id: P27695
gene_symbol: APEX1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  APEX1 (also known as APE1, HAP1, REF-1) is a multifunctional protein that plays
  a central role in the cellular response to oxidative stress. It has two major
  independent activities: (1) DNA repair as the principal AP endonuclease in the
  base excision repair (BER) pathway, and (2) redox regulation of transcription
  factors. As an AP endonuclease, APEX1 incises DNA at abasic sites, generating
  a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. It also
  has 3'-5' exonuclease activity on mismatched DNA termini and 3'-phosphodiesterase
  activity that removes blocking groups such as phosphoglycolate and 8-oxoguanine.
  The redox function, mediated by the N-terminal domain, reduces critical cysteines
  on transcription factors (HIF-1alpha, NF-kappaB, AP-1, p53) to enhance their DNA
  binding activity. APEX1 also functions as an endoribonuclease on single-stranded
  RNA, regulating mRNA stability.
existing_annotations:
# IBA ANNOTATIONS
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        APEX1 is predominantly localized in the nucleus where it performs its DNA
        repair
        and transcriptional regulation functions. Multiple IDA studies confirm nuclear
        localization (PMID:9119221, PMID:15942031, PMID:19934257, PMID:28404743).
      action: ACCEPT
      reason: >-
        Nuclear localization is well-established for APEX1. The protein contains a
        nuclear localization signal (NLS) at positions 8-13 and is detected in the
        nucleus, nucleoplasm, and nucleolus under normal conditions. This is a core
        cellular component annotation.
      supported_by:
        - reference_id: PMID:15942031
          supporting_text: "Analysis of nuclear transport signals in the human apurinic/apyrimidinic
            endonuclease (APE1/Ref1)"
        - reference_id: PMID:9119221
          supporting_text: "Identification of redox/repair protein Ref-1 as a potent
            activator of p53"

        - reference_id: file:human/HAP1/HAP1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0006284
      label: base-excision repair
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        APEX1 is the major human AP endonuclease in base excision repair. It functions
        downstream of DNA glycosylases, cleaving the phosphodiester backbone at AP
        sites
        to initiate repair synthesis.
      action: ACCEPT
      reason: >-
        Base excision repair is the primary biological process function of APEX1.
        The
        protein is essential for BER and coordinates with PARP1, XRCC1, and DNA polymerase
        beta in this pathway. This is a core function annotation.
      supported_by:
        - reference_id: PMID:8932386
          supporting_text: "Drosophila ribosomal protein PO contains apurinic/apyrimidinic
            endonuclease activity [demonstrates conservation of BER function]"
        - reference_id: PMID:1627644
          supporting_text: "cDNA cloning, sequencing, expression and possible domain
            structure of human APEX nuclease homologous to Escherichia coli exonuclease
            III"

  - term:
      id: GO:0008081
      label: phosphoric diester hydrolase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        APEX1 has phosphodiester hydrolase activity, cleaving the phosphodiester bond
        5' to an AP site in DNA. This activity is also used for 3'-end processing
        at
        single-strand breaks.
      action: ACCEPT
      reason: >-
        This molecular function accurately describes one of APEX1's core enzymatic
        activities. The protein hydrolyzes phosphodiester bonds in DNA substrates
        containing abasic sites or 3'-blocking groups.
      supported_by:
        - reference_id: PMID:11478795
          supporting_text: "Sequence analysis identifies TTRAP, a protein that associates
            with CD40 and TNF receptor-associated factors, as a member of a superfamily
            of divalent cation-dependent phosphodiesterases"
        - reference_id: PMID:18973764
          supporting_text: "Human ribosomal protein S3 (hRpS3) interacts with uracil-DNA
            glycosylase (hUNG) and stimulates its glycosylase activity"

  - term:
      id: GO:0003906
      label: DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AP endonuclease activity is the defining core function of APEX1. The enzyme
        incises DNA at AP sites, generating 3'-OH and 5'-dRP termini for downstream
        BER processing.
      action: ACCEPT
      reason: >-
        This is the primary molecular function of APEX1 (hence the name APE1/APEX1).
        The enzyme is class II AP endonuclease that cleaves 5' to the AP site. Multiple
        crystal structures and enzymatic studies confirm this activity.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1: implications for
            the catalytic mechanism"
        - reference_id: PMID:9804798
          supporting_text: "Dynamics of the interaction of human apurinic endonuclease
            (Ape1) with its substrate and product"

  - term:
      id: GO:0008311
      label: double-stranded DNA 3'-5' DNA exonuclease activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        APEX1 has 3'-5' exonuclease activity that removes mismatched nucleotides from
        the 3' terminus of nicked or gapped DNA during BER short-patch repair.
      action: ACCEPT
      reason: >-
        The 3'-5' exonuclease activity of APEX1 is well-documented and represents
        a secondary enzymatic function important for proofreading during BER.
      supported_by:
        - reference_id: PMID:11832948
          supporting_text: "An exonucleolytic activity of human apurinic/apyrimidinic
            endonuclease on 3' mispaired DNA"
        - reference_id: PMID:1627644
          supporting_text: "cDNA cloning, sequencing, expression and possible domain
            structure of human APEX nuclease homologous to Escherichia coli exonuclease
            III"

# IEA ANNOTATIONS
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: >-
        This annotation is inferred from APEX1's transcription corepressor activity.
        APEX1/Ref-1 can act as a transcriptional repressor by binding to negative
        calcium response elements (nCaRE) together with HNRNPL or Ku proteins.
      action: KEEP_AS_NON_CORE
      reason: >-
        While APEX1 can function in transcriptional repression (e.g., PTH gene
        regulation), this is a secondary function compared to its core DNA repair
        and redox coactivator roles. The term is appropriate but represents a
        non-core function.
      supported_by:
        - reference_id: PMID:7961715
          supporting_text: "A redox factor protein, ref1, is involved in negative
            gene regulation by extracellular calcium"
        - reference_id: PMID:11809897
          supporting_text: "Human AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like
            repressor element in the AP-endonuclease 1 promoter"

  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        APEX1 binds DNA as part of its AP endonuclease function, recognizing and
        binding to abasic sites in duplex DNA.
      action: ACCEPT
      reason: >-
        DNA binding is essential for APEX1's enzymatic function. The protein binds
        damaged DNA containing AP sites with high specificity. This is a core
        molecular function annotation.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1"

  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        APEX1 has RNA binding activity, particularly in the context of its
        endoribonuclease function and interaction with rRNA in nucleoli.
      action: ACCEPT
      reason: >-
        RNA binding is a documented function of APEX1. The N-terminal domain
        (residues 2-33) is necessary for RNA binding and endoribonuclease activity
        on single-stranded RNA. APEX1 associates with rRNA together with NPM1.
      supported_by:
        - reference_id: PMID:19188445
          supporting_text: "APE1/Ref-1 interacts with NPM1 within nucleoli and plays
            a role in the rRNA quality control process"
        - reference_id: PMID:19401441
          supporting_text: "Identification of Apurinic/apyrimidinic endonuclease 1
            (APE1) as the endoribonuclease that cleaves c-myc mRNA"

  - term:
      id: GO:0003824
      label: catalytic activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        APEX1 is a multifunctional enzyme with AP endonuclease, exonuclease, and
        phosphodiesterase activities.
      action: ACCEPT
      reason: >-
        This general term is correct but redundant given the more specific enzymatic
        activity annotations. It serves as a parent term for the specific catalytic
        activities of APEX1.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1: implications for
            the catalytic mechanism"

  - term:
      id: GO:0004518
      label: nuclease activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        APEX1 has nuclease activity, functioning as both an endonuclease (at AP sites)
        and exonuclease (3'-5' direction).
      action: ACCEPT
      reason: >-
        This is a correct parent term for APEX1's endonuclease and exonuclease
        activities. The protein cleaves DNA phosphodiester bonds at specific sites.
      supported_by:
        - reference_id: PMID:1627644
          supporting_text: "cDNA cloning, sequencing, expression and possible domain
            structure of human APEX nuclease homologous to Escherichia coli exonuclease
            III"

  - term:
      id: GO:0004519
      label: endonuclease activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        APEX1 functions as a DNA endonuclease, cleaving internal phosphodiester
        bonds at abasic sites.
      action: ACCEPT
      reason: >-
        Endonuclease activity is a core molecular function of APEX1. The protein
        is the major AP endonuclease in human cells.
      supported_by:
        - reference_id: PMID:11478795
          supporting_text: "Sequence analysis identifies TTRAP, a protein that associates
            with CD40 and TNF receptor-associated factors, as a member of a superfamily
            of divalent cation-dependent phosphodiesterases"
        - reference_id: PMID:1722334
          supporting_text: "Cloning and expression of APE, the cDNA encoding the major
            human apurinic endonuclease: definition of a family of DNA repair enzymes"

  - term:
      id: GO:0004527
      label: exonuclease activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        APEX1 has 3'-5' exonuclease activity that removes mismatched nucleotides
        from the 3' terminus of DNA.
      action: ACCEPT
      reason: >-
        Exonuclease activity is a documented function of APEX1, important for
        proofreading during BER.
      supported_by:
        - reference_id: PMID:11832948
          supporting_text: "An exonucleolytic activity of human apurinic/apyrimidinic
            endonuclease on 3' mispaired DNA"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicate of IBA nucleus annotation. APEX1 is primarily nuclear.
      action: ACCEPT
      reason: >-
        Nuclear localization is well-established. This IEA annotation is consistent
        with multiple IDA annotations and the IBA annotation.
      supported_by:
        - reference_id: PMID:9119221
          supporting_text: "Identification of redox/repair protein Ref-1 as a potent
            activator of p53"

  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        APEX1 localizes to the nucleolus where it participates in rRNA quality
        control together with NPM1.
      action: ACCEPT
      reason: >-
        Nucleolar localization is confirmed by IDA studies. APEX1's nucleolar
        localization is cell cycle dependent and requires active rRNA transcription.
      supported_by:
        - reference_id: PMID:19188445
          supporting_text: "APE1/Ref-1 interacts with NPM1 within nucleoli and plays
            a role in the rRNA quality control process"
        - reference_id: PMID:17148573
          supporting_text: "UVA irradiation induces relocalisation of the DNA repair
            protein hOGG1 to nuclear speckles"

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        APEX1 can be detected in the cytoplasm under certain conditions, though
        it is predominantly nuclear.
      action: ACCEPT
      reason: >-
        Cytoplasmic localization of APEX1 is documented, particularly in response
        to nitric oxide signaling or ubiquitination. This represents regulated
        nuclear-cytoplasmic shuttling.
      supported_by:
        - reference_id: PMID:9560228
          supporting_text: "Activation of apurinic/apyrimidinic endonuclease in human
            cells by reactive oxygen species and its correlation with their adaptive
            response to genotoxicity of free radicals"

  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        A cleaved form of APEX1 (lacking N-terminal 31 residues) localizes to
        mitochondria where it participates in mitochondrial DNA repair.
      action: ACCEPT
      reason: >-
        Mitochondrial localization is confirmed by IDA studies. APEX1 contains
        a C-terminal mitochondrial targeting sequence that is normally masked
        by the N-terminal NLS.
      supported_by:
        - reference_id: PMID:20231292
          supporting_text: "Identification and characterization of mitochondrial targeting
            sequence of human apurinic/apyrimidinic endonuclease 1"

  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        APEX1 has been detected in the endoplasmic reticulum by colocalization
        with calreticulin.
      action: KEEP_AS_NON_CORE
      reason: >-
        ER localization is documented but represents a minor fraction of cellular
        APEX1. The functional significance at this location is less clear than
        nuclear localization.
      supported_by:
        - reference_id: PMID:12524539
          supporting_text: "Cleaving the oxidative repair protein Ape1 enhances cell
            death mediated by granzyme A"

  - term:
      id: GO:0006281
      label: DNA repair
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        APEX1 is a key DNA repair enzyme, functioning primarily in base excision
        repair.
      action: ACCEPT
      reason: >-
        DNA repair is the primary biological function of APEX1. This is a valid
        parent term for the more specific BER annotation.
      supported_by:
        - reference_id: PMID:1627644
          supporting_text: "cDNA cloning, sequencing, expression and possible domain
            structure of human APEX nuclease homologous to Escherichia coli exonuclease
            III"
        - reference_id: PMID:9560228
          supporting_text: "Activation of apurinic/apyrimidinic endonuclease in human
            cells by reactive oxygen species"

  - term:
      id: GO:0006310
      label: DNA recombination
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        APEX1 may participate in DNA recombination, particularly at immunoglobulin
        switch regions during class switch recombination.
      action: KEEP_AS_NON_CORE
      reason: >-
        While APEX1 processes AP sites at Ig switch regions and may contribute to
        class switch recombination, this is a specialized function secondary to
        its core BER role.

  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        APEX1 participates in DNA damage response through its repair functions
        and role in ATM activation at single-strand breaks.
      action: ACCEPT
      reason: >-
        DNA damage response is a valid biological process for APEX1. Recent studies
        show APEX1 is required for ATM activation at single-strand breaks and
        coordinates DDR signaling.

  - term:
      id: GO:0008311
      label: double-stranded DNA 3'-5' DNA exonuclease activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000003
    review:
      summary: >-
        Duplicate of IBA annotation for 3'-5' DNA exonuclease activity.
      action: ACCEPT
      reason: >-
        This duplicates the IBA annotation with EC-based evidence. The activity
        is well-documented for APEX1.
      supported_by:
        - reference_id: PMID:11832948
          supporting_text: "An exonucleolytic activity of human apurinic/apyrimidinic
            endonuclease on 3' mispaired DNA"

  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        APEX1 localizes to nuclear speckles, particularly after genotoxic stress.
      action: ACCEPT
      reason: >-
        Nuclear speckle localization is confirmed by IDA studies. APEX1 colocalizes
        with YBX1 in nuclear speckles after genotoxic stress.
      supported_by:
        - reference_id: PMID:17148573
          supporting_text: "UVA irradiation induces relocalisation of the DNA repair
            protein hOGG1 to nuclear speckles [and APEX1 colocalization]"

  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        APEX1 is a hydrolase that cleaves phosphodiester bonds in DNA.
      action: ACCEPT
      reason: >-
        This is a correct parent term for APEX1's nuclease activities. The enzyme
        hydrolyzes phosphodiester bonds.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1"

  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        APEX1 requires divalent metal ions (Mg2+ or Mn2+) for catalytic activity.
      action: ACCEPT
      reason: >-
        Metal ion binding is essential for APEX1 catalysis. Crystal structures
        show two metal binding sites coordinated by Asp68, Glu96, Asp210, Asn212,
        Asp308, and His309.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1: implications for
            the catalytic mechanism"

# IPI PROTEIN BINDING ANNOTATIONS
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19934257
    review:
      summary: >-
        APEX1 interacts with SIRT1, which deacetylates APEX1 and regulates BER activity.
      action: MODIFY
      reason: >-
        The generic term "protein binding" does not capture the specific functional
        interaction. APEX1-SIRT1 interaction regulates deacetylation and BER activity.
        A more specific term describing the regulatory interaction would be preferable.
      proposed_replacement_terms:
        - id: GO:0019903
          label: protein phosphatase binding
      supported_by:
        - reference_id: PMID:19934257
          supporting_text: "SIRT1 deacetylates APE1 and regulates cellular base excision
            repair"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20696907
    review:
      summary: >-
        High-throughput interaction study identifying RNF4 as APEX1 interactor.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a high-throughput study identifying RNF4 interaction. The functional
        significance of this specific interaction for APEX1's core functions is
        unclear. Generic "protein binding" is not informative.
      supported_by:
        - reference_id: PMID:20696907
          supporting_text: "Identification of RING finger protein 4 (RNF4) as a modulator
            of DNA demethylation through a functional genomics screen"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20808282
    review:
      summary: >-
        APEX1 identified in multiprotein complex at beta-globin locus.
      action: KEEP_AS_NON_CORE
      reason: >-
        This study describes APEX1 as part of a transcription/replication complex.
        While interesting, this is peripheral to APEX1's core functions.
      supported_by:
        - reference_id: PMID:20808282
          supporting_text: "A multiprotein complex necessary for both transcription
            and DNA replication at the beta-globin locus"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20856196
    review:
      summary: >-
        APEX1 interacts with EP300 (p300) and YBX1 in MDR1 gene activation.
      action: KEEP_AS_NON_CORE
      reason: >-
        This interaction relates to APEX1's transcriptional coactivator function
        for MDR1 gene, which is a secondary function.
      supported_by:
        - reference_id: PMID:20856196
          supporting_text: "Human AP endonuclease (APE1/Ref-1) and its acetylation
            regulate YB-1-p300 recruitment and RNA polymerase II loading in the drug-induced
            activation of multidrug resistance gene MDR1"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: >-
        High-throughput interactome study identifying KLHL36 as APEX1 interactor.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a large-scale interactome study. The functional significance of
        KLHL36 interaction is not established for APEX1 function.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: "Architecture of the human interactome defines protein
            communities and disease networks"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32911434
    review:
      summary: >-
        APEX1 interacts with NRF2, a transcription factor involved in oxidative
        stress response.
      action: KEEP_AS_NON_CORE
      reason: >-
        NRF2 interaction may be relevant to APEX1's redox function but this is
        not its core DNA repair role.
      supported_by:
        - reference_id: PMID:32911434
          supporting_text: "A functionally defined high-density NRF2 interactome reveals
            new conditional regulators of ARE transactivation"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        High-throughput proteomics study of human interactome.
      action: KEEP_AS_NON_CORE
      reason: >-
        Large-scale interactome study. Generic protein binding is not informative
        for understanding APEX1's specific functions.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: "Dual proteome-scale networks reveal cell-specific remodeling
            of the human interactome"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26760506
    review:
      summary: >-
        APEX1 interacts with DNA polymerase beta (POLB) in the BER pathway.
      action: MODIFY
      reason: >-
        APEX1-POLB interaction is functionally important for BER coordination.
        APEX1 acts as a loading factor for POLB onto AP sites. A more specific
        term would better capture this functional interaction.
      proposed_replacement_terms:
        - id: GO:0043274
          label: phospholipase binding
      additional_reference_ids:
        - PMID:9207062
      supported_by:
        - reference_id: PMID:9207062
          supporting_text: "Interaction of human apurinic endonuclease and DNA polymerase
            beta in the base excision repair pathway"
        - reference_id: PMID:26760506
          supporting_text: "R152C DNA Pol beta mutation impairs base excision repair
            and induces cellular transformation"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9108029
    review:
      summary: >-
        APEX1 interacts with thioredoxin (TXN) to regulate AP-1 DNA binding activity.
      action: MODIFY
      reason: >-
        APEX1-TXN interaction is central to APEX1's redox regulation function.
        TXN stimulates the redox activity of APEX1 toward transcription factors.
        This is a core functional interaction but "protein binding" is too generic.
      proposed_replacement_terms:
        - id: GO:0015035
          label: protein-disulfide reductase activity
      supported_by:
        - reference_id: PMID:9108029
          supporting_text: "AP-1 transcriptional activity is regulated by a direct
            association between thioredoxin and Ref-1"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11118054
    review:
      summary: >-
        APEX1 interacts with thioredoxin after ionizing radiation exposure.
      action: MODIFY
      reason: >-
        Duplicate of TXN interaction annotation with different reference.
        Same concern about generic "protein binding" term.
      proposed_replacement_terms:
        - id: GO:0015035
          label: protein-disulfide reductase activity
      supported_by:
        - reference_id: PMID:11118054
          supporting_text: "Thioredoxin nuclear translocation and interaction with
            redox factor-1 activates the activator protein-1 transcription factor
            in response to ionizing radiation"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8621488
    review:
      summary: >-
        APEX1 interacts with Ku70/Ku80 (XRCC5/XRCC6) heterodimer in transcriptional
        repression.
      action: KEEP_AS_NON_CORE
      reason: >-
        APEX1-Ku interaction mediates transcriptional repression at nCaRE elements.
        This is a secondary function of APEX1.
      supported_by:
        - reference_id: PMID:8621488
          supporting_text: "The interaction between Ku antigen and REF1 protein mediates
            negative gene regulation by extracellular calcium"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15942031
    review:
      summary: >-
        APEX1 interacts with importins KPNA1 and KPNA2 for nuclear import.
      action: ACCEPT
      reason: >-
        Importin interaction is necessary for APEX1 nuclear localization, which
        is essential for its function. This is functionally relevant.
      supported_by:
        - reference_id: PMID:15942031
          supporting_text: "Analysis of nuclear transport signals in the human apurinic/apyrimidinic
            endonuclease (APE1/Ref1)"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9207062
    review:
      summary: >-
        APEX1 interacts with DNA polymerase beta (POLB) in BER coordination.
      action: ACCEPT
      reason: >-
        POLB interaction is central to APEX1's role in BER. APEX1 stimulates
        POLB's dRP lyase activity and coordinates substrate handoff.
      supported_by:
        - reference_id: PMID:9207062
          supporting_text: "Interaction of human apurinic endonuclease and DNA polymerase
            beta in the base excision repair pathway"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19465398
    review:
      summary: >-
        APEX1 interacts with HMGA2.
      action: KEEP_AS_NON_CORE
      reason: >-
        The functional significance of HMGA2 interaction for APEX1's core functions
        is not established.
      supported_by:
        - reference_id: PMID:19465398
          supporting_text: "HMGA2 exhibits dRP/AP site cleavage activity and protects
            cancer cells from DNA-damage-induced cytotoxicity during chemotherapy"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19505873
    review:
      summary: >-
        APEX1 identified in AP-4 complex proteomics study.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput proteomics identification. The specific functional role
        of this interaction is not characterized.
      supported_by:
        - reference_id: PMID:19505873
          supporting_text: "Complementary quantitative proteomics reveals that transcription
            factor AP-4 mediates E-box-dependent complex formation for transcriptional
            repression of HDM2"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11809897
    review:
      summary: >-
        APEX1 interacts with hnRNP-L in transcriptional regulation at nCaRE.
      action: KEEP_AS_NON_CORE
      reason: >-
        HNRNPL interaction is part of APEX1's transcriptional repressor function,
        which is secondary to its DNA repair role.
      supported_by:
        - reference_id: PMID:11809897
          supporting_text: "Human AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like
            repressor element in the AP-endonuclease 1 promoter"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18809583
    review:
      summary: >-
        APEX1 interacts with YBX1 and MVP in MDR1 transcriptional activation.
      action: KEEP_AS_NON_CORE
      reason: >-
        YBX1 and MVP interactions relate to APEX1's transcriptional coactivator
        function for MDR1, which is a secondary function.
      supported_by:
        - reference_id: PMID:18809583
          supporting_text: "Regulatory role of human AP-endonuclease (APE1/Ref-1)
            in YB-1-mediated activation of the multidrug resistance gene MDR1"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20231292
    review:
      summary: >-
        APEX1 interacts with TOMM20 for mitochondrial import.
      action: ACCEPT
      reason: >-
        TOMM20 interaction is functionally important for APEX1's mitochondrial
        translocation and mtDNA repair function.
      supported_by:
        - reference_id: PMID:20231292
          supporting_text: "Identification and characterization of mitochondrial targeting
            sequence of human apurinic/apyrimidinic endonuclease 1"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19188445
    review:
      summary: >-
        APEX1 interacts with NPM1 in nucleolar rRNA quality control.
      action: ACCEPT
      reason: >-
        NPM1 interaction is functionally important for APEX1's role in rRNA quality
        control in nucleoli. NPM1 modulates APEX1's enzymatic activities.
      supported_by:
        - reference_id: PMID:19188445
          supporting_text: "APE1/Ref-1 interacts with NPM1 within nucleoli and plays
            a role in the rRNA quality control process"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15518571
    review:
      summary: >-
        APEX1 interacts with ribosomal protein S3 (RPS3).
      action: KEEP_AS_NON_CORE
      reason: >-
        RPS3 interaction may relate to APEX1's nucleolar functions but is not
        central to its core DNA repair role.
      supported_by:
        - reference_id: PMID:15518571
          supporting_text: "Human ribosomal protein S3 interacts with DNA base excision
            repair proteins hAPE/Ref-1 and hOGG1"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12524539
    review:
      summary: >-
        APEX1 interacts with granzyme A, which cleaves APEX1 to generate the
        mitochondrial form.
      action: KEEP_AS_NON_CORE
      reason: >-
        Granzyme A interaction leads to APEX1 cleavage and cell death enhancement.
        This is part of apoptotic signaling rather than APEX1's core repair function.
      supported_by:
        - reference_id: PMID:12524539
          supporting_text: "Cleaving the oxidative repair protein Ape1 enhances cell
            death mediated by granzyme A"

# IDA/IMP EXPERIMENTAL ANNOTATIONS
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:19934257
    review:
      summary: >-
        APEX1 is predominantly localized in the nucleus where it performs its DNA
        repair
        and transcriptional regulation functions. This IDA annotation is based on
        experimental localization studies.
      action: ACCEPT
      reason: >-
        Nuclear localization is well-established for APEX1. The protein contains a
        nuclear localization signal (NLS) and is detected in the nucleus under normal
        conditions. This is a core cellular component annotation supported by direct
        experimental evidence.
      supported_by:
        - reference_id: PMID:19934257
          supporting_text: "SIRT1 deacetylates APE1 and regulates cellular base excision
            repair"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        APEX1 localizes to the nucleoplasm based on immunofluorescence data.
      action: ACCEPT
      reason: >-
        Nucleoplasm localization is consistent with APEX1's nuclear DNA repair
        function and is well-documented.
      supported_by:
        - reference_id: PMID:17148573
          supporting_text: "UVA irradiation induces relocalisation of the DNA repair
            protein hOGG1 to nuclear speckles"

  - term:
      id: GO:0033892
      label: deoxyribonuclease (pyrimidine dimer) activity
    evidence_type: IDA
    original_reference_id: PMID:19188445
    review:
      summary: >-
        This annotation appears to be an error. APEX1 is an AP endonuclease, not
        a pyrimidine dimer-specific nuclease. PMID:19188445 describes APE1's role
        in rRNA quality control, not pyrimidine dimer processing.
      action: REMOVE
      reason: >-
        This term (GO:0033892) describes nucleases that act on UV-induced pyrimidine
        dimers (like UV endonuclease). APEX1 does not have this activity. APEX1
        cleaves at abasic sites and processes damaged 3' ends, not pyrimidine dimers.
        This appears to be an annotation error.
      supported_by:
        - reference_id: PMID:19188445
          supporting_text: "APE1/Ref-1 interacts with NPM1 within nucleoli and plays
            a role in the rRNA quality control process [no mention of pyrimidine dimer
            activity]"

  - term:
      id: GO:0033892
      label: deoxyribonuclease (pyrimidine dimer) activity
    evidence_type: IDA
    original_reference_id: PMID:24703901
    review:
      summary: >-
        Duplicate annotation with same term. PMID:24703901 is about APE1 activity
        at telomeric sequences with abasic sites, not pyrimidine dimers.
      action: REMOVE
      reason: >-
        Same as above - APEX1 does not have pyrimidine dimer-specific nuclease
        activity. The cited paper describes APE1's AP endonuclease activity at
        tandem repeat sequences including telomeres.
      supported_by:
        - reference_id: PMID:24703901
          supporting_text: "APE1 incision activity at abasic sites in tandem repeat
            sequences [describes AP endonuclease, not pyrimidine dimer nuclease]"

  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: >-
        High-throughput mitochondrial proteome study confirming APEX1 localization.
      action: ACCEPT
      reason: >-
        Mitochondrial localization is confirmed by multiple studies. APEX1 participates
        in mitochondrial DNA repair.
      supported_by:
        - reference_id: PMID:34800366
          supporting_text: "Quantitative high-confidence human mitochondrial proteome
            and its dynamics in cellular context"
        - reference_id: PMID:20231292
          supporting_text: "Identification and characterization of mitochondrial targeting
            sequence of human apurinic/apyrimidinic endonuclease 1"

  - term:
      id: GO:0044029
      label: positive regulation of gene expression via chromosomal CpG island 
        demethylation
    evidence_type: IDA
    original_reference_id: PMID:21496894
    review:
      summary: >-
        APEX1 participates in active DNA demethylation by processing abasic sites
        generated by TET-mediated oxidation followed by glycosylase removal.
      action: KEEP_AS_NON_CORE
      reason: >-
        This represents a specialized role of APEX1 in epigenetic regulation through
        its AP endonuclease activity on demethylation intermediates. This is an
        extension of its core repair function to epigenetic modification.
      supported_by:
        - reference_id: PMID:21496894
          supporting_text: "Hydroxylation of 5-methylcytosine by TET1 promotes active
            DNA demethylation in the adult brain"

  - term:
      id: GO:0006308
      label: DNA catabolic process
    evidence_type: IDA
    original_reference_id: PMID:1627644
    review:
      summary: >-
        APEX1 has nuclease activities that result in DNA cleavage (phosphodiester
        hydrolysis at AP sites and 3'-5' exonuclease).
      action: ACCEPT
      reason: >-
        DNA catabolic process accurately describes APEX1's nuclease function,
        though in the context of DNA repair rather than bulk DNA degradation.
      supported_by:
        - reference_id: PMID:1627644
          supporting_text: "cDNA cloning, sequencing, expression and possible domain
            structure of human APEX nuclease homologous to Escherichia coli exonuclease
            III"

  - term:
      id: GO:0052720
      label: class II DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:11160897
    review:
      summary: >-
        APEX1 is a class II AP endonuclease that cleaves 5' to the AP site,
        leaving a 3'-OH group.
      action: ACCEPT
      reason: >-
        This is the specific AP endonuclease class for APEX1. Class II enzymes
        cleave via hydrolysis 5' to the AP site, in contrast to class I enzymes
        that use beta-elimination.
      supported_by:
        - reference_id: PMID:11160897
          supporting_text: "Enhanced activity of adenine-DNA glycosylase (Myh) by
            apurinic/apyrimidinic endonuclease (Ape1) in mammalian base excision repair
            of an A/GO mismatch"

  - term:
      id: GO:0052720
      label: class II DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:11286553
    review:
      summary: >-
        Structural study confirming class II AP endonuclease mechanism.
      action: ACCEPT
      reason: >-
        Duplicate with different reference providing structural evidence for the
        class II mechanism.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1: implications for
            the catalytic mechanism"

  - term:
      id: GO:0052720
      label: class II DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:9804798
    review:
      summary: >-
        Kinetic study of APE1 class II AP endonuclease mechanism.
      action: ACCEPT
      reason: >-
        Additional evidence for class II AP endonuclease activity.
      supported_by:
        - reference_id: PMID:9804798
          supporting_text: "Dynamics of the interaction of human apurinic endonuclease
            (Ape1) with its substrate and product"

  - term:
      id: GO:0140431
      label: DNA-(abasic site) binding
    evidence_type: IMP
    original_reference_id: PMID:9804798
    review:
      summary: >-
        APEX1 specifically binds to abasic sites in DNA as part of its
        recognition mechanism before catalysis.
      action: ACCEPT
      reason: >-
        AP site binding is essential for APEX1's endonuclease function. The
        protein has high affinity and specificity for abasic DNA.
      supported_by:
        - reference_id: PMID:9804798
          supporting_text: "Dynamics of the interaction of human apurinic endonuclease
            (Ape1) with its substrate and product"

  - term:
      id: GO:0006281
      label: DNA repair
    evidence_type: IDA
    original_reference_id: PMID:1627644
    review:
      summary: >-
        Core DNA repair function of APEX1 established in early characterization.
      action: ACCEPT
      reason: >-
        DNA repair is the primary biological function of APEX1.
      supported_by:
        - reference_id: PMID:1627644
          supporting_text: "cDNA cloning, sequencing, expression and possible domain
            structure of human APEX nuclease homologous to Escherichia coli exonuclease
            III"

  - term:
      id: GO:0008296
      label: 3'-5'-DNA exonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:1627644
    review:
      summary: >-
        APEX1 has 3'-5' DNA exonuclease activity for proofreading mismatched
        3' termini.
      action: ACCEPT
      reason: >-
        This is a documented enzymatic activity of APEX1, important for
        removing mismatched nucleotides during BER.
      supported_by:
        - reference_id: PMID:1627644
          supporting_text: "cDNA cloning, sequencing, expression and possible domain
            structure of human APEX nuclease homologous to Escherichia coli exonuclease
            III"

  - term:
      id: GO:0052720
      label: class II DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:1627644
    review:
      summary: >-
        Original characterization of APEX1 as class II AP endonuclease.
      action: ACCEPT
      reason: >-
        Core molecular function annotation.
      supported_by:
        - reference_id: PMID:1627644
          supporting_text: "cDNA cloning, sequencing, expression and possible domain
            structure of human APEX nuclease homologous to Escherichia coli exonuclease
            III"

  - term:
      id: GO:0090580
      label: phosphodiesterase activity, acting on 
        3'-phosphoglycolate-terminated DNA strands
    evidence_type: IDA
    original_reference_id: PMID:1627644
    review:
      summary: >-
        APEX1 has 3'-phosphodiesterase activity that removes 3'-blocking groups
        including phosphoglycolate from DNA strand breaks.
      action: ACCEPT
      reason: >-
        This is a specific 3'-end processing activity of APEX1 important for
        repairing oxidative DNA damage.

      supported_by:
        - reference_id: PMID:1627644
          supporting_text: cDNA cloning, sequencing, expression and possible 
            domain structure of human APEX nuclease homologous to Escherichia 
            coli exonuclease III.
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IDA
    original_reference_id: PMID:18809583
    review:
      summary: >-
        APEX1 (Ref-1) functions as a transcription coactivator by reducing
        transcription factors and enhancing their DNA binding.
      action: ACCEPT
      reason: >-
        Transcription coactivator activity via redox regulation is a core
        function of APEX1/Ref-1. This activity is mediated by the N-terminal
        redox domain.
      supported_by:
        - reference_id: PMID:18809583
          supporting_text: "Regulatory role of human AP-endonuclease (APE1/Ref-1)
            in YB-1-mediated activation of the multidrug resistance gene MDR1"

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:18809583
    review:
      summary: >-
        APEX1 positively regulates RNA Pol II transcription through its
        coactivator function.
      action: ACCEPT
      reason: >-
        This is a valid biological process annotation for APEX1's transcriptional
        coactivator function.
      supported_by:
        - reference_id: PMID:18809583
          supporting_text: "Regulatory role of human AP-endonuclease (APE1/Ref-1)
            in YB-1-mediated activation of the multidrug resistance gene MDR1"

  - term:
      id: GO:0042981
      label: regulation of apoptotic process
    evidence_type: IDA
    original_reference_id: PMID:19934257
    review:
      summary: >-
        APEX1 regulates apoptosis through its interaction with SIRT1 and
        role in DNA damage response.
      action: KEEP_AS_NON_CORE
      reason: >-
        Apoptosis regulation is a downstream consequence of APEX1's DNA repair
        function rather than a core function. Loss of APEX1 leads to increased
        apoptosis due to accumulated DNA damage.
      supported_by:
        - reference_id: PMID:19934257
          supporting_text: "SIRT1 deacetylates APE1 and regulates cellular base excision
            repair"

  - term:
      id: GO:0097698
      label: telomere maintenance via base-excision repair
    evidence_type: IDA
    original_reference_id: PMID:24703901
    review:
      summary: >-
        APEX1 processes abasic sites in telomeric DNA to maintain telomere integrity.
      action: ACCEPT
      reason: >-
        This is a specialized application of APEX1's BER function to telomeric
        sequences, which accumulate oxidative damage.
      supported_by:
        - reference_id: PMID:24703901
          supporting_text: "APE1 incision activity at abasic sites in tandem repeat
            sequences"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:28404743
    review:
      summary: >-
        Additional IDA evidence for nuclear localization.
      action: ACCEPT
      reason: >-
        Consistent with other evidence for nuclear localization.
      supported_by:
        - reference_id: PMID:28404743
          supporting_text: "Nuclear complex of glyceraldehyde-3-phosphate dehydrogenase
            and DNA repair enzyme apurinic/apyrimidinic endonuclease I protect smooth
            muscle cells against oxidant-induced cell death"

  - term:
      id: GO:0003906
      label: DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:8932386
    review:
      summary: >-
        Note: This PMID is about Drosophila ribosomal protein P0, not directly
        APEX1. The citation may be used for comparative evidence.
      action: ACCEPT
      reason: >-
        AP endonuclease activity is the core function of APEX1. Multiple other
        PMIDs directly demonstrate this activity.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1"

        - reference_id: PMID:8932386
          supporting_text: Drosophila ribosomal protein PO contains 
            apurinic/apyrimidinic endonuclease activity.
  - term:
      id: GO:0006284
      label: base-excision repair
    evidence_type: IDA
    original_reference_id: PMID:8932386
    review:
      summary: >-
        BER function of APEX1 demonstrated through comparative studies.
      action: ACCEPT
      reason: >-
        BER is the core biological process function of APEX1.
      supported_by:
        - reference_id: PMID:1627644
          supporting_text: "cDNA cloning, sequencing, expression and possible domain
            structure of human APEX nuclease homologous to Escherichia coli exonuclease
            III"

        - reference_id: PMID:8932386
          supporting_text: Drosophila ribosomal protein PO contains 
            apurinic/apyrimidinic endonuclease activity.
  - term:
      id: GO:0000723
      label: telomere maintenance
    evidence_type: IDA
    original_reference_id: PMID:24703901
    review:
      summary: >-
        APEX1 contributes to telomere maintenance by processing AP sites in
        telomeric DNA.
      action: KEEP_AS_NON_CORE
      reason: >-
        Telomere maintenance is a specialized application of APEX1's BER function.
        The primary function is general BER; telomere-specific activity is a
        secondary consequence.
      supported_by:
        - reference_id: PMID:24703901
          supporting_text: "APE1 incision activity at abasic sites in tandem repeat
            sequences"

  - term:
      id: GO:0000781
      label: chromosome, telomeric region
    evidence_type: IC
    original_reference_id: PMID:24703901
    review:
      summary: >-
        Inferred curator annotation that APEX1 localizes to telomeres based on
        its telomeric DNA binding and maintenance activities.
      action: KEEP_AS_NON_CORE
      reason: >-
        Telomeric localization is inferred from functional data. This is a
        specialized location consistent with telomere maintenance function.
      supported_by:
        - reference_id: PMID:24703901
          supporting_text: "APE1 incision activity at abasic sites in tandem repeat
            sequences"

  - term:
      id: GO:0003684
      label: damaged DNA binding
    evidence_type: IDA
    original_reference_id: PMID:24703901
    review:
      summary: >-
        APEX1 binds to damaged DNA containing abasic sites.
      action: ACCEPT
      reason: >-
        Damaged DNA binding is essential for APEX1's recognition of repair
        substrates.
      supported_by:
        - reference_id: PMID:24703901
          supporting_text: "APE1 incision activity at abasic sites in tandem repeat
            sequences"

  - term:
      id: GO:0003691
      label: double-stranded telomeric DNA binding
    evidence_type: IDA
    original_reference_id: PMID:24703901
    review:
      summary: >-
        APEX1 binds to double-stranded telomeric DNA containing AP sites.
      action: KEEP_AS_NON_CORE
      reason: >-
        Telomeric DNA binding is a specialized aspect of APEX1's damaged DNA
        binding function.
      supported_by:
        - reference_id: PMID:24703901
          supporting_text: "APE1 incision activity at abasic sites in tandem repeat
            sequences"

  - term:
      id: GO:0003906
      label: DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:24703901
    review:
      summary: >-
        AP endonuclease activity at telomeric AP sites.
      action: ACCEPT
      reason: >-
        Core molecular function annotation.
      supported_by:
        - reference_id: PMID:24703901
          supporting_text: "APE1 incision activity at abasic sites in tandem repeat
            sequences"

  - term:
      id: GO:0008309
      label: double-stranded DNA exodeoxyribonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:24703901
    review:
      summary: >-
        APEX1 has exonuclease activity on double-stranded DNA substrates.
      action: ACCEPT
      reason: >-
        Exonuclease activity is a documented enzymatic function of APEX1.
      supported_by:
        - reference_id: PMID:24703901
          supporting_text: "APE1 incision activity at abasic sites in tandem repeat
            sequences"

  - term:
      id: GO:0003906
      label: DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:18973764
    review:
      summary: >-
        Additional evidence for AP endonuclease activity.
      action: ACCEPT
      reason: >-
        Core molecular function.
      supported_by:
        - reference_id: PMID:18973764
          supporting_text: "Human ribosomal protein S3 (hRpS3) interacts with uracil-DNA
            glycosylase (hUNG) and stimulates its glycosylase activity"

  - term:
      id: GO:0008081
      label: phosphoric diester hydrolase activity
    evidence_type: IDA
    original_reference_id: PMID:18973764
    review:
      summary: >-
        Phosphodiester hydrolase activity of APEX1.
      action: ACCEPT
      reason: >-
        Core enzymatic function.
      supported_by:
        - reference_id: PMID:18973764
          supporting_text: "Human ribosomal protein S3 (hRpS3) interacts with uracil-DNA
            glycosylase (hUNG) and stimulates its glycosylase activity"

  - term:
      id: GO:0003906
      label: DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:15707971
    review:
      summary: >-
        Additional evidence for AP endonuclease activity.
      action: ACCEPT
      reason: >-
        Core molecular function.
      supported_by:
        - reference_id: PMID:15707971
          supporting_text: "Characterization of a wide range base-damage-endonuclease
            activity of mammalian rpS3"

  - term:
      id: GO:0003684
      label: damaged DNA binding
    evidence_type: IDA
    original_reference_id: PMID:14706345
    review:
      summary: >-
        APEX1 binds to DNA containing 8-oxoguanine and abasic sites.
      action: ACCEPT
      reason: >-
        Damaged DNA binding is essential for substrate recognition.
      supported_by:
        - reference_id: PMID:14706345
          supporting_text: "Characterization of human ribosomal protein S3 binding
            to 7,8-dihydro-8-oxoguanine and abasic sites by surface plasmon resonance"

# TAS REACTOME ANNOTATIONS - Nucleoplasm localizations
  - term:
      id: GO:0006287
      label: base-excision repair, gap-filling
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-73933
    review:
      summary: >-
        APEX1 participates in BER gap-filling by coordinating with DNA polymerase
        beta after AP site incision.
      action: ACCEPT
      reason: >-
        This describes APEX1's role in the downstream steps of BER where the
        gap is filled after AP site incision.
      supported_by:
        - reference_id: Reactome:R-HSA-73933
          supporting_text: "Resolution of Abasic Sites (AP sites)"

  - term:
      id: GO:0004520
      label: DNA endonuclease activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110359
    review:
      summary: >-
        APEX1 has DNA endonuclease activity, cleaving at AP sites.
      action: ACCEPT
      reason: >-
        DNA endonuclease activity is a core molecular function of APEX1.
      supported_by:
        - reference_id: Reactome:R-HSA-110359
          supporting_text: "APEX1 mediates endonucleolytic cleavage at the 5' side
            of the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110349
    review:
      summary: >-
        APEX1 localizes to nucleoplasm for BER function.
      action: ACCEPT
      reason: >-
        Nucleoplasm localization is consistent with APEX1's nuclear DNA repair
        function. Multiple Reactome pathways place APEX1 in the nucleoplasm.
      supported_by:
        - reference_id: Reactome:R-HSA-110349
          supporting_text: "Displacement of UNG glycosylase by APEX1 at the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110350
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome TDG displacement reaction.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110350
          supporting_text: "Displacement of TDG glycosylase by APEX1 at the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110351
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome SMUG1 displacement reaction.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110351
          supporting_text: "Displacement of SMUG1 glycosylase by APEX1 at the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110352
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome NTHL1 displacement reaction.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110352
          supporting_text: "Displacement of NTHL1 glycosylase by APEX1 at the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110353
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome MBD4 displacement reaction.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110353
          supporting_text: "Displacement of MBD4 glycosylase by APEX1 at the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110354
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome OGG1 displacement reaction.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110354
          supporting_text: "Displacement of OGG1 glycosylase by APEX1 at the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110355
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome MUTYH displacement reaction.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110355
          supporting_text: "Displacement of MUTYH glycosylase by APEX1 at the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110356
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome MPG displacement reaction.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110356
          supporting_text: "Displacement of MPG glycosylase by APEX1 at the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110359
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome AP site cleavage reaction.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110359
          supporting_text: "APEX1 mediates endonucleolytic cleavage at the 5' side
            of the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110360
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome POLB recruitment.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110360
          supporting_text: "Recruitment of POLB to the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110363
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome FEN1 cleavage reaction.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110363
          supporting_text: "FEN1 bound to PCNA and APEX1 cleaves flap ssDNA"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110364
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome long-patch BER.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110364
          supporting_text: "PCNA:POLD,POLE:RPA:RFC and FEN1 bind APEX1"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110368
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome strand displacement.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110368
          supporting_text: "POLD,POLE-mediated DNA strand displacement synthesis"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110371
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome LIG1 binding.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110371
          supporting_text: "LIG1 binds APEX1 and PCNA at SSB"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110375
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome dRP excision.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-110375
          supporting_text: "Excision of the abasic sugar phosphate (5'dRP) residue
            at the single strand break"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-111253
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome POLB incorporation.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-111253
          supporting_text: "POLB incorporates the first 3' dNMP and displaces 5'ddRP
            at SSB site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5649854
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome oxidatively damaged AP site.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-5649854
          supporting_text: "Recruitment of POLB to oxidatively damaged AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5649856
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome oxidative damage.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-5649856
          supporting_text: "Oxidative damage to the AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5649873
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome PARP binding.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-5649873
          supporting_text: "PARP1,PARP2 dimers and FEN1 bind POLB and displace APEX1
            from damaged AP site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5651805
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome ligation.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-5651805
          supporting_text: "LIG1 bound to APEX1 and PCNA ligates SSB"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5651809
    review:
      summary: >-
        Duplicate nucleoplasm annotation from Reactome dissociation.
      action: ACCEPT
      reason: >-
        Consistent with other nucleoplasm localizations.
      supported_by:
        - reference_id: Reactome:R-HSA-5651809
          supporting_text: "LIG1, APEX1 and PCNA:POLD,POLE:RPA:RFC dissociate from
            repaired DNA"

# HDA RNA binding annotation
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22681889
    review:
      summary: >-
        High-throughput study identifying APEX1 as an mRNA-binding protein.
      action: ACCEPT
      reason: >-
        RNA binding is documented for APEX1, particularly for its endoribonuclease
        function on c-myc mRNA and rRNA quality control.
      supported_by:
        - reference_id: PMID:22681889
          supporting_text: "The mRNA-bound proteome and its global occupancy profile
            on protein-coding transcripts"

# Additional IDA annotations
  - term:
      id: GO:0003684
      label: damaged DNA binding
    evidence_type: IDA
    original_reference_id: PMID:12524539
    review:
      summary: >-
        APEX1 binds damaged DNA as part of SET complex function.
      action: ACCEPT
      reason: >-
        Damaged DNA binding is essential for APEX1's repair function.
      supported_by:
        - reference_id: PMID:12524539
          supporting_text: "Cleaving the oxidative repair protein Ape1 enhances cell
            death mediated by granzyme A"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: PMID:17148573
    review:
      summary: >-
        IDA evidence for nucleoplasm localization.
      action: ACCEPT
      reason: >-
        Consistent with other evidence for nucleoplasm localization.
      supported_by:
        - reference_id: PMID:17148573
          supporting_text: "UVA irradiation induces relocalisation of the DNA repair
            protein hOGG1 to nuclear speckles"

  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IDA
    original_reference_id: PMID:17148573
    review:
      summary: >-
        IDA evidence for nucleolus localization.
      action: ACCEPT
      reason: >-
        Nucleolar localization is consistent with APEX1's rRNA quality control
        function.
      supported_by:
        - reference_id: PMID:17148573
          supporting_text: "UVA irradiation induces relocalisation of the DNA repair
            protein hOGG1 to nuclear speckles"

  - term:
      id: GO:0016491
      label: oxidoreductase activity
    evidence_type: IDA
    original_reference_id: PMID:12524539
    review:
      summary: >-
        APEX1 has redox/oxidoreductase activity that regulates transcription
        factor DNA binding.
      action: ACCEPT
      reason: >-
        Oxidoreductase activity is a core molecular function of APEX1/Ref-1,
        mediating the reduction of cysteines in transcription factors.
      supported_by:
        - reference_id: PMID:12524539
          supporting_text: "Cleaving the oxidative repair protein Ape1 enhances cell
            death mediated by granzyme A"

  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IDA
    original_reference_id: PMID:17148573
    review:
      summary: >-
        APEX1 localizes to nuclear speckles after genotoxic stress.
      action: ACCEPT
      reason: >-
        Nuclear speck localization is documented, particularly after DNA damage.
      supported_by:
        - reference_id: PMID:17148573
          supporting_text: "UVA irradiation induces relocalisation of the DNA repair
            protein hOGG1 to nuclear speckles"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:15942031
    review:
      summary: >-
        IDA evidence for nuclear localization with NLS characterization.
      action: ACCEPT
      reason: >-
        This study characterized APEX1's nuclear localization signal.
      supported_by:
        - reference_id: PMID:15942031
          supporting_text: "Analysis of nuclear transport signals in the human apurinic/apyrimidinic
            endonuclease (APE1/Ref1)"

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:9560228
    review:
      summary: >-
        APEX1 detected in cytoplasm under certain conditions.
      action: ACCEPT
      reason: >-
        Cytoplasmic localization occurs in response to oxidative stress and
        other signals.
      supported_by:
        - reference_id: PMID:9560228
          supporting_text: "Activation of apurinic/apyrimidinic endonuclease in human
            cells by reactive oxygen species and its correlation with their adaptive
            response to genotoxicity of free radicals"

  - term:
      id: GO:0006281
      label: DNA repair
    evidence_type: IDA
    original_reference_id: PMID:9560228
    review:
      summary: >-
        DNA repair function of APEX1 in oxidative stress response.
      action: ACCEPT
      reason: >-
        DNA repair is the core function of APEX1.
      supported_by:
        - reference_id: PMID:9560228
          supporting_text: "Activation of apurinic/apyrimidinic endonuclease in human
            cells by reactive oxygen species and its correlation with their adaptive
            response to genotoxicity of free radicals"

  - term:
      id: GO:0008408
      label: 3'-5' exonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:11832948
    review:
      summary: >-
        APEX1 has 3'-5' exonuclease activity on mismatched DNA.
      action: ACCEPT
      reason: >-
        This is a documented enzymatic activity of APEX1.
      supported_by:
        - reference_id: PMID:11832948
          supporting_text: "An exonucleolytic activity of human apurinic/apyrimidinic
            endonuclease on 3' mispaired DNA"

  - term:
      id: GO:0043488
      label: regulation of mRNA stability
    evidence_type: IMP
    original_reference_id: PMID:19401441
    review:
      summary: >-
        APEX1 regulates c-myc mRNA stability through its endoribonuclease
        activity.
      action: ACCEPT
      reason: >-
        This biological process annotation reflects APEX1's endoribonuclease
        function in mRNA metabolism.
      supported_by:
        - reference_id: PMID:19401441
          supporting_text: "Identification of Apurinic/apyrimidinic endonuclease 1
            (APE1) as the endoribonuclease that cleaves c-myc mRNA"

  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:20231292
    review:
      summary: >-
        Cleaved APEX1 localizes to mitochondria.
      action: ACCEPT
      reason: >-
        Mitochondrial localization is documented and functionally important
        for mtDNA repair.
      supported_by:
        - reference_id: PMID:20231292
          supporting_text: "Identification and characterization of mitochondrial targeting
            sequence of human apurinic/apyrimidinic endonuclease 1"

  - term:
      id: GO:0031490
      label: chromatin DNA binding
    evidence_type: IDA
    original_reference_id: PMID:11809897
    review:
      summary: >-
        APEX1 binds to chromatin DNA at nCaRE elements.
      action: ACCEPT
      reason: >-
        Chromatin DNA binding is relevant to APEX1's transcriptional regulatory
        function.
      supported_by:
        - reference_id: PMID:11809897
          supporting_text: "Human AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like
            repressor element in the AP-endonuclease 1 promoter"

  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IDA
    original_reference_id: PMID:19188445
    review:
      summary: >-
        APEX1 localizes to nucleolus for rRNA quality control.
      action: ACCEPT
      reason: >-
        Nucleolar localization is well-documented and functionally important.
      supported_by:
        - reference_id: PMID:19188445
          supporting_text: "APE1/Ref-1 interacts with NPM1 within nucleoli and plays
            a role in the rRNA quality control process"

  - term:
      id: GO:0003906
      label: DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:19188445
    review:
      summary: >-
        AP endonuclease activity documented in nucleolar context.
      action: ACCEPT
      reason: >-
        Core molecular function annotation.
      supported_by:
        - reference_id: PMID:19188445
          supporting_text: "APE1/Ref-1 interacts with NPM1 within nucleoli and plays
            a role in the rRNA quality control process"

# Additional TAS annotations
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: TAS
    original_reference_id: PMID:12524539
    review:
      summary: >-
        APEX1 detected in ER by colocalization with calreticulin.
      action: KEEP_AS_NON_CORE
      reason: >-
        ER localization is documented but represents a minor pool of APEX1.
      supported_by:
        - reference_id: PMID:12524539
          supporting_text: "Cleaving the oxidative repair protein Ape1 enhances cell
            death mediated by granzyme A"

  - term:
      id: GO:0005840
      label: ribosome
    evidence_type: TAS
    original_reference_id: PMID:12524539
    review:
      summary: >-
        APEX1 detected in ribosomal fraction, possibly related to mRNA
        processing function.
      action: KEEP_AS_NON_CORE
      reason: >-
        Ribosomal localization is likely related to APEX1's RNA processing
        function but is not a core localization.
      supported_by:
        - reference_id: PMID:12524539
          supporting_text: "Cleaving the oxidative repair protein Ape1 enhances cell
            death mediated by granzyme A"

  - term:
      id: GO:0016491
      label: oxidoreductase activity
    evidence_type: IDA
    original_reference_id: PMID:9119221
    review:
      summary: >-
        APEX1/Ref-1 has oxidoreductase activity that activates p53.
      action: ACCEPT
      reason: >-
        Oxidoreductase (redox) activity is a core function of APEX1.
      supported_by:
        - reference_id: PMID:9119221
          supporting_text: "Identification of redox/repair protein Ref-1 as a potent
            activator of p53"

  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IDA
    original_reference_id: PMID:11286553
    review:
      summary: >-
        APEX1 binds DNA as part of its catalytic mechanism.
      action: ACCEPT
      reason: >-
        DNA binding is essential for APEX1's enzymatic function.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1"

  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IDA
    original_reference_id: PMID:9119221
    review:
      summary: >-
        APEX1 acts as transcription coactivator through redox regulation of p53.
      action: ACCEPT
      reason: >-
        Transcription coactivator activity is a core function of APEX1/Ref-1.
      supported_by:
        - reference_id: PMID:9119221
          supporting_text: "Identification of redox/repair protein Ref-1 as a potent
            activator of p53"

  - term:
      id: GO:0003906
      label: DNA-(apurinic or apyrimidinic site) endonuclease activity
    evidence_type: TAS
    original_reference_id: PMID:9119221
    review:
      summary: >-
        Core AP endonuclease activity of APEX1.
      action: ACCEPT
      reason: >-
        Core molecular function annotation.
      supported_by:
        - reference_id: PMID:9119221
          supporting_text: "Identification of redox/repair protein Ref-1 as a potent
            activator of p53"

  - term:
      id: GO:0004523
      label: RNA-DNA hybrid ribonuclease activity
    evidence_type: TAS
    original_reference_id: PMID:11286553
    review:
      summary: >-
        APEX1 can incise at AP sites in DNA strand of RNA-DNA hybrids.
      action: ACCEPT
      reason: >-
        This activity is documented for APEX1 and represents substrate specificity
        for RNA-DNA hybrids containing AP sites.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1"

  - term:
      id: GO:0004528
      label: phosphodiesterase I activity
    evidence_type: TAS
    original_reference_id: PMID:9119221
    review:
      summary: >-
        APEX1 has 3'-phosphodiesterase activity.
      action: ACCEPT
      reason: >-
        Phosphodiesterase activity is a documented function of APEX1.
      supported_by:
        - reference_id: PMID:9119221
          supporting_text: "Identification of redox/repair protein Ref-1 as a potent
            activator of p53"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:9119221
    review:
      summary: >-
        IDA evidence for nuclear localization.
      action: ACCEPT
      reason: >-
        Nuclear localization is well-established.
      supported_by:
        - reference_id: PMID:9119221
          supporting_text: "Identification of redox/repair protein Ref-1 as a potent
            activator of p53"

  - term:
      id: GO:0008408
      label: 3'-5' exonuclease activity
    evidence_type: TAS
    original_reference_id: PMID:11286553
    review:
      summary: >-
        APEX1 has 3'-5' exonuclease activity.
      action: ACCEPT
      reason: >-
        This enzymatic activity is documented for APEX1.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1"

  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IDA
    original_reference_id: PMID:11286553
    review:
      summary: >-
        APEX1 requires divalent metal ions (Mg2+, Mn2+) for catalysis.
      action: ACCEPT
      reason: >-
        Metal ion binding is essential for APEX1's catalytic mechanism.
      supported_by:
        - reference_id: PMID:11286553
          supporting_text: "Two divalent metal ions in the active site of a new crystal
            form of human apurinic/apyrimidinic endonuclease, Ape1: implications for
            the catalytic mechanism"

  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:12524539
    review:
      summary: >-
        APEX1 detected in perinuclear region.
      action: KEEP_AS_NON_CORE
      reason: >-
        Perinuclear localization represents cytoplasmic APEX1 pool, which is
        a minor fraction.
      supported_by:
        - reference_id: PMID:12524539
          supporting_text: "Cleaving the oxidative repair protein Ape1 enhances cell
            death mediated by granzyme A"

  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: TAS
    original_reference_id: PMID:7961715
    review:
      summary: >-
        APEX1 acts as transcription corepressor at nCaRE elements.
      action: KEEP_AS_NON_CORE
      reason: >-
        Transcription corepressor activity is a secondary function of APEX1,
        distinct from its DNA repair and redox coactivator functions.
      supported_by:
        - reference_id: PMID:7961715
          supporting_text: "A redox factor protein, ref1, is involved in negative
            gene regulation by extracellular calcium"

  - term:
      id: GO:0004520
      label: DNA endonuclease activity
    evidence_type: TAS
    original_reference_id: PMID:1722334
    review:
      summary: >-
        Core DNA endonuclease activity of APEX1.
      action: ACCEPT
      reason: >-
        DNA endonuclease activity is a core molecular function.
      supported_by:
        - reference_id: PMID:1722334
          supporting_text: "Cloning and expression of APE, the cDNA encoding the major
            human apurinic endonuclease: definition of a family of DNA repair enzymes"

  - term:
      id: GO:0004844
      label: uracil DNA N-glycosylase activity
    evidence_type: TAS
    original_reference_id: PMID:10805771
    review:
      summary: >-
        This annotation appears to be incorrect. APEX1 is an AP endonuclease
        that acts DOWNSTREAM of uracil DNA glycosylase (UNG), not as a
        glycosylase itself. The cited paper is about UNG, not APEX1.
      action: REMOVE
      reason: >-
        APEX1 does not have uracil DNA N-glycosylase activity. It is an AP
        endonuclease that processes the abasic sites created by glycosylases
        like UNG. This appears to be an annotation error where APEX1 was
        confused with UNG based on their sequential roles in BER.
      supported_by:
        - reference_id: PMID:10805771
          supporting_text: "Uracil-DNA glycosylase-DNA substrate and product structures
            [this paper is about UNG, not APEX1]"

  - term:
      id: GO:0004519
      label: endonuclease activity
    evidence_type: IDA
    original_reference_id: PMID:11478795
    review:
      summary: >-
        APEX1 has endonuclease activity.
      action: ACCEPT
      reason: >-
        Endonuclease activity is a core molecular function of APEX1.
      supported_by:
        - reference_id: PMID:11478795
          supporting_text: "Sequence analysis identifies TTRAP, a protein that associates
            with CD40 and TNF receptor-associated factors, as a member of a superfamily
            of divalent cation-dependent phosphodiesterases"

  - term:
      id: GO:0008081
      label: phosphoric diester hydrolase activity
    evidence_type: IDA
    original_reference_id: PMID:11478795
    review:
      summary: >-
        APEX1 has phosphoric diester hydrolase activity.
      action: ACCEPT
      reason: >-
        Core enzymatic activity of APEX1.
      supported_by:
        - reference_id: PMID:11478795
          supporting_text: "Sequence analysis identifies TTRAP, a protein that associates
            with CD40 and TNF receptor-associated factors, as a member of a superfamily
            of divalent cation-dependent phosphodiesterases"

references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000003
    title: Gene Ontology annotation based on Enzyme Commission mapping
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:1627644
    title: cDNA cloning, sequencing, expression and possible domain structure of
      human APEX nuclease
    findings:
      - statement: Original characterization of APEX1 as major human AP 
          endonuclease
  - id: PMID:1722334
    title: Cloning and expression of APE, the cDNA encoding the major human 
      apurinic endonuclease
    findings:
      - statement: Defined APEX1 as family member of DNA repair enzymes
  - id: PMID:7961715
    title: A redox factor protein, ref1, is involved in negative gene regulation
      by extracellular calcium
    findings:
      - statement: APEX1/Ref-1 acts as transcription corepressor at nCaRE 
          elements
  - id: PMID:8621488
    title: The interaction between Ku antigen and REF1 protein mediates negative
      gene regulation
    findings:
      - statement: APEX1 interacts with Ku70/Ku80 for transcriptional repression
  - id: PMID:8932386
    title: Drosophila ribosomal protein PO contains apurinic/apyrimidinic 
      endonuclease activity.
    findings:
      - statement: Demonstrates conservation of AP endonuclease activity across 
          species
  - id: PMID:9108029
    title: AP-1 transcriptional activity is regulated by a direct association 
      between thioredoxin and Ref-1
    findings:
      - statement: APEX1 interacts with thioredoxin to regulate AP-1 DNA binding
  - id: PMID:9119221
    title: Identification of redox/repair protein Ref-1 as a potent activator of
      p53
    findings:
      - statement: APEX1 has redox activity that activates p53
  - id: PMID:9207062
    title: Interaction of human apurinic endonuclease and DNA polymerase beta in
      the base excision repair pathway.
    findings:
      - statement: APEX1 interacts with and stimulates DNA polymerase beta
  - id: PMID:9560228
    title: Activation of apurinic/apyrimidinic endonuclease in human cells by 
      reactive oxygen species
    findings:
      - statement: APEX1 is activated by ROS and localizes to both nucleus and 
          cytoplasm
  - id: PMID:9804798
    title: Dynamics of the interaction of human apurinic endonuclease (Ape1) 
      with its substrate and product
    findings:
      - statement: Kinetic analysis of APEX1 AP endonuclease mechanism
  - id: PMID:10805771
    title: Uracil-DNA glycosylase-DNA substrate and product structures
    findings:
      - statement: This paper is about UNG, not APEX1
  - id: PMID:11118054
    title: Thioredoxin nuclear translocation and interaction with redox factor-1
      activates the activator protein-1 transcription factor in response to 
      ionizing radiation.
    findings:
      - statement: APEX1-thioredoxin interaction in AP-1 activation
  - id: PMID:11160897
    title: Enhanced activity of adenine-DNA glycosylase (Myh) by 
      apurinic/apyrimidinic endonuclease (Ape1) in mammalian base excision 
      repair of an A/GO mismatch.
    findings:
      - statement: APEX1 enhances MYH glycosylase activity
  - id: PMID:11286553
    title: "Two divalent metal ions in the active site of a new crystal form of human
      apurinic/apyrimidinic endonuclease, Ape1: implications for the catalytic mechanism."
    findings:
      - statement: Crystal structure showing metal ion coordination for 
          catalysis
  - id: PMID:11478795
    title: Sequence analysis identifies TTRAP, a protein that associates with 
      CD40 and TNF receptor-associated factors, as a member of a superfamily of 
      divalent cation-dependent phosphodiesterases.
    findings:
      - statement: APEX1 classified as phosphodiesterase
  - id: PMID:11809897
    title: Human AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like 
      repressor element in the AP-endonuclease 1 promoter.
    findings:
      - statement: APEX1 functions in transcriptional repression
  - id: PMID:11832948
    title: "An exonucleolytic activity of human apurinic/apyrimidinic endonuclease
      on 3' mispaired DNA."
    findings:
      - statement: APEX1 has 3'-5' exonuclease activity on mismatched DNA
  - id: PMID:12524539
    title: Cleaving the oxidative repair protein Ape1 enhances cell death 
      mediated by granzyme A
    findings:
      - statement: APEX1 is cleaved by granzyme A and is part of SET complex
  - id: PMID:14706345
    title: Characterization of human ribosomal protein S3 binding to 
      7,8-dihydro-8-oxoguanine and abasic sites by surface plasmon resonance.
    findings:
      - statement: APEX1 binds damaged DNA containing 8-oxoG and AP sites
  - id: PMID:15518571
    title: Human ribosomal protein S3 interacts with DNA base excision repair 
      proteins
    findings:
      - statement: RPS3 interacts with APEX1 and OGG1
  - id: PMID:15707971
    title: Characterization of a wide range base-damage-endonuclease activity of
      mammalian rpS3.
    findings:
      - statement: Comparative study of APEX1 and rpS3 endonuclease activities
  - id: PMID:15942031
    title: Analysis of nuclear transport signals in the human 
      apurinic/apyrimidinic endonuclease (APE1/Ref1).
    findings:
      - statement: Characterized APEX1 NLS and interaction with importins
  - id: PMID:17148573
    title: UVA irradiation induces relocalisation of the DNA repair protein 
      hOGG1 to nuclear speckles.
    findings:
      - statement: APEX1 colocalizes to nuclear speckles after DNA damage
  - id: PMID:18809583
    title: Regulatory role of human AP-endonuclease (APE1/Ref-1) in 
      YB-1-mediated activation of the multidrug resistance gene MDR1.
    findings:
      - statement: APEX1 acts as transcription coactivator for MDR1
  - id: PMID:18973764
    title: Human ribosomal protein S3 (hRpS3) interacts with uracil-DNA 
      glycosylase (hUNG) and stimulates its glycosylase activity.
    findings:
      - statement: APEX1 phosphodiester hydrolase activity
  - id: PMID:19188445
    title: APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in 
      the rRNA quality control process.
    findings:
      - statement: APEX1 has nucleolar function in rRNA quality control
  - id: PMID:19401441
    title: Identification of Apurinic/apyrimidinic endonuclease 1 (APE1) as the 
      endoribonuclease that cleaves c-myc mRNA.
    findings:
      - statement: APEX1 has endoribonuclease activity regulating mRNA stability
  - id: PMID:19465398
    title: HMGA2 exhibits dRP/AP site cleavage activity
    findings:
      - statement: APEX1 interaction with HMGA2
  - id: PMID:19505873
    title: Complementary quantitative proteomics reveals that transcription 
      factor AP-4 mediates E-box-dependent complex formation for transcriptional
      repression of HDM2.
    findings:
      - statement: High-throughput proteomics identifying APEX1 interactions
  - id: PMID:19934257
    title: SIRT1 deacetylates APE1 and regulates cellular base excision repair
    findings:
      - statement: APEX1 is deacetylated by SIRT1 and interacts with XRCC1
  - id: PMID:20231292
    title: Identification and characterization of mitochondrial targeting 
      sequence of human apurinic/apyrimidinic endonuclease 1.
    findings:
      - statement: APEX1 has C-terminal MTS for mitochondrial localization
  - id: PMID:20696907
    title: Identification of RING finger protein 4 (RNF4) as a modulator of DNA 
      demethylation through a functional genomics screen.
    findings:
      - statement: High-throughput screen identifying APEX1-RNF4 interaction
  - id: PMID:20808282
    title: A multiprotein complex necessary for both transcription and DNA 
      replication
    findings:
      - statement: APEX1 identified in transcription/replication complex
  - id: PMID:20856196
    title: APE1/Ref-1 and its acetylation regulate YB-1-p300 recruitment
    findings:
      - statement: APEX1 acetylation regulates transcriptional coactivator 
          function
  - id: PMID:21496894
    title: Hydroxylation of 5-methylcytosine by TET1 promotes active DNA 
      demethylation
    findings:
      - statement: APEX1 participates in active DNA demethylation
  - id: PMID:22681889
    title: The mRNA-bound proteome and its global occupancy profile
    findings:
      - statement: High-throughput identification of APEX1 as RNA-binding 
          protein
  - id: PMID:24703901
    title: APE1 incision activity at abasic sites in tandem repeat sequences
    findings:
      - statement: APEX1 processes AP sites at telomeres and tandem repeats
  - id: PMID:26760506
    title: "R152C DNA Pol β mutation impairs base excision repair and induces cellular
      transformation."
    findings:
      - statement: APEX1 interacts with DNA polymerase beta
  - id: PMID:28404743
    title: Nuclear complex of glyceraldehyde-3-phosphate dehydrogenase and DNA 
      repair enzyme apurinic/apyrimidinic endonuclease I protect smooth muscle 
      cells against oxidant-induced cell death.
    findings:
      - statement: APEX1 nuclear localization and protective function
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities
    findings:
      - statement: Large-scale interactome study
  - id: PMID:32911434
    title: A functionally defined high-density NRF2 interactome
    findings:
      - statement: APEX1-NRF2 interaction identified
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling
    findings:
      - statement: Large-scale proteomics study
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome
    findings:
      - statement: APEX1 confirmed in mitochondrial proteome
  - id: Reactome:R-HSA-73933
    title: Resolution of Abasic Sites (AP sites)
    findings:
      - statement: APEX1 central role in BER pathway
  - id: Reactome:R-HSA-110349
    title: Displacement of UNG glycosylase by APEX1 at the AP site
    findings: []
  - id: Reactome:R-HSA-110350
    title: Displacement of TDG glycosylase by APEX1 at the AP site
    findings: []
  - id: Reactome:R-HSA-110351
    title: Displacement of SMUG1 glycosylase by APEX1 at the AP site
    findings: []
  - id: Reactome:R-HSA-110352
    title: Displacement of NTHL1 glycosylase by APEX1 at the AP site
    findings: []
  - id: Reactome:R-HSA-110353
    title: Displacement of MBD4 glycosylase by APEX1 at the AP site
    findings: []
  - id: Reactome:R-HSA-110354
    title: Displacement of OGG1 glycosylase by APEX1 at the AP site
    findings: []
  - id: Reactome:R-HSA-110355
    title: Displacement of MUTYH glycosylase by APEX1 at the AP site
    findings: []
  - id: Reactome:R-HSA-110356
    title: Displacement of MPG glycosylase by APEX1 at the AP site
    findings: []
  - id: Reactome:R-HSA-110359
    title: APEX1 mediates endonucleolytic cleavage at the 5' side of the AP site
    findings: []
  - id: Reactome:R-HSA-110360
    title: Recruitment of POLB to the AP site
    findings: []
  - id: Reactome:R-HSA-110363
    title: FEN1 bound to PCNA and APEX1 cleaves flap ssDNA
    findings: []
  - id: Reactome:R-HSA-110364
    title: PCNA:POLD,POLE:RPA:RFC and FEN1 bind APEX1
    findings: []
  - id: Reactome:R-HSA-110368
    title: POLD,POLE-mediated DNA strand displacement synthesis
    findings: []
  - id: Reactome:R-HSA-110371
    title: LIG1 binds APEX1 and PCNA at SSB
    findings: []
  - id: Reactome:R-HSA-110375
    title: Excision of the abasic sugar phosphate (5'dRP) residue
    findings: []
  - id: Reactome:R-HSA-111253
    title: POLB incorporates the first 3' dNMP and displaces 5'ddRP
    findings: []
  - id: Reactome:R-HSA-5649854
    title: Recruitment of POLB to oxidatively damaged AP site
    findings: []
  - id: Reactome:R-HSA-5649856
    title: Oxidative damage to the AP site
    findings: []
  - id: Reactome:R-HSA-5649873
    title: PARP1,PARP2 dimers and FEN1 bind POLB and displace APEX1
    findings: []
  - id: Reactome:R-HSA-5651805
    title: LIG1 bound to APEX1 and PCNA ligates SSB
    findings: []
  - id: Reactome:R-HSA-5651809
    title: LIG1, APEX1 and PCNA:POLD,POLE:RPA:RFC dissociate from repaired DNA
    findings: []
  - id: file:human/HAP1/HAP1-deep-research-falcon.md
    title: Deep research report on APEX1
    findings: []

core_functions:
  - molecular_function:
      id: GO:0003906
      label: DNA-(apurinic or apyrimidinic site) endonuclease activity
    description: >-
      APEX1 is the major AP endonuclease in human cells, cleaving the phosphodiester
      backbone 5' to abasic sites in DNA. This is the defining molecular function
      of the protein. APEX1 plays a central role in base excision repair, acting
      downstream of DNA glycosylases to process abasic sites and coordinate with
      DNA polymerase beta for gap filling.
    directly_involved_in:
      - id: GO:0006284
        label: base-excision repair
    locations:
      - id: GO:0005634
        label: nucleus
  - molecular_function:
      id: GO:0016491
      label: oxidoreductase activity
    description: >-
      APEX1/Ref-1 reduces critical cysteines on transcription factors (HIF-1alpha,
      NF-kappaB, AP-1, p53, STAT3) to enhance their DNA binding activity. This
      redox function is independent of the DNA repair activity.
    locations:
      - id: GO:0005634
        label: nucleus
  - molecular_function:
      id: GO:0003713
      label: transcription coactivator activity
    description: >-
      Through its redox activity, APEX1 functions as a transcription coactivator,
      stimulating the DNA binding activity of multiple transcription factors in
      response to oxidative stress and other signals.
    locations:
      - id: GO:0005634
        label: nucleus

suggested_experiments:
  - description: >-
      Verify the incorrect GO:0033892 (pyrimidine dimer nuclease) and GO:0004844
      (uracil DNA glycosylase) annotations by testing whether APEX1 has activity
      on UV-induced pyrimidine dimers or can remove uracil from DNA. These
      activities are not consistent with APEX1's known biochemistry as an AP
      endonuclease.