletion in a partial ligation mouse model

    PMID:34810252

    Open questions at the time
    • Acetylated residues and NF-κB engagement mechanism not fully mapped
    • Single lab
  22. 2024 High

    Demonstrated the endonuclease repair function is required in vivo for adaptive immunity, with T-cell Apex1 loss causing abasic-site accumulation, genomic instability, and failed T effector generation.

    Evidence Conditional T-cell Apex1 knockout with domain-specific mutagenesis and chemical inhibition in autoimmune models

    PMID:39739423

    Open questions at the time
    • Redox-domain contribution to T-cell function not isolated
    • Substrate context driving the requirement not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How APE1's multiple activities—repair, redox, RNA processing, and condensate scaffolding—are coordinately partitioned across nucleus, nucleolus, mitochondria, and the secreted pool in a single cell remains unresolved.
  • No unified model linking PTM state to activity selection
  • Quantitative partitioning between compartments unknown
  • Crosstalk between redox and repair functions in vivo undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 5 GO:0016787 hydrolase activity 4 GO:0003677 DNA binding 3 GO:0016491 oxidoreductase activity 3 GO:0140110 transcription regulator activity 3 GO:0003723 RNA binding 2 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005634 nucleus 3 GO:0005739 mitochondrion 2 GO:0005576 extracellular region 1 GO:0005730 nucleolus 1
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
APEX2EP300MAPK1PCNAPDIA3POLBTP53XRCC1

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 The redox and DNA repair activities of APE1/Ref-1 are encoded by distinct, non-overlapping domains: the N-terminal domain (not conserved in other organisms) is required for redox activity, while conserved C-terminal sequences are required for DNA repair activity. Chemical alkylation or oxidation of cysteine sulfhydryls inhibits redox activity without affecting DNA repair activity. Crosslinking studies suggest a direct cysteine-mediated interaction between Ref-1 and Jun. Deletion mutagenesis, chemical alkylation/oxidation of cysteines, crosslinking assays, in vitro functional assays Proceedings of the National Academy of Sciences of the United States of America High 7506414
1997 APE1/Ref-1 is a potent activator of p53 DNA-binding activity, acting by both redox-dependent and redox-independent mechanisms. Purified Ref-1 from HeLa nuclear extracts stimulates DNA binding by latent, oxidized p53. In the presence of reducing agent, Ref-1 stimulates full-length p53 but not the C-terminally truncated p53Δ30, indicating a redox-independent mechanism requiring the p53 C-terminus. Ref-1 also stimulates p53 transactivation in vivo. Protein purification from HeLa nuclear extracts, in vitro DNA-binding assays, in vivo transactivation assays, oxidized p53 stimulation assays Genes & development High 9119221
1998 APE1/Ref-1 stimulates the DNA-binding activity of the Pax-8 paired domain in vitro and enhances Pax-8-dependent transcriptional activation of the thyroglobulin promoter in co-transfection experiments, with nuclear Ref-1 levels correlating with reduced (active) Pax-8 levels in thyroid cell nuclear extracts. In vitro DNA-binding assay, co-transfection/reporter gene assay, immunoreactivity analysis of nuclear extracts Biochemical and biophysical research communications Medium 9813166
1999 Ref-1 associates physically with p53 in vivo and in vitro. Ref-1 overexpression enhances p53 transactivation of multiple target promoters (p21, cyclin G, Bax) and increases p53-induced apoptosis. Antisense-mediated downregulation of Ref-1 markedly reduces p53 induction of p21 mRNA/protein and p53 transactivation of p21 and Bax promoters. Co-immunoprecipitation (in vivo and in vitro), antisense knockdown, reporter gene assays, endogenous gene expression analysis The EMBO journal High 10523305
2006 ERp57 (a protein disulfide isomerase) interacts with APE1/Ref-1 in vivo (by immunoprecipitation in HepG2, M14, and Raji cells). Oxidative stress increases nuclear Ref-1 associated with ERp57. ERp57 reduced by the thioredoxin-reductase/thioredoxin system stimulates AP-1 binding to DNA, and cells overexpressing ERp57 are protected against H2O2-induced cell killing, demonstrating cooperative activity between ERp57 and Ref-1 in reductive activation of transcription factors. Co-immunoprecipitation in multiple cell lines, DNA-binding assay, overexpression with oxidative stress challenge Free radical biology & medicine Medium 16962936
2007 Both APE1 and APE2 function in immunoglobulin class switch recombination (CSR) in mice. Mice haploinsufficient for APE1 (and deficient in APE2) show reduced CSR and decreased double-strand breaks in switch regions, placing APE1 downstream of abasic site generation (by UNG) in the CSR pathway and demonstrating a novel in vivo function for APE1 in converting abasic sites to single-strand and double-strand breaks required for CSR. Genetic mouse models (haploinsufficiency, knockout), CSR assay, DSB measurement The Journal of experimental medicine High 18025127
2008 APE1/Ref-1 regulates PTEN expression via Egr-1. Acetylation of APE1 enhances its binding to distinct trans-acting complexes involved in activation or repression of the PTEN promoter. The acetylated form is deacetylated by histone deacetylases in vivo. H2O2 and HDAC inhibitors increase APE1 acetylation and PTEN induction; this induction is absent in APE1-depleted cells. Acetylatable APE1 is required for PTEN gene activation. siRNA knockdown, overexpression, HDAC inhibitor treatment, promoter-reporter assay, co-immunoprecipitation Free radical research Medium 18324520
2009 APE1 depletion by siRNA causes arrest of cell proliferation and apoptosis in human cell lines in culture, correlated with accumulation of unrepaired abasic DNA damage. All effects are reversed by expression of S. cerevisiae Apn1, which shares only the AP endonuclease repair function with Ape1, demonstrating that the essential cellular function of APE1 is its DNA repair (AP endonuclease) activity. RNA interference (siRNA), complementation with heterologous AP endonuclease (Apn1), cell proliferation and apoptosis assays, abasic site accumulation measurement DNA repair High 16199212
2012 STAT3 DNA-binding and transcriptional activity is directly regulated by the redox function of APE1/Ref-1. Pharmacological blockade of APE1/Ref-1 redox function with E3330 abrogates STAT3 DNA binding. A redox-specific APE1 mutant strategy and gene knockdown confirmed the redox-dependence of this regulation. Overexpression, redox-specific mutagenesis, siRNA knockdown, redox inhibitor (E3330) treatment, reporter gene/DNA-binding assays PloS one Medium 23094050
2014 APE1 has 3' RNA phosphatase and 3'-5' exoribonuclease activities that share the same active site as its DNA nuclease activities, as demonstrated by site-directed mutagenesis of active-site residues (H309N, H309S, D283N, N68A, D210N, Y171F, D308A, F266A, D70A) that abolish 3' RNA phosphatase activity. Several population variants including the common D148E variant show >80% reduction in 3' RNA phosphatase activity. In vitro RNA substrate assays, site-directed mutagenesis of active-site residues, functional characterization of population variants Journal of molecular biology High 25498387
2014 APE1/Ref-1 redox function negatively regulates NRF2: repression of Ref-1 (by genetic or small molecule inhibitor approaches) potently activates NRF2 and its downstream targets in a dose-dependent fashion. This effect requires the redox function, not the DNA repair function, of APE1, and does not involve reactive oxygen species. siRNA/shRNA knockdown, small molecule inhibitor (E3330), NRF2 reporter/target gene assays, genetic and pharmacological dissection of redox vs. repair functions The Journal of biological chemistry Medium 25492865
2015 High-resolution crystal structures of human APE1 bound to DNA revealed: (1) the metal-binding site and nucleophile for AP-site incision; (2) arginine clamps that mediate product release; and (3) that a T-G mismatch 5' to the AP site is molded into a Watson-Crick-like geometry that distorts the active site and reduces incision efficiency, providing the molecular basis for clustered lesion processing. X-ray crystallography (multiple high-resolution APE1-DNA complex structures), kinetic/activity assays Nature structural & molecular biology High 26458045
2016 Endogenous APE1 protects against ischemic infarction in both gray and white matter. Conditional knockout of Apex1 in mice dramatically enlarges infarct volume, increases AP sites, and activates prodeath signaling (PUMA and PARP1) after focal cerebral ischemia. APE1 cKO also worsens demyelination and axonal conduction, demonstrating a role for endogenous APE1 in neurological recovery after stroke. Conditional knockout mouse (tamoxifen-inducible Cre), focal cerebral ischemia model, AP site measurement, γ-H2AX/PUMA/PARP1 signaling, behavioral/electrophysiological readouts Proceedings of the National Academy of Sciences of the United States of America High 27274063
2016 APE1 variants D283G, L104R, and R237C have reduced AP endonuclease activity and impaired ability to associate with XRCC1 and DNA polymerase β (downstream BER partners), leading to persistent H2AX phosphorylation, elevated PAR protein levels, and growth defects through combined apoptotic and autophagic processes even without exogenous stress. shRNA silencing with variant complementation, Co-immunoprecipitation with XRCC1 and Pol β, γ-H2AX and PAR assays, cell growth analysis Oncotarget Medium 27050370
2017 APE1 facilitates BRCA1-mediated homologous recombination (HR) repair while counteracting error-prone non-homologous end joining of DNA double-strand breaks. APE1, coordinated with checkpoint kinase Chk2, regulates drug response of glioblastoma cells, and suppression of APE1/Chk2 signaling facilitates alternative HR protein recruitment. APE1 knockdown/overexpression, HR and NHEJ reporter assays, co-immunoprecipitation with Chk2 and HR proteins, glioblastoma cell drug response assays Scientific reports Medium 28852018
2018 High-resolution APE1-DNA crystal structures with 3' mismatches and DNA damage reveal that APE1 removes 3' mismatches and 3' damage by placing the 3' group within the intra-helical DNA cavity via a non-base-flipping mechanism. This process is facilitated by a DNA nick, instability of the mismatched/damaged base, and DNA bending by APE1. X-ray crystallography (multiple high-resolution APE1-DNA structural snapshots with mismatches/damage), biochemical activity assays Nature communications High 29374164
2018 APE1 deficiency (via shRNA in primary human fibroblasts) induces cellular senescence associated with global DNA damage accumulation, induction of p16INK4a and p21WAF1, and pronounced DNA damage response (γ-H2AX) particularly at telomeres. Conditional Apex1 knockout in post-natal mice causes impaired growth, reduced organ size, increased cellular senescence, and premature aging features. Telomerase expression prevents the senescence phenotype. shRNA knockdown in primary fibroblasts and telomerase-expressing cells, conditional knockout mouse, γ-H2AX/p16/p21 assays, telomere FISH Nucleic acids research High 29750271
2020 APE1 senses DNA single-strand breaks (SSBs) and initiates 3'-5' SSB end resection via its exonuclease activity. APE1's exonuclease activity is critical for both SSB repair and SSB signaling in Xenopus egg extracts and in vitro reconstitution. APE1 interacts with APE2 and PCNA (though PCNA is dispensable for APE1 exonuclease activity). An APE1 exonuclease-deficient mutant identified in cancer tissue lacks this SSB repair function. Xenopus egg extract system, in vitro reconstitution, exonuclease mutant analysis, Co-IP of APE1 with APE2 and PCNA Nucleic acids research Medium 31828326
2021 APE1 distinguishes DNA substrates in exonucleolytic cleavage by an induced space-filling mechanism. Binding dsDNA induces an RM (Arg176 and Met269) bridge that defines a long and narrow product pocket, providing substrate selectivity based on hydrophobicity and steric hindrance rather than base identity. Crystal structures of APE1-dsDNA complexes displaying end-binding were determined, and both endonucleolytic and exonucleolytic cleavage are explained by this induced space-filling model. X-ray crystallography of APE1-dsDNA end-binding complexes, enzymatic activity assays, binding affinity measurements for varied substrates Nature communications High 33504804
2021 Mitochondrial APE1 degrades dysfunctional (abasic) mitochondrial mRNA via endoribonuclease activity. Loss of APE1 results in accumulation of damaged mitochondrial mRNA, impaired mitochondrial protein translation, reduced expression of mitochondrial-encoded proteins, and less efficient mitochondrial respiration (oxidative phosphorylation). APE1 knockdown/depletion, mitochondrial mRNA association assays, endoribonuclease activity on abasic RNA, mitochondrial respiration (Seahorse), protein translation assays Journal of molecular biology Medium 34224750
2021 Oscillatory shear stress promotes acetylation of APE1 by acetyltransferase p300, leading to APE1 nuclear translocation. Nuclear APE1 promotes inflammation by orchestrating the NF-κB pathway. Endothelial-specific deletion of APEX1 ameliorates atherogenesis in a partial ligation mouse model, and overexpression of APEX1 negates the anti-inflammatory effect of vitexin. Co-immunoprecipitation of p300 with APEX1, siRNA knockdown, endothelial-specific APEX1 deletion (mouse), overexpression, NF-κB pathway analysis, carotid partial ligation model Proceedings of the National Academy of Sciences of the United States of America Medium 34810252
2022 APE1 assembles biomolecular condensates via its extreme N-terminal motif in nucleoli, recruits ATR and its activators TopBP1 and ETAA1, and directly activates ATR to phosphorylate Chk1 in vitro. This activity is independent of APE1 nuclease and redox functions. A W119R mutant is deficient in nucleolar condensation and cannot activate the nucleolar ATR DDR pathway or ATR kinase in vitro. APE1 overexpression/knockdown, biomolecular condensate assays in vitro and in cells, in vitro ATR kinase assay, nucleolar co-localization with NPM1, Co-IP with ATR/TopBP1/ETAA1, W119R mutagenesis Nucleic acids research Medium 36200829
2022 APE1 cleaves solvent-exposed AP sites in nucleosomes with 3–6 orders of magnitude higher efficiency than occluded AP sites. A cryo-EM structure of APE1 bound to a nucleosome containing a solvent-exposed AP site reveals that APE1 uses a DNA sculpting mechanism, bending the nucleosomal DNA to access the AP site. Occluded AP sites are blocked by contacts between nucleosomal DNA and the histone octamer. Cryo-electron microscopy (APE1-nucleosome complex), kinetic AP site cleavage assays, biochemical analysis of nucleosomal substrates Nature communications High 36104361
2016 Secreted APE1/Ref-1, whose secretion is triggered by acetylation, inhibits TNF-α binding to TNFR1 by inducing a conformational change (thiol-disulfide exchange) in the TNF receptor 1. Recombinant APE1/Ref-1 with reducing activity induced conformational change in rh-TNFR1, and neutralizing anti-APE1 antibody reversed the anti-inflammatory effect, recovering ROS generation and VCAM-1 upregulation. Recombinant protein treatment, anti-APE1 neutralizing antibody, thiol-disulfide exchange assay with rh-TNFR1, VCAM-1/ROS measurement Scientific reports Medium 26964514
2013 APE1 redox activity prevents oxidative inactivation of ERK2, forming a direct complex with ERK2 and rescuing ERK kinase activity from ROS-induced inactivation. This effect is dependent on Cys65-mediated redox activity and facilitates Cyclin D1 expression and G1-to-S cell cycle progression after lead acetate exposure. Co-immunoprecipitation of APE1 with ERK2, siRNA knockdown, redox inhibitor (E3330), forced APE1 overexpression, ERK activity assays, cell cycle analysis Toxicology Medium 23370007
2024 Conditional deletion of Apex1 in T cells results in accumulation of abasic DNA sites in proliferating T cells, genomic instability, and apoptotic death, preventing acquisition of T effector features. Mutational analyses pinpointed the endonuclease domain as essential for T effector cell generation. Chemical inhibition of APE1 base repair activity similarly abrogated autoimmune disease induction in mouse models. Conditional knockout of Apex1 in T cells, mutational analysis of endonuclease domain, chemical inhibitors, autoimmune disease mouse models, abasic site quantification, apoptosis assays The Journal of clinical investigation High 39739423
2024 APE1 inhibition promotes ferroptosis in hepatocellular carcinoma by activating AKT oxidation, impairing AKT phosphorylation/activation, which leads to GSK3β dephosphorylation/activation and ubiquitin-proteasome-dependent NRF2 degradation, thereby suppressing SLC7A11 and GPX4 expression and triggering lipid peroxidation. This pathway requires the redox activity of APE1. Genetic and chemical inhibition of APE1, AKT oxidation assay, GSK3β phosphorylation, NRF2 ubiquitination/degradation assay, SLC7A11/GPX4 expression, lipid peroxidation measurement Cell death and differentiation Medium 38418695
2022 APE1 controls DICER1 expression in non-small-cell lung cancer via regulation of miR-33a-5p and miR-130b-3p. DICER1 is validated as a direct functional target of APE1-regulated miRNAs, and IHC analyses confirmed a negative correlation between APE1 and DICER1 protein levels in human tumors. siRNA-mediated APE1 depletion, high-throughput miRNA profiling, miRNA target validation (DICER1 as target of miR-33a-5p and miR-130b-3p), IHC on human tumor tissue Cellular and molecular life sciences : CMLS Medium 35876890
2014 Mitochondrial APE1/Ref-1 suppresses PKC-induced mitochondrial dysfunction (hyperpolarization and ROS generation) in mouse endothelial cells. PMA-induced PKC activation increases mitochondrial translocation of APE1/Ref-1, and a mitochondrial targeting sequence-fused APE1 more effectively suppresses mitochondrial dysfunction than wild-type APE1. PKC activator (PMA) treatment, APE1 overexpression and gene silencing, MTS-fused APE1 construct, mitochondrial membrane potential and ROS assays Mitochondrion Medium 24861944
2021 APE1 inhibits pyroptosis in lung adenocarcinoma cells by inactivating the STING pathway via direct interaction with AIM2 and DDX41 (as detected by co-immunoprecipitation). This interaction prevents STING pathway activation, contributing to radiation resistance. RNA-seq, co-immunoprecipitation (APE1 with AIM2 and DDX41), APE1 knockdown/overexpression, pyroptosis and STING pathway assays, radiation resistance assays Translational oncology Low 37544034

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Going APE over ref-1. Mutation research 478 11018583
1997 Identification of redox/repair protein Ref-1 as a potent activator of p53. Genes & development 423 9119221
2009 The many functions of APE1/Ref-1: not only a DNA repair enzyme. Antioxidants & redox signaling 417 18976116
1994 The redox and DNA-repair activities of Ref-1 are encoded by nonoverlapping domains. Proceedings of the National Academy of Sciences of the United States of America 326 7506414
2005 The intracellular localization of APE1/Ref-1: more than a passive phenomenon? Antioxidants & redox signaling 324 15706084
2007 The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target. Molecular aspects of medicine 226 17560642
2009 Transcriptional regulatory functions of mammalian AP-endonuclease (APE1/Ref-1), an essential multifunctional protein. Antioxidants & redox signaling 216 18715144
1999 Ref-1 regulates the transactivation and pro-apoptotic functions of p53 in vivo. The EMBO journal 201 10523305
2005 Molecular and biological roles of Ape1 protein in mammalian base excision repair. DNA repair 181 16199212
2010 Human AP endonuclease 1 (APE1): from mechanistic insights to druggable target in cancer. Cancer treatment reviews 180 20056333
2015 Capturing snapshots of APE1 processing DNA damage. Nature structural & molecular biology 141 26458045
2012 APE1/Ref-1 role in redox signaling: translational applications of targeting the redox function of the DNA repair/redox protein APE1/Ref-1. Current molecular pharmacology 141 22122463
2014 APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions. Experimental & molecular medicine 136 25033834
2007 APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination. The Journal of experimental medicine 129 18025127
2017 Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. NPJ precision oncology 123 28825044
2018 APE1: A skilled nucleic acid surgeon. DNA repair 122 30170830
2011 Impact of APE1/Ref-1 redox inhibition on pancreatic tumor growth. Molecular cancer therapeutics 100 21700832
2018 Molecular snapshots of APE1 proofreading mismatches and removing DNA damage. Nature communications 90 29374164
2012 APE1/Ref-1 regulates STAT3 transcriptional activity and APE1/Ref-1-STAT3 dual-targeting effectively inhibits pancreatic cancer cell survival. PloS one 90 23094050
2009 Genome-wide analysis and proteomic studies reveal APE1/Ref-1 multifunctional role in mammalian cells. Proteomics 86 19180539
2008 Association of MUTYH Gln324His and APEX1 Asp148Glu with colorectal cancer and smoking in a Japanese population. Journal of experimental & clinical cancer research : CR 84 18823566
1998 Ref-1 controls pax-8 DNA-binding activity. Biochemical and biophysical research communications 80 9813166
2013 Emerging roles of the nucleolus in regulating the DNA damage response: the noncanonical DNA repair enzyme APE1/Ref-1 as a paradigmatical example. Antioxidants & redox signaling 78 23879289
2010 Small molecule inhibitors of DNA repair nuclease activities of APE1. Cellular and molecular life sciences : CMLS 76 20809131
2003 APE/Ref-1 and the mammalian response to genotoxic stress. Toxicology 76 14599768
2006 Cooperative activity of Ref-1/APE and ERp57 in reductive activation of transcription factors. Free radical biology & medicine 66 16962936
2000 Human APE/Ref-1 protein. The international journal of biochemistry & cell biology 63 11084372
2014 Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1) redox function negatively regulates NRF2. The Journal of biological chemistry 60 25492865
2009 Downregulation of APE1/Ref-1 is involved in the senescence of mesenchymal stem cells. Stem cells (Dayton, Ohio) 60 19492297
2020 Revascularization and limb salvage following critical limb ischemia by nanoceria-induced Ref-1/APE1-dependent angiogenesis. Biomaterials 59 32146371
2015 APE1/Ref-1 as a Serological Biomarker for the Detection of Bladder Cancer. Cancer research and treatment 59 25672588
2016 APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury. Proceedings of the National Academy of Sciences of the United States of America 55 27274063
2022 APE1/Ref-1 Role in Inflammation and Immune Response. Frontiers in immunology 54 35296074
2021 APE1 distinguishes DNA substrates in exonucleolytic cleavage by induced space-filling. Nature communications 54 33504804
2018 APE1 deficiency promotes cellular senescence and premature aging features. Nucleic acids research 54 29750271
2015 APE1/REF-1 down-regulation enhances the cytotoxic effects of temozolomide in a resistant glioblastoma cell line. Mutation research. Genetic toxicology and environmental mutagenesis 54 26520369
2017 In vivo measurements of interindividual differences in DNA glycosylases and APE1 activities. Proceedings of the National Academy of Sciences of the United States of America 53 29122935
2024 APE1 inhibition enhances ferroptotic cell death and contributes to hepatocellular carcinoma therapy. Cell death and differentiation 51 38418695
2008 APE1/Ref-1 regulates PTEN expression mediated by Egr-1. Free radical research 50 18324520
2020 APE1 senses DNA single-strand breaks for repair and signaling. Nucleic acids research 49 31828326
2022 Structural basis for APE1 processing DNA damage in the nucleosome. Nature communications 46 36104361
2021 Vitexin inhibits APEX1 to counteract the flow-induced endothelial inflammation. Proceedings of the National Academy of Sciences of the United States of America 45 34810252
2017 Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1). Bioorganic & medicinal chemistry 45 28161249
2016 Urinary APE1/Ref-1: A Potential Bladder Cancer Biomarker. Disease markers 44 27057081
2023 Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons. Cells 43 37508559
2018 Ref-1/APE1 Inhibition with Novel Small Molecules Blocks Ocular Neovascularization. The Journal of pharmacology and experimental therapeutics 43 30076264
2010 APEX1 gene amplification and its protein overexpression in osteosarcoma: correlation with recurrence, metastasis, and survival. Technology in cancer research & treatment 43 20218738
2010 Posttranslational modification of mammalian AP endonuclease (APE1). Cellular and molecular life sciences : CMLS 43 20711647
2020 Functions of the major abasic endonuclease (APE1) in cell viability and genotoxin resistance. Mutagenesis 42 31816044
2019 AP endonuclease 1 (Apex1) influences brain development linking oxidative stress and DNA repair. Cell death & disease 42 31024003
1995 APX-1 can substitute for its homolog LAG-2 to direct cell interactions throughout Caenorhabditis elegans development. Proceedings of the National Academy of Sciences of the United States of America 41 7568229
2022 APE1 assembles biomolecular condensates to promote the ATR-Chk1 DNA damage response in nucleolus. Nucleic acids research 40 36200829
2016 Dynamic Regulation of APE1/Ref-1 as a Therapeutic Target Protein. Chonnam medical journal 40 27231670
2014 Aberrant expression of redox protein Ape1 in colon cancer stem cells. Oncology letters 37 24944672
2012 Small-molecule inhibitors of APE1 DNA repair function: an overview. Current molecular pharmacology 37 22122462
2021 APE1/Ref-1 - One Target with Multiple Indications: Emerging Aspects and New Directions. Journal of cellular signaling 35 34557865
2023 Development of a DNAzyme Walker for the Detection of APE1 in Living Cancer Cells. Analytical chemistry 34 37725609
2019 Antitumor Activity and Mechanistic Characterization of APE1/Ref-1 Inhibitors in Bladder Cancer. Molecular cancer therapeutics 34 31413178
1997 The structure and functions of the HAP1/Ref-1 protein. Oncology research 34 9406232
2016 Secreted APE1/Ref-1 inhibits TNF-α-stimulated endothelial inflammation via thiol-disulfide exchange in TNF receptor. Scientific reports 33 26964514
2006 A new standard nomenclature for proteins related to Apx and Shroom. BMC cell biology 33 16615870
2017 Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma. Scientific reports 32 28852018
2023 Closed Cyclic DNA Machine for Sensitive Logic Operation and APE1 Detection. Small (Weinheim an der Bergstrasse, Germany) 31 36916696
2014 Human apurinic/apyrimidinic endonuclease 1 (APE1) has 3' RNA phosphatase and 3' exoribonuclease activities. Journal of molecular biology 28 25498387
2010 Base excision repair genes XRCC1 and APEX1 and the risk for prostate cancer. Molecular biology reports 28 20852942
2013 Functional assessment of population and tumor-associated APE1 protein variants. PloS one 27 23776569
2017 APE1/Ref-1 Inhibits Phosphate-Induced Calcification and Osteoblastic Phenotype Changes in Vascular Smooth Muscle Cells. International journal of molecular sciences 26 28946662
2016 APE1 polymorphic variants cause persistent genomic stress and affect cancer cell proliferation. Oncotarget 26 27050370
2024 New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types. Pharmacological research 24 38311014
2014 Suppression of choroidal neovascularization through inhibition of APE1/Ref-1 redox activity. Investigative ophthalmology & visual science 24 24970265
2013 Genetic and expressional variations of APEX1 are associated with increased risk of head and neck cancer. Mutagenesis 24 23408843
2024 The APE1/REF-1 and the hallmarks of cancer. Molecular biology reports 23 38165468
2022 Pharmacological inhibition of Ref-1 enhances the therapeutic sensitivity of papillary thyroid carcinoma to vemurafenib. Cell death & disease 22 35136031
2021 Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy. International journal of molecular sciences 22 34638620
2014 Association between OGG1 Ser326Cys and APEX1 Asp148Glu polymorphisms and breast cancer risk: a meta-analysis. Diagnostic pathology 22 24893568
2012 Association between the OGG1 Ser326Cys and APEX1 Asp148Glu polymorphisms and lung cancer risk: a meta-analysis. Molecular biology reports 22 23065211
2023 APE1 promotes radiation resistance against radiation-induced pyroptosis by inhibiting the STING pathway in lung adenocarcinoma. Translational oncology 21 37544034
2022 APE1 controls DICER1 expression in NSCLC through miR-33a and miR-130b. Cellular and molecular life sciences : CMLS 21 35876890
2021 DNA Repair Protein APE1 Degrades Dysfunctional Abasic mRNA in Mitochondria Affecting Oxidative Phosphorylation. Journal of molecular biology 21 34224750
2021 APE1/Ref-1 as a Novel Target for Retinal Diseases. Journal of cellular signaling 21 34322687
2014 5-HMF prevents against oxidative injury via APE/Ref-1. Free radical research 21 25363495
2024 Apex1 safeguards genomic stability to ensure a cytopathic T cell fate in autoimmune disease models. The Journal of clinical investigation 20 39739423
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
2021 Characterization of APX and APX-R gene family in Brassica juncea and B. rapa for tolerance against abiotic stresses. Plant cell reports 20 34115169
2009 APE1/Ref-1: versatility in progress. Antioxidants & redox signaling 20 18715142
2009 HIF-1 attenuates Ref-1 expression in endothelial cells: reversal by siRNA and inhibition of geranylgeranylation. Vascular pharmacology 20 19524065
2022 Genome-Wide Identification and Analysis of the Ascorbate Peroxidase (APX) Gene Family of Winter Rapeseed (Brassica rapa L.) Under Abiotic Stress. Frontiers in genetics 19 35126448
2021 Understanding APE1 cellular functions by the structural preference of exonuclease activities. Computational and structural biotechnology journal 19 34285771
2019 Serum Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) Level as a Potential Biomarker of Cholangiocarcinoma. Biomolecules 19 31454981
2017 Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia. Molecular cancer therapeutics 19 28446640
2022 APEX1 regulates alternative splicing of key tumorigenesis genes in non-small-cell lung cancer. BMC medical genomics 18 35780128
2021 LINC00470 accelerates the proliferation and metastasis of melanoma through promoting APEX1 expression. Cell death & disease 18 33875645
2021 New Horizons for the Roles and Association of APE1/Ref-1 and ABCA1 in Atherosclerosis. Journal of inflammation research 18 34703267
2020 Plasma APE1/Ref-1 Correlates with Atherosclerotic Inflammation in ApoE-/- Mice. Biomedicines 18 32967121
2013 APE1/Ref-1 prevents oxidative inactivation of ERK for G1-to-S progression following lead acetate exposure. Toxicology 18 23370007
2022 Potential Role of APEX1 During Ferroptosis. Frontiers in oncology 17 35311089
2022 Genome-wide, evolutionary, and functional analyses of ascorbate peroxidase (APX) family in Poaceae species. Genetics and molecular biology 17 36512713
2021 Ascorbate Peroxidase Neofunctionalization at the Origin of APX-R and APX-L: Evidence from Basal Archaeplastida. Antioxidants (Basel, Switzerland) 17 33924520
2017 Elevation of Serum APE1/Ref-1 in Experimental Murine Myocarditis. International journal of molecular sciences 17 29292734
2014 Mitochondrial APE1/Ref-1 suppressed protein kinase C-induced mitochondrial dysfunction in mouse endothelial cells. Mitochondrion 17 24861944

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