id: Q92889
gene_symbol: ERCC4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ERCC4/XPF is the catalytic subunit of the ERCC1-XPF structure-specific DNA
  endonuclease, a Mg2+-dependent nuclease that cleaves DNA at single-stranded/
  double-stranded junctions and makes the incision 5' to a lesion on the damaged
  strand. XPF houses the nuclease active site (N-terminal helicase-like/nuclease
  region), while its obligate partner ERCC1 (bound through the C-terminal double
  helix-hairpin-helix domain) contributes additional DNA binding but is
  catalytically inert. As the enzyme that makes the 5' incision, ERCC1-XPF is
  essential for nucleotide excision repair (NER), where it is recruited to lesions
  via XPA and, together with the 3'-incising ERCC5/XPG nuclease, excises the
  damage-containing oligonucleotide. The same structure-specific endonuclease
  performs the unhooking incisions that release DNA interstrand crosslinks (ICLs),
  where it is coordinated by SLX4/FANCP, and it processes recombination
  intermediates in homology-directed pathways including single-strand annealing
  (acting on 3' non-homologous flaps, stimulated by RAD52). ERCC1-XPF also acts at
  telomeres, removing the 3' single-stranded overhang from uncapped telomeres and
  negatively regulating telomere length. The enzyme localizes to the nucleus and to
  chromatin sites of DNA damage. Loss of XPF function underlies a spectrum of human
  disease that all reflects the same endonuclease deficiency - xeroderma pigmentosum
  group F, XPF-Cockayne syndrome, XFE progeroid syndrome, and Fanconi anemia
  complementation group Q.
alternative_products:
- name: '1'
  id: Q92889-1
- name: '2'
  id: Q92889-2
  sequence_note: VSP_056341, VSP_056342
existing_annotations:
- term:
    id: GO:0006312
    label: mitotic recombination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred role in mitotic recombination, consistent with the
      conserved function of XPF-family nucleases (yeast Rad1/Rad16, fly Mei-9) in
      processing recombination intermediates.
    action: KEEP_AS_NON_CORE
    reason: >-
      ERCC1-XPF genuinely participates in homology-directed recombination (notably
      single-strand annealing, cleaving 3' non-homologous flaps), so the term is
      correct, but recombination is a specialized application of the core
      structure-specific endonuclease activity rather than the gene's primary
      (NER/ICL) function.
    supported_by:
      - reference_id: PMID:22547097
        supporting_text: >-
          ERCC1-XPF is a heterodimeric, structure-specific endonuclease that cleaves
          single-stranded/double-stranded DNA junctions and has roles in nucleotide
          excision repair (NER), interstrand crosslink (ICL) repair, homologous
          recombination, and possibly other pathways.
- term:
    id: GO:1990599
    label: 3' overhang single-stranded DNA endonuclease activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: >-
      Structure-specific endonuclease activity on 3' single-stranded overhangs;
      experimentally demonstrated at telomeres and phylogenetically conserved.
    action: ACCEPT
    reason: >-
      This is a specific, correct molecular-function term for the catalytic subunit;
      it is directly supported experimentally by XPF-dependent removal of the
      telomeric 3' overhang.
    supported_by:
      - reference_id: PMID:14690602
        supporting_text: >-
          ERCC1/XPF-deficient cells retained the telomeric overhang after TRF2
          inhibition, identifying this nucleotide excision repair endonuclease as the
          culprit in overhang removal.
- term:
    id: GO:1901255
    label: nucleotide-excision repair involved in interstrand cross-link repair
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Role in the incision (unhooking) step of interstrand crosslink repair,
      phylogenetically inferred and experimentally confirmed.
    action: ACCEPT
    reason: >-
      ERCC1-XPF makes the unhooking incisions that release ICLs; this is a core
      function of the endonuclease alongside canonical NER. Biallelic ERCC4
      mutations that selectively disrupt ICL repair (sparing NER) cause Fanconi
      anemia complementation group Q, providing human genetic evidence for this
      dedicated ICL-repair function.
    supported_by:
      - reference_id: PMID:32034146
        supporting_text: >-
          The XPF-ERCC1 heterodimer is a structure-specific endonuclease that is
          essential for nucleotide excision repair (NER) and interstrand crosslink
          (ICL) repair in mammalian cells.
      - reference_id: PMID:23623386
        supporting_text: >-
          the identified FA-causing ERCC4 mutations strongly disrupt the function
          of XPF in DNA ICL repair without severely compromising nucleotide
          excision repair.
- term:
    id: GO:0000110
    label: nucleotide-excision repair factor 1 complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      Membership in NER factor 1 (the ERCC1-XPF heterodimer), the 5'-incision
      nuclease of NER.
    action: ACCEPT
    reason: >-
      NEF1 is the ERCC1-XPF complex; XPF is a defining subunit. Correct and
      well supported.
- term:
    id: GO:0000712
    label: resolution of meiotic recombination intermediates
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred meiotic role (yeast Rad1, fly Mei-9 resolve
      heteroduplex/recombination intermediates); mouse Xpf is upregulated in meiotic
      spermatogenic cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      A conserved but specialized meiotic application of the endonuclease; not the
      primary somatic DNA-repair function of human XPF.
    supported_by:
      - reference_id: PMID:10644440
        supporting_text: >-
          support a distinct role for the XPF/ERCC1 junction-specific endonuclease
          during meiosis, most likely in the resolution of heteroduplex intermediates
          that arise during recombination.
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Role in homology-directed double-strand break repair, chiefly single-strand
      annealing where XPF-ERCC1 trims 3' non-homologous flaps.
    action: ACCEPT
    reason: >-
      A core, conserved function of the XPF family: these nucleases have dual roles in
      excision repair and recombination, and XPF-ERCC1 trims the 3' non-homologous
      flaps during single-strand annealing (stimulated by RAD52).
    supported_by:
      - reference_id: PMID:14734547
        supporting_text: >-
          The XPF/ERCC1 heterodimer is a DNA structure-specific endonuclease that
          participates in nucleotide excision repair and homology-dependent
          recombination reactions, including DNA single strand annealing and gene
          targeting.
- term:
    id: GO:0003684
    label: damaged DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Binds damaged DNA / DNA-damage sites, consistent with its recruitment to
      lesions and localization to sites of DNA damage.
    action: ACCEPT
    reason: >-
      Supported by localization of XPF to chromatin damage sites and by its
      structure-specific substrate recognition; a correct supporting molecular
      function.
    supported_by:
      - reference_id: PMID:11790111
        supporting_text: XPF forms a heterodimeric complex with ERCC1 and is required for the repair of DNA interstrand cross-links.
- term:
    id: GO:0003697
    label: single-stranded DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Binds single-stranded DNA; the XPF HhH motifs contact the ssDNA arm at ss/ds
      junctions.
    action: ACCEPT
    reason: >-
      Directly supported biochemically (XPF binds DNA without ERCC1) and structurally
      (XPF-ssDNA complex); a real, specific supporting function.
    supported_by:
      - reference_id: PMID:22483113
        supporting_text: >-
          A positively charged region within the second helix of the first HhH motif
          contacts the ssDNA phosphate backbone.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: General DNA-binding activity inferred from the ERCC4/XPF InterPro domain.
    action: ACCEPT
    reason: >-
      Correct but general; the more informative ssDNA/damaged-DNA/junction binding is
      captured by other annotations. Acceptable as a broad electronic annotation.
- term:
    id: GO:0003697
    label: single-stranded DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ssDNA binding inferred from InterPro (XPF domain).
    action: ACCEPT
    reason: >-
      Consistent with experimental and structural evidence for ssDNA binding by XPF;
      a correct electronic annotation.
- term:
    id: GO:0004520
    label: DNA endonuclease activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: DNA endonuclease activity inferred from the XPF InterPro nuclease domain.
    action: ACCEPT
    reason: >-
      Correct core catalytic activity, matching abundant experimental evidence. Could
      be refined to structure-specific/ssDNA endodeoxyribonuclease, but the general
      term is not wrong.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization (UniProt subcellular location mapping).
    action: ACCEPT
    reason: XPF is a nuclear DNA-repair enzyme; consistent with experimental localization.
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Chromosome/chromatin localization (UniProt subcellular location mapping).
    action: ACCEPT
    reason: XPF localizes to chromatin sites of DNA damage; consistent with experimental data.
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: General DNA repair, the parent process for XPF's NER/ICL/recombination roles.
    action: ACCEPT
    reason: >-
      Correct though broad; more specific processes (NER, ICL repair) are annotated
      separately. Acceptable as a high-level electronic annotation.
- term:
    id: GO:0009411
    label: response to UV
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Response to UV, reflecting XPF's role in repair of UV photolesions via NER.
    action: ACCEPT
    reason: >-
      Consistent with XP-F photosensitivity and the requirement of XPF nuclease
      activity for repair of UV-induced damage.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16338413
  qualifier: enables
  review:
    summary: >-
      IntAct-curated binary interaction with ERCC1 (P07992), the obligate partner in
      the XPF-ERCC1 heterodimer.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'protein binding' is uninformative; the functionally meaningful ERCC1
      association is captured by the ERCC4-ERCC1 complex (GO:0070522) annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17289582
  qualifier: enables
  review:
    summary: IntAct-curated binary interaction (with ERCC1, P07992).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; complex membership is captured by GO:0070522.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19596235
  qualifier: enables
  review:
    summary: >-
      IntAct-curated interaction with SLX4/BTBD12 (Q8IY92), which scaffolds
      XPF-ERCC1 with other structure-specific nucleases.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic term is uninformative; the SLX4-coordinated function is reflected in
      the ICL-repair and recombination process annotations.
    supported_by:
      - reference_id: PMID:19596235
        supporting_text: >-
          Human SLX4 forms a multiprotein complex with the ERCC4(XPF)-ERCC1,
          MUS81-EME1, and SLX1 endonucleases
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19596236
  qualifier: enables
  review:
    summary: IntAct-curated interaction with SLX4 (Q8IY92).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; SLX4 coordination is captured functionally elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24780295
  qualifier: enables
  review:
    summary: IntAct-curated interaction (with ERCC1, P07992).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; not a core function statement.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome interaction (with ERCC1, P07992).
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic term from a large-scale interactome screen; uninformative for function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary interactome interaction (with TACC1 isoform, O75410-7).
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic term from a proteome-scale two-hybrid map; not functionally interpretable here.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: High-throughput interactome interactions (ERCC1 P07992; SLX4 Q8IY92).
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic term from a large-scale interactome study; uninformative for function.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22483113
  qualifier: enables
  review:
    summary: IntAct self-interaction (XPF-XPF, Q92889) recorded from the XPF-ssDNA structural study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The physiological human enzyme is the XPF-ERCC1 heterodimer, not an XPF
      homodimer; a curated self-interaction is not an informative functional
      annotation for this gene.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization by immunofluorescence (HPA).
    action: ACCEPT
    reason: Consistent with a soluble nuclear DNA-repair enzyme.
- term:
    id: GO:0016604
    label: nuclear body
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Localization to nuclear bodies/foci, consistent with damage-induced XPF nuclear
      foci.
    action: ACCEPT
    reason: >-
      XPF is recruited into damage-induced nuclear foci; nuclear body localization is
      consistent with this behavior.
    supported_by:
      - reference_id: PMID:12571280
        supporting_text: FANCA and the known DNA repair protein XPF localize to the same nuclear foci.
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: IDA
  original_reference_id: PMID:22547097
  qualifier: involved_in
  review:
    summary: >-
      Direct role in NER as the 5'-incising nuclease; ComplexPortal annotation of the
      ERCC1-XPF endonuclease.
    action: ACCEPT
    reason: Core function. Recruited to lesions via XPA and incises 5' to the damage.
    supported_by:
      - reference_id: PMID:22547097
        supporting_text: >-
          In NER, ERCC1-XPF is recruited to DNA lesions by interaction with XPA and
          incises the DNA 5' to the lesion.
- term:
    id: GO:0070522
    label: ERCC4-ERCC1 complex
  evidence_type: IPI
  original_reference_id: PMID:16076955
  qualifier: part_of
  review:
    summary: Member of the ERCC1-XPF (ERCC4-ERCC1) structure-specific endonuclease heterodimer.
    action: ACCEPT
    reason: >-
      The definitive physiological complex for XPF; established structurally and
      biochemically. Core.
    supported_by:
      - reference_id: PMID:16076955
        supporting_text: >-
          Human XPF-ERCC1 is a DNA endonuclease that incises a damaged DNA strand on
          the 5' side of a lesion during nucleotide excision repair
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:19596235
  qualifier: located_in
  review:
    summary: >-
      Experimental nuclear localization; XPF/ERCC4 functions as part of the nuclear
      SLX4-coordinated structure-specific nuclease machinery.
    action: ACCEPT
    reason: >-
      Consistent with a nuclear DNA-repair enzyme; XPF acts within nuclear DNA-repair
      complexes.
    supported_by:
      - reference_id: PMID:19596235
        supporting_text: >-
          Human SLX4 forms a multiprotein complex with the ERCC4(XPF)-ERCC1,
          MUS81-EME1, and SLX1 endonucleases
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: EXP
  original_reference_id: PMID:11790111
  qualifier: located_in
  review:
    summary: Experimental chromosome/chromatin localization; localizes to sites of DNA damage.
    action: ACCEPT
    reason: >-
      Chromatin association at damage sites is consistent with UniProt's note that XPF
      localizes to sites of DNA damage.
- term:
    id: GO:0006303
    label: double-strand break repair via nonhomologous end joining
  evidence_type: IMP
  original_reference_id: PMID:14690602
  qualifier: involved_in
  review:
    summary: >-
      At uncapped telomeres, XPF-mediated removal of the 3' overhang is a prerequisite
      for NHEJ-mediated end fusion.
    action: KEEP_AS_NON_CORE
    reason: >-
      XPF is not a core NHEJ factor; its involvement is indirect and telomere-specific
      (processing the overhang so ends become NHEJ substrates). Retain as a specialized,
      non-core role (experimental IMP, not removed).
    supported_by:
      - reference_id: PMID:14690602
        supporting_text: >-
          overhang processing is a prerequisite for NHEJ of telomeres.
- term:
    id: GO:1990599
    label: 3' overhang single-stranded DNA endonuclease activity
  evidence_type: IMP
  original_reference_id: PMID:14690602
  qualifier: contributes_to
  review:
    summary: Removes the telomeric 3' single-stranded overhang from uncapped telomeres.
    action: ACCEPT
    reason: >-
      Directly demonstrated: XPF-deficient cells retain the 3' overhang after TRF2
      inhibition, identifying XPF as the overhang-removing nuclease.
    supported_by:
      - reference_id: PMID:14690602
        supporting_text: >-
          ERCC1/XPF-deficient cells retained the telomeric overhang after TRF2
          inhibition, identifying this nucleotide excision repair endonuclease as the
          culprit in overhang removal.
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: IDA
  original_reference_id: PMID:10413517
  qualifier: involved_in
  review:
    summary: Direct role in NER; the XPF/ERCC1 complex makes one of the two NER incisions.
    action: ACCEPT
    reason: Core function, biochemically established with purified protein.
    supported_by:
      - reference_id: PMID:10413517
        supporting_text: >-
          During nucleotide excision repair, one of the two incisions necessary for
          removal of a broad spectrum of DNA adducts is made by the human XPF/ERCC1
          protein complex.
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: IMP
  original_reference_id: PMID:14728600
  qualifier: involved_in
  review:
    summary: XPF-deficient cells show defective repair; XPF required for NER incision.
    action: ACCEPT
    reason: >-
      Core function; XPF nuclear extract and cellular repair assays establish its NER
      requirement.
    supported_by:
      - reference_id: PMID:14728600
        supporting_text: >-
          the XPF nuclear extract is normal in introducing dual incisions during the
          nucleotide excision repair process.
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: IDA
  original_reference_id: PMID:32034146
  qualifier: involved_in
  review:
    summary: >-
      XPF-ERCC1 endonuclease essential for NER; acetylation-regulated complex assembly
      is required for repair.
    action: ACCEPT
    reason: Core function; loss of XPF acetylation impairs NER.
    supported_by:
      - reference_id: PMID:32034146
        supporting_text: >-
          The XPF-ERCC1 heterodimer is a structure-specific endonuclease that is
          essential for nucleotide excision repair (NER) and interstrand crosslink
          (ICL) repair in mammalian cells.
- term:
    id: GO:0034644
    label: cellular response to UV
  evidence_type: IDA
  original_reference_id: PMID:32034146
  qualifier: involved_in
  review:
    summary: >-
      Cellular response to UV; TIP60-mediated acetylation of XPF is induced by UV and
      required for repair.
    action: ACCEPT
    reason: >-
      Consistent with UV-induced regulation of XPF-ERCC1 assembly and the essential
      role of XPF in repairing UV lesions.
    supported_by:
      - reference_id: PMID:32034146
        supporting_text: >-
          TIP60, also known as KAT5, a haplo-insufficient tumor suppressor, directly
          acetylates XPF at Lys911 following UV irradiation
- term:
    id: GO:0070522
    label: ERCC4-ERCC1 complex
  evidence_type: IDA
  original_reference_id: PMID:32034146
  qualifier: part_of
  review:
    summary: Member of the XPF-ERCC1 heterodimer; assembly regulated by Lys911 acetylation.
    action: ACCEPT
    reason: Directly demonstrated complex assembly. Core.
    supported_by:
      - reference_id: PMID:32034146
        supporting_text: this acetylation is required for XPF-ERCC1 complex assembly and subsequent activation.
- term:
    id: GO:1901255
    label: nucleotide-excision repair involved in interstrand cross-link repair
  evidence_type: IDA
  original_reference_id: PMID:32034146
  qualifier: involved_in
  review:
    summary: Direct role in interstrand crosslink repair by the XPF-ERCC1 endonuclease.
    action: ACCEPT
    reason: >-
      Core function; XPF-ERCC1 is essential for ICL repair and loss of XPF acetylation
      causes ICL repair defects.
    supported_by:
      - reference_id: PMID:32034146
        supporting_text: >-
          loss of XPF acetylation impairs the damage-induced XPF-ERCC1 interaction,
          resulting in defects in both NER and ICL repair.
- term:
    id: GO:0061819
    label: telomeric DNA-containing double minutes formation
  evidence_type: IMP
  original_reference_id: PMID:14690602
  qualifier: involved_in
  review:
    summary: >-
      XPF represses formation of Telomeric DNA-containing Double Minute chromosomes
      (TDMs); ERCC1/XPF-deficient mouse cells accumulate TDMs.
    action: KEEP_AS_NON_CORE
    reason: >-
      A highly specialized telomere phenotype (XPF acts as a repressor of TDM
      formation). Genuine experimental finding but far from the gene's core function.
    supported_by:
      - reference_id: PMID:14690602
        supporting_text: >-
          ERCC1/XPF-deficient mouse cells had a novel telomere phenotype,
          characterized by Telomeric DNA-containing Double Minute chromosomes (TDMs).
- term:
    id: GO:0000781
    label: chromosome, telomeric region
  evidence_type: IDA
  original_reference_id: PMID:14690602
  qualifier: located_in
  review:
    summary: >-
      Localizes to telomeres as a component of the telomeric TRF2 complex.
    action: ACCEPT
    reason: >-
      ERCC1/XPF was identified as a component of the telomeric TRF2 complex,
      supporting telomeric-region localization.
    supported_by:
      - reference_id: PMID:14690602
        supporting_text: ERCC1/XPF was also identified as a component of the telomeric TRF2 complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18812185
  qualifier: enables
  review:
    summary: IntAct-curated interaction (with ERCC1, P07992) from the TRF2/telomere study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; not a core function statement.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24012755
  qualifier: enables
  review:
    summary: IntAct-curated interaction with SLX4 (Q8IY92) in the telomere-maintenance toolkit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic term; the SLX4-bridged telomeric function is captured by process annotations.
    supported_by:
      - reference_id: PMID:24012755
        supporting_text: >-
          SLX4 assembles a telomere maintenance toolkit by bridging multiple
          endonucleases with telomeres.
- term:
    id: GO:0010521
    label: telomerase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:18812185
  qualifier: enables
  negated: true
  review:
    summary: >-
      XPF controls telomere length via TRF2 regulation and a nuclease-independent
      mechanism, NOT by inhibiting telomerase; the negated annotation is informative.
    action: ACCEPT
    reason: >-
      The negation correctly records that XPF's effect on telomere length is not
      mediated by telomerase inhibition; retain as a valid NOT annotation.
    supported_by:
      - reference_id: PMID:18812185
        supporting_text: >-
          XPF-ERCC1 controls TRF2 and telomere length maintenance through two
          distinctive mechanisms, with the former requiring its nuclease activity.
- term:
    id: GO:0070522
    label: ERCC4-ERCC1 complex
  evidence_type: IDA
  original_reference_id: PMID:14690602
  qualifier: part_of
  review:
    summary: Member of the ERCC1-XPF heterodimer (here acting at telomeres).
    action: ACCEPT
    reason: Established complex membership. Core.
- term:
    id: GO:1904357
    label: negative regulation of telomere maintenance via telomere lengthening
  evidence_type: IDA
  original_reference_id: PMID:18812185
  qualifier: involved_in
  review:
    summary: >-
      XPF-ERCC1 acts as a negative mediator of telomere length; XPF overexpression
      induces telomere shortening.
    action: KEEP_AS_NON_CORE
    reason: >-
      Well-documented but specialized telomeric regulatory role, distinct from the core
      DNA-repair endonuclease function.
    supported_by:
      - reference_id: PMID:18812185
        supporting_text: >-
          overexpression of XPF induces telomere shortening in XPF-proficient cells
          whereas XPF complementation suppresses telomere lengthening in XPF-deficient
          cells.
- term:
    id: GO:1905765
    label: negative regulation of protection from non-homologous end joining at telomere
  evidence_type: IMP
  original_reference_id: PMID:14690602
  qualifier: involved_in
  review:
    summary: >-
      By removing the protective 3' overhang from uncapped telomeres, XPF antagonizes
      the protection of telomeres from NHEJ.
    action: KEEP_AS_NON_CORE
    reason: >-
      A precise but highly specialized telomere phenotype supported by the IMP data;
      retained as non-core.
    supported_by:
      - reference_id: PMID:14690602
        supporting_text: >-
          TRF2 prevents NHEJ at telomeres through protection of the telomeric overhang
          from ERCC1/XPF.
- term:
    id: GO:0000723
    label: telomere maintenance
  evidence_type: IGI
  original_reference_id: PMID:17055345
  qualifier: involved_in
  review:
    summary: >-
      Functions with TRF2 in telomere-length regulation; required for TRF2-promoted
      telomere shortening.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine telomere role established by genetic interaction with TRF2, but secondary
      to the core repair function.
    supported_by:
      - reference_id: PMID:17055345
        supporting_text: >-
          TRF2-induced telomere shortening is abrogated in human cells deficient in
          XPF, demonstrating that XPF-ERCC1 is required for TRF2-promoted telomere
          shortening.
- term:
    id: GO:0004520
    label: DNA endonuclease activity
  evidence_type: IMP
  original_reference_id: PMID:17055345
  qualifier: enables
  review:
    summary: >-
      Nuclease-domain point mutants are repair-defective, demonstrating the requirement
      for XPF endonuclease activity.
    action: ACCEPT
    reason: >-
      Core catalytic function; nuclease-inactive XPF fails to repair UV damage. Could be
      refined to the structure-specific/ssDNA endonuclease level.
    supported_by:
      - reference_id: PMID:17055345
        supporting_text: >-
          the nuclease-inactive XPF proteins fail to do so, indicating that the nuclease
          activity of XPF is essential for nucleotide excision repair.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17055345
  qualifier: enables
  review:
    summary: IntAct-curated interaction (with ERCC1, P07992).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; ERCC1 partnership is captured by GO:0070522.
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IGI
  original_reference_id: PMID:17055345
  qualifier: involved_in
  review:
    summary: General DNA repair, established through genetic interaction with TRF2 and repair assays.
    action: ACCEPT
    reason: Correct though broad; specific NER role is annotated separately.
- term:
    id: GO:0034644
    label: cellular response to UV
  evidence_type: IGI
  original_reference_id: PMID:17055345
  qualifier: involved_in
  review:
    summary: XPF nuclease activity required for repair of UV-induced DNA damage.
    action: ACCEPT
    reason: >-
      Consistent with XPF's role in NER of UV photolesions; wild-type but not
      nuclease-dead XPF complements repair of UV damage.
    supported_by:
      - reference_id: PMID:17055345
        supporting_text: >-
          wild type XPF can complement XPF-deficient cells for repair of UV-induced DNA
          damage
- term:
    id: GO:0070522
    label: ERCC4-ERCC1 complex
  evidence_type: IDA
  original_reference_id: PMID:17055345
  qualifier: part_of
  review:
    summary: Member of the XPF-ERCC1 structure-specific endonuclease.
    action: ACCEPT
    reason: Established complex membership. Core.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-109955
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; formation of the ERCC1:XPF complex).
    action: ACCEPT
    reason: Consistent with nuclear localization of the repair enzyme.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686657
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; ERCC1:XPF cleaves SSA flaps).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant with other nucleoplasm annotations.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686663
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; completion of SSA).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant Reactome annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690213
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; GG-NER).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant Reactome annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690988
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; 3'-incision by XPG in GG-NER).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant Reactome annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690990
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; 5'-incision by ERCC1:ERCC4 in GG-NER).
    action: ACCEPT
    reason: Consistent nuclear localization; this step is XPF's own 5' incision in NER.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690991
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; binding of ERCC1:ERCC4 to GG-NER pre-incision complex).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant Reactome annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6782141
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; ERCC1:ERCC4 binding in TC-NER).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant Reactome annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6782204
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; 5' incision by ERCC1:ERCC4 in TC-NER).
    action: ACCEPT
    reason: Consistent nuclear localization; XPF's 5' incision in TC-NER.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6782211
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; TC-NER).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant Reactome annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6782224
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; 3' incision by XPG in TC-NER).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant Reactome annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785732
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; DNA nucleases bind monoubiquitinated ID2 in FA pathway).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant Reactome annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785986
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; DNA nucleases unhook the ICL).
    action: ACCEPT
    reason: Consistent nuclear localization; this is XPF's ICL unhooking step.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9980006
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; ERCC1:XPF binds DSBs with SSA overhangs/flaps).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant Reactome annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9980021
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome; LIG1 binds SSA sites).
    action: ACCEPT
    reason: Consistent nuclear localization; redundant Reactome annotation.
- term:
    id: GO:0000110
    label: nucleotide-excision repair factor 1 complex
  evidence_type: IDA
  original_reference_id: PMID:10413517
  qualifier: part_of
  review:
    summary: Component of NER factor 1 (ERCC1-XPF), directly demonstrated by domain-mapping/interaction.
    action: ACCEPT
    reason: XPF C-terminal domain binds ERCC1 to form NEF1. Core complex membership.
    supported_by:
      - reference_id: PMID:10413517
        supporting_text: the C-terminal 214 residues are capable of binding specifically to ERCC1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19595721
  qualifier: enables
  review:
    summary: IntAct-curated interaction with SLX4 (Q8IY92).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; SLX4 coordination captured by process annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19595722
  qualifier: enables
  review:
    summary: IntAct-curated interaction with SLX4/BTBD12 (Q8IY92).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; SLX4 coordination captured functionally elsewhere.
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IMP
  original_reference_id: PMID:19596235
  qualifier: involved_in
  review:
    summary: >-
      Required for efficient DNA repair as part of the SLX4-coordinated nuclease
      toolkit.
    action: ACCEPT
    reason: >-
      Correct though broad; the specific NER/ICL functions are annotated separately.
    supported_by:
      - reference_id: PMID:19596235
        supporting_text: >-
          Depletion of SLX4 causes sensitivity to mitomycin C and camptothecin and
          reduces the efficiency of DSB repair in vivo.
- term:
    id: GO:0000723
    label: telomere maintenance
  evidence_type: IMP
  original_reference_id: PMID:14690602
  qualifier: involved_in
  review:
    summary: Regulates telomere integrity by processing the telomeric 3' overhang.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine telomere role, but a specialized application of the endonuclease rather
      than the core repair function.
    supported_by:
      - reference_id: PMID:14690602
        supporting_text: >-
          these data reveal an unanticipated involvement of the ERCC1/XPF NER
          endonuclease in the regulation of telomere integrity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14690602
  qualifier: enables
  review:
    summary: IntAct-curated interactions (TRF2, Q15554; and RAP1/TERF2IP, Q9NYB0) in the telomeric TRF2 complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; telomeric-complex association is captured by localization/process annotations.
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IMP
  original_reference_id: PMID:14728600
  qualifier: involved_in
  review:
    summary: >-
      Role in homology-directed repair, consistent with XPF-ERCC1 function in
      single-strand annealing and recombination.
    action: ACCEPT
    reason: >-
      Core recombination function of the XPF-family nuclease (dual excision-repair and
      recombination roles); XPF is required for homology-dependent DSB repair.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IDA
  original_reference_id: PMID:14734547
  qualifier: contributes_to
  review:
    summary: DNA binding by the XPF/ERCC1 structure-specific endonuclease.
    action: ACCEPT
    reason: >-
      Correct but general; more specific ssDNA/junction binding is annotated elsewhere.
      Retained as a supporting activity.
- term:
    id: GO:0004520
    label: DNA endonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:8797827
  qualifier: contributes_to
  review:
    summary: >-
      Catalytic endonuclease that makes the 5' incision in DNA repair; the XPF-ERCC1
      complex is a structure-specific endonuclease.
    action: ACCEPT
    reason: >-
      Core catalytic function established by purification of the XPF-ERCC1
      structure-specific endonuclease responsible for the 5' incision.
    supported_by:
      - reference_id: PMID:8797827
        supporting_text: >-
          This complex is a structure-specific endonuclease responsible for the 5'
          incision during repair.
- term:
    id: GO:0004520
    label: DNA endonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:14734547
  qualifier: enables
  review:
    summary: Structure-specific endonuclease activity, stimulated by hRad52 during recombinational repair.
    action: ACCEPT
    reason: >-
      Core catalytic activity; complex formation with hRad52 stimulates the XPF/ERCC1
      endonuclease.
    supported_by:
      - reference_id: PMID:14734547
        supporting_text: >-
          Complex formation between hRad52 and XPF/ERCC1 concomitantly stimulates the
          DNA structure-specific endonuclease activity of XPF/ERCC1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14734547
  qualifier: enables
  review:
    summary: IntAct-curated interaction with hRAD52 (P43351).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic term is uninformative; the functionally relevant RAD52 stimulation of
      the endonuclease is captured by the endonuclease-activity and recombination
      annotations.
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: IMP
  original_reference_id: PMID:8797827
  qualifier: involved_in
  review:
    summary: >-
      XP-F cells are NER-defective; XPF corrects the repair defect, establishing its
      essential NER role.
    action: ACCEPT
    reason: Core function; classic genetic/biochemical evidence for XPF in NER.
    supported_by:
      - reference_id: PMID:8797827
        supporting_text: >-
          We isolated a human gene homologous to yeast Rad1 and found that it corrects
          the repair defects of XP group F as well as rodent groups 4 and 11.
- term:
    id: GO:0032205
    label: negative regulation of telomere maintenance
  evidence_type: IMP
  original_reference_id: PMID:17055345
  qualifier: involved_in
  review:
    summary: Negatively regulates telomere maintenance via TRF2-mediated telomere shortening.
    action: KEEP_AS_NON_CORE
    reason: >-
      Specialized telomeric regulatory role established genetically; not the gene's core
      repair function.
    supported_by:
      - reference_id: PMID:17055345
        supporting_text: XPF-ERCC1 is required for TRF2-promoted telomere shortening.
- term:
    id: GO:0003684
    label: damaged DNA binding
  evidence_type: IMP
  original_reference_id: PMID:11790111
  qualifier: enables
  review:
    summary: >-
      Binds damaged DNA / DNA-damage sites (localizes to the site of a psoralen
      interstrand crosslink).
    action: ACCEPT
    reason: >-
      Consistent with XPF's recruitment to damage and its structure-specific substrate
      recognition at lesion sites.
    supported_by:
      - reference_id: PMID:11790111
        supporting_text: >-
          it is involved in production of the 5' incision at the site of a psoralen
          interstrand cross-link as well as the 3' incision.
- term:
    id: GO:0003697
    label: single-stranded DNA binding
  evidence_type: IDA
  original_reference_id: PMID:10413517
  qualifier: enables
  review:
    summary: >-
      Binds DNA (including ssDNA) independently of ERCC1, via its N-terminal domain.
    action: ACCEPT
    reason: >-
      Directly demonstrated: recombinant XPF binds DNA in the absence of the ERCC1
      subunit, and the N-terminal region binds and hydrolyzes DNA.
    supported_by:
      - reference_id: PMID:10413517
        supporting_text: >-
          the N-terminal 378 amino acids of XPF are capable of binding and hydrolyzing
          DNA
- term:
    id: GO:0004520
    label: DNA endonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:10413517
  qualifier: enables
  review:
    summary: >-
      Intrinsic endonuclease activity; recombinant XPF is an endonuclease that binds
      and hydrolyzes DNA even without ERCC1.
    action: ACCEPT
    reason: >-
      Core catalytic function directly demonstrated with purified recombinant XPF; XPF
      is the catalytic subunit. Mg2+-dependent (EC 3.1.-.-).
    supported_by:
      - reference_id: PMID:10413517
        supporting_text: >-
          determined that it is an endonuclease and can bind DNA in the absence of the
          ERCC1 subunit.
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: IMP
  original_reference_id: PMID:11790111
  qualifier: involved_in
  review:
    summary: Required for the incisions in nucleotide excision repair and ICL repair.
    action: ACCEPT
    reason: Core function; XPF functional domains determine the 5' and 3' repair incisions.
    supported_by:
      - reference_id: PMID:11790111
        supporting_text: >-
          XPF forms a heterodimeric complex with ERCC1 and is required for the repair
          of DNA interstrand cross-links.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12571280
  qualifier: enables
  review:
    summary: IntAct-curated interactions with FANCA (O15360) and nonerythroid alphaII-spectrin/SPTAN1 (Q13813).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative generic term; the ICL-repair foci relationship with FANCA/spectrin
      is captured by the nuclear-body localization and ICL-repair annotations.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:12571280
  qualifier: located_in
  review:
    summary: >-
      Nuclear localization; XPF forms damage-induced nuclear foci at interstrand
      crosslinks.
    action: ACCEPT
    reason: Consistent with XPF's nuclear DNA-repair function.
    supported_by:
      - reference_id: PMID:12571280
        supporting_text: FANCA and the known DNA repair protein XPF localize to the same nuclear foci.
- term:
    id: GO:0009411
    label: response to UV
  evidence_type: IMP
  original_reference_id: PMID:16678501
  qualifier: involved_in
  review:
    summary: >-
      Required for the DNA-damage signaling response to crosslinking agents (gamma-H2AX
      formation); XPF-deficient cells fail to mount this response.
    action: ACCEPT
    reason: >-
      Consistent with XPF's role in processing UV/crosslink damage; ectopic XPF
      restores the damage response.
    supported_by:
      - reference_id: PMID:16678501
        supporting_text: >-
          XPF is required to form gamma-H2AX and likely double strand breaks in
          response to interstrand crosslinks in human cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9722633
  qualifier: enables
  review:
    summary: IntAct-curated interaction with ERCC1 (P07992); mapping of ERCC1-XPF interaction domains.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; ERCC1 partnership captured by GO:0070522.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7559382
  qualifier: enables
  review:
    summary: IntAct-curated interaction with ERCC1 (P07992); purification of the XPF-ERCC1 excision nuclease.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; ERCC1 partnership captured by GO:0070522.
- term:
    id: GO:0000109
    label: nucleotide-excision repair complex
  evidence_type: IDA
  original_reference_id: PMID:10644440
  qualifier: part_of
  review:
    summary: Component of a nucleotide-excision repair complex (the XPF/ERCC1 endonuclease).
    action: ACCEPT
    reason: >-
      Correct, more general parent of the ERCC1-XPF (NEF1) complex; XPF is an essential
      subunit of the NER excision machinery.
    supported_by:
      - reference_id: PMID:10644440
        supporting_text: >-
          The human XPF protein, an endonuclease subunit essential for DNA excision
          repair, may also function in homologous recombination.
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: IDA
  original_reference_id: PMID:10644440
  qualifier: acts_upstream_of_or_within
  review:
    summary: Role in nucleotide excision repair (XPF is an endonuclease subunit essential for excision repair).
    action: ACCEPT
    reason: >-
      Core function; the qualifier reflects the older annotation style but the NER
      involvement is correct.
    supported_by:
      - reference_id: PMID:10644440
        supporting_text: >-
          The human XPF protein, an endonuclease subunit essential for DNA excision
          repair, may also function in homologous recombination.
- term:
    id: GO:0000014
    label: single-stranded DNA endodeoxyribonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:22483113
  qualifier: enables
  review:
    summary: >-
      XPF is a single-stranded DNA endodeoxyribonuclease that, within the ERCC1-XPF
      heterodimer, nicks the damaged strand at the 5' end of a lesion at ss/ds
      junctions. This is the precise molecular function underlying the more general
      "DNA endonuclease activity" annotations.
    action: NEW
    reason: >-
      Added as a more specific molecular-function term than GO:0004520 (DNA
      endonuclease activity), which is already annotated. UniProt annotates this term
      (IDA), and the structure-specific 5'-incising, ssDNA/junction-cleaving activity
      is directly supported. Used as the core molecular function of XPF as the
      catalytic subunit.
    supported_by:
      - reference_id: PMID:22483113
        supporting_text: >-
          Human XPF/ERCC1 is a structure-specific DNA endonuclease that nicks the
          damaged DNA strand at the 5' end during nucleotide excision repair.
      - reference_id: PMID:10413517
        supporting_text: >-
          determined that it is an endonuclease and can bind DNA in the absence of the
          ERCC1 subunit.
core_functions:
- description: >-
    Catalytic subunit of the ERCC1-XPF structure-specific endonuclease that makes the
    5' incision on the damaged strand at single-stranded/double-stranded DNA junctions,
    the incision step required for nucleotide excision repair and for the unhooking of
    DNA interstrand crosslinks. XPF provides the Mg2+-dependent nuclease active site and
    the ssDNA-junction recognition, while its obligate partner ERCC1 provides additional
    DNA binding.
  molecular_function:
    id: GO:0000014
    label: single-stranded DNA endodeoxyribonuclease activity
  directly_involved_in:
    - id: GO:0006289
      label: nucleotide-excision repair
    - id: GO:1901255
      label: nucleotide-excision repair involved in interstrand cross-link repair
  locations:
    - id: GO:0005654
      label: nucleoplasm
  in_complex:
    id: GO:0070522
    label: ERCC4-ERCC1 complex
  supported_by:
    - reference_id: PMID:8797827
      supporting_text: >-
        This complex is a structure-specific endonuclease responsible for the 5'
        incision during repair.
    - reference_id: PMID:22547097
      supporting_text: >-
        In NER, ERCC1-XPF is recruited to DNA lesions by interaction with XPA and
        incises the DNA 5' to the lesion.
    - reference_id: PMID:10413517
      supporting_text: >-
        determined that it is an endonuclease and can bind DNA in the absence of the
        ERCC1 subunit.
- description: >-
    The same ERCC1-XPF structure-specific endonuclease cleaves non-homologous 3' flaps
    and 3' single-stranded overhangs, processing recombination intermediates during
    homology-directed double-strand break repair, most notably single-strand annealing
    where the activity is stimulated by RAD52. The identical 3'-overhang endonuclease
    activity also removes the 3' overhang from uncapped telomeres.
  molecular_function:
    id: GO:1990599
    label: 3' overhang single-stranded DNA endonuclease activity
  directly_involved_in:
    - id: GO:0000724
      label: double-strand break repair via homologous recombination
  locations:
    - id: GO:0005654
      label: nucleoplasm
  in_complex:
    id: GO:0070522
    label: ERCC4-ERCC1 complex
  supported_by:
    - reference_id: PMID:14690602
      supporting_text: >-
        ERCC1/XPF-deficient cells retained the telomeric overhang after TRF2
        inhibition, identifying this nucleotide excision repair endonuclease as the
        culprit in overhang removal.
    - reference_id: PMID:14734547
      supporting_text: >-
        The XPF/ERCC1 heterodimer is a DNA structure-specific endonuclease that
        participates in nucleotide excision repair and homology-dependent recombination
        reactions, including DNA single strand annealing and gene targeting.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10413517
  title: Domain mapping of the DNA binding, endonuclease, and ERCC1 binding properties
    of the human DNA repair protein XPF.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Directly establishes XPF as an intrinsic endonuclease that
      binds DNA without ERCC1, maps the N-terminal catalytic domain and C-terminal
      ERCC1-binding domain, and reports Mg2+ cofactor. Anchors the core endonuclease,
      ssDNA-binding, and complex-membership annotations.
- id: PMID:10644440
  title: Characterization of the mouse Xpf DNA repair gene and differential expression
    during spermatogenesis.
  findings: []
- id: PMID:11790111
  title: Contribution of XPF functional domains to the 5' and 3' incisions produced
    at the site of a psoralen interstrand cross-link.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes XPF-ERCC1 requirement for the 5' (and 3') incisions
      at a psoralen ICL and localization to the damage site; supports ICL-repair,
      damaged-DNA-binding, and chromosome localization annotations.
- id: PMID:12571280
  title: Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF
    to nuclear foci induced by DNA interstrand cross-links.
  findings: []
- id: PMID:14690602
  title: ERCC1/XPF removes the 3' overhang from uncapped telomeres and represses formation
    of telomeric DNA-containing double minute chromosomes.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Demonstrates XPF-dependent removal of the telomeric 3' overhang,
      identifies ERCC1/XPF in the telomeric TRF2 complex, and underlies the telomere,
      TDM, and telomere-NHEJ annotations.
- id: PMID:14728600
  title: Defining the function of xeroderma pigmentosum group F protein in psoralen
    interstrand cross-link-mediated DNA repair and mutagenesis.
  findings: []
- id: PMID:14734547
  title: Physical and functional interaction between the XPF/ERCC1 endonuclease and
    hRad52.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Shows XPF/ERCC1 is a structure-specific endonuclease acting in
      NER and homology-dependent recombination (single-strand annealing), stimulated by
      hRad52; supports the recombination core function.
- id: PMID:16076955
  title: Crystal structure and DNA binding functions of ERCC1, a subunit of the DNA
    structure-specific endonuclease XPF-ERCC1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified structural study confirming XPF-ERCC1 incises the damaged strand
      5' to the lesion and defining the ss/ds junction recognition and HhH2
      dimerization; supports complex membership and 5'-incision mechanism.
- id: PMID:16338413
  title: The structure of the human ERCC1/XPF interaction domains reveals a complementary
    role for the two proteins in nucleotide excision repair.
  findings: []
- id: PMID:16678501
  title: gamma-H2AX formation in response to interstrand crosslinks requires XPF in
    human cells.
  findings: []
- id: PMID:17055345
  title: XPF with mutations in its conserved nuclease domain is defective in DNA repair
    but functions in TRF2-mediated telomere shortening.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Nuclease-domain mutants are NER-defective (nuclease activity
      essential for NER) yet still support TRF2-mediated telomere shortening, revealing
      a nuclease-independent telomere function; supports endonuclease, telomere, and
      negative-regulation-of-telomere annotations.
- id: PMID:17289582
  title: Identification of FAAP24, a Fanconi anemia core complex protein that interacts
    with FANCM.
  findings: []
- id: PMID:18812185
  title: Human XPF controls TRF2 and telomere length maintenance through distinctive
    mechanisms.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes XPF-ERCC1 as a negative mediator of telomere length
      through two mechanisms; grounds the negated telomerase-inhibitor annotation and
      the negative-regulation-of-telomere-lengthening annotation.
- id: PMID:19595721
  title: Coordination of structure-specific nucleases by human SLX4/BTBD12 is required
    for DNA repair.
  findings: []
- id: PMID:19595722
  title: Drosophila MUS312 and the vertebrate ortholog BTBD12 interact with DNA structure-specific
    endonucleases in DNA repair and recombination.
  findings: []
- id: PMID:19596235
  title: Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required
    for DNA repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Shows SLX4 assembles ERCC4(XPF)-ERCC1 with MUS81-EME1 and SLX1
      into a repair nuclease toolkit; supports SLX4 coordination and the DNA-repair
      involvement of XPF.
- id: PMID:19596236
  title: Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA
    repair/recombination endonucleases.
  findings: []
- id: PMID:22483113
  title: The structure of the XPF-ssDNA complex underscores the distinct roles of
    the XPF and ERCC1 helix- hairpin-helix domains in ss/ds DNA recognition.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified structural study of the XPF C-terminal domain bound to ssDNA;
      confirms XPF nicks the damaged strand at the 5' end and that XPF HhH motifs
      recognize the ssDNA arm at ss/ds junctions. Supports ssDNA-binding annotations.
- id: PMID:22547097
  title: Multiple DNA binding domains mediate the function of the ERCC1-XPF protein
    in nucleotide excision repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Defines ERCC1-XPF as a heterodimeric structure-specific
      endonuclease cleaving ss/ds junctions and incising 5' to the lesion in NER;
      primary anchor for the core molecular function.
- id: PMID:23623386
  title: Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi
    anemia.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Identifies biallelic ERCC4 mutations as the cause of Fanconi
      anemia complementation group Q (FA-Q), the disease that defines this gene's
      FANCQ synonym. Shows FA-causing mutations selectively disrupt XPF's ICL-repair
      function while largely sparing NER, giving human genetic evidence for the
      separable NER and ICL-repair activities and grounding the ICL-repair
      annotation. Abstract-only in cache (full text not available from PMC).
- id: PMID:24012755
  title: SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases
    with telomeres.
  findings: []
- id: PMID:24780295
  title: Importance of EGFR/ERCC1 interaction following radiation-induced DNA damage.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:32034146
  title: Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex assembly and activation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Confirms XPF-ERCC1 is essential for NER and ICL repair and
      defines TIP60/KAT5 acetylation of XPF Lys911 as a regulator of complex assembly;
      supports NER, ICL-repair, complex-membership, and cellular-response-to-UV
      annotations.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:7559382
  title: Purification and characterization of the XPF-ERCC1 complex of human DNA repair
    excision nuclease.
  findings: []
- id: PMID:8797827
  title: Xeroderma pigmentosum group F caused by a defect in a structure-specific
    DNA repair endonuclease.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified landmark paper identifying XPF/ERCC4 and showing the XPF-ERCC1
      complex is the structure-specific endonuclease responsible for the 5' incision in
      repair; core reference for endonuclease and NER annotations.
- id: PMID:9722633
  title: Mapping of interaction domains between human repair proteins ERCC1 and XPF.
  findings: []
- id: Reactome:R-HSA-109955
  title: Formation of ERCC1:XPF heterodimeric complex
  findings: []
- id: Reactome:R-HSA-5686657
  title: ERCC1:XPF cleaves flaps generated by SSA
  findings: []
- id: Reactome:R-HSA-5686663
  title: Completion of SSA
  findings: []
- id: Reactome:R-HSA-5690213
  title: DNA polymerases delta, epsilon or kappa bind the GG-NER site
  findings: []
- id: Reactome:R-HSA-5690988
  title: 3'-incision of DNA by ERCC5 (XPG) in GG-NER
  findings: []
- id: Reactome:R-HSA-5690990
  title: 5'- incision of DNA by ERCC1:ERCC4 in GG-NER
  findings: []
- id: Reactome:R-HSA-5690991
  title: Binding of ERCC1:ERCC4 (ERCC1:XPF) to pre-incision complex in GG-NER
  findings: []
- id: Reactome:R-HSA-6782141
  title: Binding of ERCC1:ERCC4 (ERCC1:XPF) to pre-incision complex in TC-NER
  findings: []
- id: Reactome:R-HSA-6782204
  title: 5' incision of damaged DNA strand by ERCC1:ERCC4 in TC-NER
  findings: []
- id: Reactome:R-HSA-6782211
  title: DNA polymerases delta, epsilon or kappa bind the TC-NER site
  findings: []
- id: Reactome:R-HSA-6782224
  title: 3' incision by ERCC5 (XPG) in TC-NER
  findings: []
- id: Reactome:R-HSA-6785732
  title: DNA nucleases bind monoubiquitinated ID2 complex
  findings: []
- id: Reactome:R-HSA-6785986
  title: DNA nucleases unhook the interstrand crosslink (ICL)
  findings: []
- id: Reactome:R-HSA-9980006
  title: ERCC1:XPF binds DNA DSBs with annealed 3' ssDNA overhangs and displaced flaps
    generated by SSA
  findings: []
- id: Reactome:R-HSA-9980021
  title: LIG1 binds SSA sites
  findings: []