id: Q8IY92
gene_symbol: SLX4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SLX4 (also known as BTBD12 and FANCP) is a large (1834 aa) multidomain nuclear
  scaffold protein that assembles and coordinates structure-specific endonucleases
  to process branched DNA intermediates that arise during DNA replication,
  recombination and repair. It acts as a docking platform that physically bridges
  three endonucleases — SLX1 (with which it forms the SLX1-SLX4 complex), XPF-ERCC1
  (ERCC4-ERCC1) and MUS81-EME1 — and, as a regulatory subunit, stimulates their
  nucleolytic activity. SLX4 itself has no intrinsic nuclease activity; the
  endonucleolytic cleavage is carried out by its bound catalytic partners, which
  SLX4 activates and positions. The SLX1-SLX4 module is a Holliday-junction
  resolvase that symmetrically cleaves static and migrating junctions, while
  SLX4-directed MUS81-EME1 and XPF-ERCC1 cut 3'-flaps, replication-fork-like and
  bubble structures. Through these coordinated incisions SLX4 promotes interstrand
  crosslink repair (unhooking), homologous-recombination-mediated double-strand
  break repair, single-strand annealing and replication-fork/telomere maintenance.
  It contains tandem UBZ4 ubiquitin-binding zinc fingers that recruit it to
  ubiquitinated repair sites, a BTB/POZ oligomerization domain, a SAP DNA-binding
  motif, and separate binding regions for SLX1, MUS81, XPF/MSH2 and TRF2, and it is
  extensively SUMOylated and phosphorylated. Biallelic loss-of-function mutations
  cause Fanconi anemia complementation group P (FANCP), characterized by
  hypersensitivity to DNA crosslinking agents and chromosomal instability.
alternative_products:
- name: '1'
  id: Q8IY92-1
- name: '2'
  id: Q8IY92-2
  sequence_note: VSP_035295, VSP_035296
existing_annotations:
- term:
    id: GO:0000712
    label: resolution of meiotic recombination intermediates
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) inference that SLX4 resolves recombination intermediates,
      framed in the meiotic context of orthologs such as fly MUS312.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the conserved role of SLX4/Slx4/MUS312 in resolving branched
      recombination intermediates via the SLX1-SLX4 resolvase. In human somatic
      cells the demonstrated activity is on mitotic Holliday junctions; the
      meiosis-specific term is a reasonable ortholog-based inference but is not the
      core, experimentally-established human function, so it is retained as non-core.
    supported_by:
    - reference_id: PMID:19596236
      supporting_text: >-
        including fly MUS312, essential for meiotic recombination, and human BTBD12
- term:
    id: GO:0033557
    label: Slx1-Slx4 complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      SLX4 is a defining subunit of the SLX1-SLX4 structure-specific endonuclease
      complex; supported by phylogenetic inference and abundant experimental data.
    action: ACCEPT
    reason: >-
      The SLX1-SLX4 heterodimer is one of the best-established facts about SLX4 and
      is directly demonstrated experimentally (see IDA/IPI entries for the same
      term). Correct and core.
    supported_by:
    - reference_id: PMID:19595721
      supporting_text: >-
        human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and
        SLX1
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based inference of DNA binding, consistent with SLX4's SAP/MLR
      DNA-binding motif and the branched-DNA binding of the SLX1-SLX4 complex.
    action: ACCEPT
    reason: >-
      SLX4 contains a SAP domain (SAP_SLX4, cd22999) and the SLX1-SLX4 module binds
      and cleaves branched DNA substrates, so DNA binding is a reasonable (if broad)
      molecular-function assignment. Not the most informative MF but not incorrect.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: SLX4 is a nuclear protein that relocalizes to sites of DNA damage.
    action: ACCEPT
    reason: >-
      Consistent with experimentally-determined nuclear localization (nucleoplasm,
      chromatin, nuclear chromosome, telomeric foci). Correct, if unspecific.
    supported_by:
    - reference_id: PMID:19596235
      supporting_text: >-
        SLX4 assembles a modular toolkit for repair of specific
- term:
    id: GO:0006260
    label: DNA replication
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-based inference that SLX4 is involved in DNA replication.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      SLX4 acts on replication-associated intermediates (stalled/collapsed forks,
      replication-fork-like structures) and in fork/genome maintenance, but it is
      not part of the DNA replication machinery itself. Annotating to the broad
      process "DNA replication" is misleading; the accurate roles are captured by
      DNA repair and recombination-intermediate resolution terms.
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Broad DNA repair process, well supported: SLX4 coordinates nucleases in
      crosslink repair, DSB repair and recombination-intermediate processing.
    action: ACCEPT
    reason: >-
      DNA repair is a correct high-level process for SLX4 and is independently
      supported by experimental IMP annotations. Retained as a valid parent term.
    supported_by:
    - reference_id: PMID:19595721
      supporting_text: >-
        Coordination of structure-specific nucleases by human SLX4/BTBD12 is
        required for DNA repair
- term:
    id: GO:0032206
    label: positive regulation of telomere maintenance
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA machine-learning inference that SLX4 positively regulates telomere
      maintenance; the same term is also asserted by IDA (PMID:24012755).
    action: KEEP_AS_NON_CORE
    reason: >-
      SLX4 participates in telomere length homeostasis via a SLX4-TRF2 scaffold that
      recruits SLX1/XPF/MUS81 to telomeres and resolves telomeric DNA structures.
      This telomere-maintenance role is genuine but is a specialized deployment of
      the scaffold, not the core somatic function (crosslink/recombination repair),
      so it is retained as non-core.
    supported_by:
    - reference_id: PMID:24012755
      supporting_text: >-
        the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple
        endonucleases with telomeres for recombination-based telomere maintenance
- term:
    id: GO:0033557
    label: Slx1-Slx4 complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: InterPro-based inference of Slx1-Slx4 complex membership.
    action: ACCEPT
    reason: >-
      Duplicate of the well-supported Slx1-Slx4 complex assignment; correct and core.
    supported_by:
    - reference_id: PMID:19595721
      supporting_text: >-
        human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and
        SLX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19596235
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotations to SLX4 interaction partners (endonuclease
      subunits, MSH2, PLK1, TERF2/TERF2IP, SLX4IP) from the Svendsen et al. complex
      purification.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "protein binding" (GO:0005515) is an uninformative parent term. The
      underlying interactions are real and biologically important, but their
      informative content — that SLX4 is a scaffold/adaptor that assembles and
      activates structure-specific endonucleases — is captured by molecular adaptor
      activity and enzyme activator activity in core_functions rather than by the
      generic protein-binding term.
    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: >-
      IPI protein-binding annotation from Fekairi et al., documenting SLX4 binding
      to XPF(ERCC4) and MUS81 endonuclease subunits.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Real interaction but the generic "protein binding" term is uninformative; the
      scaffold/docking function is represented by protein-macromolecule adaptor activity in
      core_functions.
    supported_by:
    - reference_id: PMID:19596236
      supporting_text: >-
        SLX4 binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1
        endonucleases
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25852190
  qualifier: enables
  review:
    summary: >-
      Protein-binding annotation with PLK1 derived from a high-throughput kinase
      interaction study (TRAIL-induced apoptosis network).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein-binding term from a large-scale interactome dataset;
      uninformative for molecular function. Interaction with PLK1 is documented but
      does not warrant a core molecular-function annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29892012
  qualifier: enables
  review:
    summary: >-
      Protein-binding annotation from a systematic interactome-perturbation
      framework for developmental-disorder missense variants.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative high-throughput "protein binding" call; no specific molecular
      function conveyed.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Protein-binding annotation from the HuRI reference map of the human binary
      interactome.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein-binding term from a proteome-scale two-hybrid map;
      uninformative for molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  qualifier: enables
  review:
    summary: >-
      Protein-binding annotation from a large-scale kinase interaction network study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative high-throughput protein-binding call.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Protein-binding annotation from the BioPlex dual proteome-scale interactome
      networks.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein-binding term from a proteome-scale AP-MS dataset;
      uninformative for molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      Protein-binding annotation from a multimodal cell-map foundation dataset.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative high-throughput protein-binding call; no specific molecular
      function conveyed.
- term:
    id: GO:0090656
    label: t-circle formation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic inference that SLX4 is involved in t-circle (telomeric circle)
      formation, mirroring the mouse ortholog and the human IMP data.
    action: KEEP_AS_NON_CORE
    reason: >-
      SLX4-directed SLX1 nucleolytic resolution of telomeric structures generates
      extrachromosomal telomeric circles; this is experimentally supported
      (PMID:24012755) but represents a specialized telomere role rather than the
      core somatic function.
    supported_by:
    - reference_id: PMID:24012755
      supporting_text: >-
        SLX4 assembles an endonuclease toolkit that negatively regulates telomere
        length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures
- term:
    id: GO:1904431
    label: positive regulation of t-circle formation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-based electronic transfer (from the mouse ortholog) that SLX4
      positively regulates t-circle formation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with SLX4's telomere-trimming role via SLX1-catalyzed resolution;
      genuine but specialized/non-core.
    supported_by:
    - reference_id: PMID:24012755
      supporting_text: >-
        negatively regulates telomere length via SLX1-catalyzed nucleolytic
        resolution of telomere DNA structures
- term:
    id: GO:0000228
    label: nuclear chromosome
  evidence_type: IDA
  original_reference_id: PMID:19596236
  qualifier: located_in
  review:
    summary: >-
      Direct-assay localization of SLX4 to the nuclear chromosome, consistent with
      its chromatin/DNA-repair role.
    action: ACCEPT
    reason: >-
      Experimental localization by ComplexPortal curation; consistent with
      chromatin and DNA-damage-site localization reported for SLX4.
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IDA
  original_reference_id: PMID:19596236
  qualifier: involved_in
  review:
    summary: >-
      SLX4 participates in homologous-recombination-mediated DSB repair by
      coordinating structure-specific endonucleases that process recombination
      intermediates.
    action: ACCEPT
    reason: >-
      Well supported experimentally; SLX4 depletion reduces DSB-induced HR and the
      SLX1-SLX4 resolvase processes Holliday junctions arising in HR. Core process.
    supported_by:
    - reference_id: PMID:19595721
      supporting_text: >-
        Depletion of SLX4 causes a decrease in DSB-induced homologous recombination
- term:
    id: GO:0006260
    label: DNA replication
  evidence_type: NAS
  original_reference_id: PMID:34804132
  qualifier: involved_in
  review:
    summary: >-
      Non-traceable author statement associating SLX4 with DNA replication in a
      review of SLX4-nuclease complexes.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      As with the InterPro IEA to the same term, SLX4 functions on
      replication-associated DNA structures and in fork repair, not in DNA
      replication itself. The broad process term over-annotates the gene.
- term:
    id: GO:0033557
    label: Slx1-Slx4 complex
  evidence_type: IPI
  original_reference_id: PMID:19596236
  qualifier: part_of
  review:
    summary: >-
      Physical-interaction evidence for the SLX1-SLX4 structure-specific
      endonuclease complex.
    action: ACCEPT
    reason: >-
      Directly demonstrated complex membership; correct and core.
    supported_by:
    - reference_id: PMID:19596236
      supporting_text: >-
        Human SLX1-SLX4 displays robust Holliday junction resolvase activity in
        addition to 5' flap endonuclease activity
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence localization of SLX4 to the nucleoplasm (HPA).
    action: ACCEPT
    reason: Consistent with SLX4's established nuclear/nucleoplasmic localization.
- term:
    id: GO:0000781
    label: chromosome, telomeric region
  evidence_type: IDA
  original_reference_id: PMID:24012755
  qualifier: located_in
  review:
    summary: >-
      SLX4 localizes to telomeres, where the SLX4-TRF2 complex recruits
      structure-specific endonucleases.
    action: ACCEPT
    reason: >-
      Experimentally supported telomeric localization via the SLX4-TRF2 interaction;
      consistent with the telomere-maintenance role.
    supported_by:
    - reference_id: PMID:24012755
      supporting_text: >-
        SLX4 assembles a telomere maintenance toolkit by bridging multiple
        endonucleases with telomeres
- term:
    id: GO:0032206
    label: positive regulation of telomere maintenance
  evidence_type: IDA
  original_reference_id: PMID:24012755
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay evidence that SLX4 regulates telomere maintenance/length
      homeostasis through nucleolytic resolution of telomeric structures.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine telomere-homeostasis role (SLX4-TRF2 scaffold bridging SLX1/XPF/MUS81
      to telomeres), but a specialized deployment of the scaffold; retained as
      non-core relative to the crosslink/recombination-repair core.
    supported_by:
    - reference_id: PMID:24012755
      supporting_text: >-
        the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple
        endonucleases with telomeres for recombination-based telomere maintenance
- term:
    id: GO:0061820
    label: telomeric D-loop disassembly
  evidence_type: IMP
  original_reference_id: PMID:24012755
  qualifier: involved_in
  review:
    summary: >-
      SLX4-directed nuclease activity resolves telomeric D-loop/t-loop structures,
      contributing to telomere trimming.
    action: KEEP_AS_NON_CORE
    reason: >-
      Specific and experimentally supported telomere function; a specialized aspect
      of the scaffold's telomere role rather than the core somatic function.
    supported_by:
    - reference_id: PMID:24012755
      supporting_text: >-
        negatively regulates telomere length via SLX1-catalyzed nucleolytic
        resolution of telomere DNA structures
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24012755
  qualifier: enables
  review:
    summary: >-
      Protein-binding annotations to telomeric partners (TRF2/TERF2) and
      endonucleases from the SLX4 telomere-toolkit study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The TRF2 and endonuclease interactions are important, but "protein binding" is
      uninformative; the scaffold/adaptor function is captured by molecular adaptor
      activity in core_functions.
    supported_by:
    - reference_id: PMID:24012755
      supporting_text: >-
        SLX4 also interacts with telomeric protein TRF2 in human cells
- term:
    id: GO:0033557
    label: Slx1-Slx4 complex
  evidence_type: TAS
  original_reference_id: PMID:24012755
  qualifier: part_of
  review:
    summary: Traceable-author statement of SLX1-SLX4 complex membership.
    action: ACCEPT
    reason: Correct, well-established complex; core.
- term:
    id: GO:0090656
    label: t-circle formation
  evidence_type: IMP
  original_reference_id: PMID:24012755
  qualifier: involved_in
  review:
    summary: >-
      SLX4 depletion/mutation experiments show SLX4 is required for formation of
      extrachromosomal telomeric circles (t-circles).
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported telomere-trimming output; specialized/non-core.
    supported_by:
    - reference_id: PMID:24012755
      supporting_text: >-
        SLX4 assembles an endonuclease toolkit that negatively regulates telomere
        length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures
- term:
    id: GO:1904357
    label: negative regulation of telomere maintenance via telomere lengthening
  evidence_type: IMP
  original_reference_id: PMID:24012755
  qualifier: involved_in
  review:
    summary: >-
      SLX4 negatively regulates telomere lengthening by resolving telomeric
      structures (telomere trimming).
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the demonstrated negative regulation of telomere length via
      SLX1-catalyzed resolution; genuine but specialized/non-core.
    supported_by:
    - reference_id: PMID:24012755
      supporting_text: >-
        negatively regulates telomere length via SLX1-catalyzed nucleolytic
        resolution of telomere DNA structures
- term:
    id: GO:0090656
    label: t-circle formation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer (from the mouse ortholog) of the t-circle
      formation role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicate telomere-trimming function supported by ISS and by human IMP;
      specialized/non-core.
- term:
    id: GO:1904431
    label: positive regulation of t-circle formation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of positive regulation of t-circle formation from
      the mouse ortholog.
    action: KEEP_AS_NON_CORE
    reason: Specialized telomere role; genuine but non-core.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686475
  qualifier: located_in
  review:
    summary: Reactome-curated nucleoplasmic localization (SLX1A:SLX4 binds MUS81:EME1).
    action: ACCEPT
    reason: Consistent with established nucleoplasmic localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693584
  qualifier: located_in
  review:
    summary: >-
      Reactome-curated nucleoplasmic localization (Holliday-junction cleavage by
      SLX1A:SLX4:MUS81:EME1).
    action: ACCEPT
    reason: Consistent with established nucleoplasmic localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785732
  qualifier: located_in
  review:
    summary: >-
      Reactome-curated nucleoplasmic localization (DNA nucleases bind
      monoubiquitinated ID2 complex).
    action: ACCEPT
    reason: Consistent with established nucleoplasmic localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785986
  qualifier: located_in
  review:
    summary: >-
      Reactome-curated nucleoplasmic localization (DNA nucleases unhook the
      interstrand crosslink).
    action: ACCEPT
    reason: Consistent with established nucleoplasmic localization.
- term:
    id: GO:0072429
    label: response to intra-S DNA damage checkpoint signaling
  evidence_type: IMP
  original_reference_id: PMID:23361013
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      MGI IMP annotation placing SLX4 acting upstream of or within the intra-S DNA
      damage checkpoint response, citing the FBH1/MUS81 replication-stress study.
    action: UNDECIDED
    reason: >-
      The cited paper (Fugger et al., PMID:23361013) is centered on FBH1 and MUS81
      in generating DSBs after replication stress; its cached abstract does not
      mention SLX4, and the full text is not available in the cache. Because this is
      an experimental annotation whose supporting evidence for SLX4 specifically
      cannot be verified from the available text, it is left UNDECIDED rather than
      removed (per curation policy, experimental annotations are not overruled from
      incomplete evidence).
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IMP
  original_reference_id: PMID:19595721
  qualifier: involved_in
  review:
    summary: >-
      SLX4 depletion decreases DSB-induced homologous recombination, establishing a
      functional role in HR-mediated DSB repair.
    action: ACCEPT
    reason: >-
      Directly demonstrated by loss-of-function; core process for SLX4 as a
      coordinator of nucleases that process recombination intermediates.
    supported_by:
    - reference_id: PMID:19595721
      supporting_text: >-
        Depletion of SLX4 causes a decrease in DSB-induced homologous recombination
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IMP
  original_reference_id: PMID:19596235
  qualifier: involved_in
  review:
    summary: >-
      SLX4 depletion reduces the efficiency of DSB repair; the SLX1-SLX4 resolvase
      acts on Holliday junctions formed during HR.
    action: ACCEPT
    reason: >-
      Experimentally supported role in HR-mediated DSB repair; core.
    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:0000781
    label: chromosome, telomeric region
  evidence_type: IDA
  original_reference_id: PMID:19596235
  qualifier: colocalizes_with
  review:
    summary: >-
      SLX4 colocalizes with the telomeric region, consistent with its association
      with the TERF2(TRF2)-TERF2IP(RAP1) telomere-binding complex.
    action: ACCEPT
    reason: >-
      Experimentally observed telomeric colocalization; consistent with the
      SLX4-TRF2 interaction.
    supported_by:
    - reference_id: PMID:19596235
      supporting_text: >-
        telomere binding complex TERF2(TRF2)-TERF2IP(RAP1)
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IDA
  original_reference_id: PMID:19596235
  qualifier: located_in
  review:
    summary: SLX4 localizes to chromatin.
    action: ACCEPT
    reason: >-
      Experimentally determined chromatin localization, consistent with its
      recruitment to DNA-damage sites on chromatin.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19595721
  qualifier: enables
  review:
    summary: >-
      Physical-interaction evidence (Munoz et al.) for SLX4 binding endonuclease
      partners including MUS81 and SLX1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Real, functionally-important interactions, but the generic "protein binding"
      term is uninformative; captured by molecular adaptor and enzyme activator
      activity in core_functions.
    supported_by:
    - reference_id: PMID:19595721
      supporting_text: >-
        human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and
        SLX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19595722
  qualifier: enables
  review:
    summary: >-
      Physical-interaction evidence (Andersen et al.) for BTBD12/SLX4 interaction
      with structure-specific endonucleases (e.g. MUS81).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Documented interaction but uninformative as "protein binding"; scaffold
      function captured in core_functions.
    supported_by:
    - reference_id: PMID:19595722
      supporting_text: >-
        MUS312 and BTBD12 direct Holliday junction resolution by at least two
        distinct endonucleases in different recombination and repair contexts
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IMP
  original_reference_id: PMID:19595722
  qualifier: involved_in
  review:
    summary: >-
      Loss-of-function evidence that BTBD12/SLX4 is required for DNA repair
      (including interstrand crosslink repair).
    action: ACCEPT
    reason: >-
      Experimentally supported high-level repair process; correct and core.
    supported_by:
    - reference_id: PMID:19595722
      supporting_text: >-
        MEI-9-independent role in interstrand crosslink (ICL) repair
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: IMP
  original_reference_id: PMID:19596236
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to nucleotide-excision repair, reflecting SLX4's association
      with the XPF-ERCC1 endonuclease (the NER incision nuclease).
    action: KEEP_AS_NON_CORE
    reason: >-
      XPF-ERCC1 is the structure-specific nuclease shared between NER and ICL
      repair; SLX4 modulates XPF-ERCC1 but is not a canonical core NER factor (SLX4
      loss does not confer classic UV/NER sensitivity in patient fibroblasts). The
      annotation reflects a real but peripheral connection, so it is retained as
      non-core.
    supported_by:
    - reference_id: PMID:19596236
      supporting_text: >-
        SLX4 binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1
        endonucleases and is required for DNA interstrand crosslink repair
- term:
    id: GO:0008047
    label: enzyme activator activity
  evidence_type: IDA
  original_reference_id: PMID:19596235
  qualifier: enables
  review:
    summary: >-
      Direct biochemical evidence that SLX4 stimulates the nuclease activity of its
      partner endonucleases (SLX1, MUS81, XPF).
    action: ACCEPT
    reason: >-
      This is the most informative molecular-function annotation for SLX4: as a
      catalytically-inert regulatory subunit it increases the activity of
      structure-specific endonucleases. Core molecular function.
    supported_by:
    - reference_id: PMID:19595721
      supporting_text: >-
        SLX4 enhances the nuclease activity of SLX1, MUS81, and XPF
    - reference_id: PMID:24726326
      supporting_text: >-
        Recombinant mini-SLX4 enhances XPF-ERCC1 nuclease activity up to
        100-fold, directing specificity toward DNA forks
- term:
    id: GO:0010792
    label: DNA double-strand break processing involved in repair via single-strand
      annealing
  evidence_type: IMP
  original_reference_id: PMID:19595721
  qualifier: involved_in
  review:
    summary: >-
      SLX4 depletion impairs DSB processing in the single-strand annealing pathway,
      consistent with SLX4-directed XPF-ERCC1 cleavage of 3'-flaps during SSA.
    action: ACCEPT
    reason: >-
      Experimentally supported; SLX4/XPF-ERCC1 removes 3' non-homologous flaps
      during SSA. A specific but genuine repair role supported by IMP.
    supported_by:
    - reference_id: PMID:19595721
      supporting_text: >-
        human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and
        SLX1
- term:
    id: GO:0033557
    label: Slx1-Slx4 complex
  evidence_type: IDA
  original_reference_id: PMID:19595721
  qualifier: part_of
  review:
    summary: Direct-assay evidence of SLX1-SLX4 complex membership.
    action: ACCEPT
    reason: Directly demonstrated; correct and core.
    supported_by:
    - reference_id: PMID:19595721
      supporting_text: >-
        human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and
        SLX1
- term:
    id: GO:0033557
    label: Slx1-Slx4 complex
  evidence_type: IDA
  original_reference_id: PMID:19596235
  qualifier: part_of
  review:
    summary: Direct-assay evidence of SLX1-SLX4 complex membership.
    action: ACCEPT
    reason: Directly demonstrated; correct and core.
    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:0033557
    label: Slx1-Slx4 complex
  evidence_type: IDA
  original_reference_id: PMID:19596236
  qualifier: part_of
  review:
    summary: Direct-assay evidence of SLX1-SLX4 complex membership.
    action: ACCEPT
    reason: Directly demonstrated; correct and core.
    supported_by:
    - reference_id: PMID:19596236
      supporting_text: >-
        Human SLX1-SLX4 displays robust Holliday junction resolvase activity
- term:
    id: GO:0048476
    label: Holliday junction resolvase complex
  evidence_type: IDA
  original_reference_id: PMID:19595721
  qualifier: colocalizes_with
  review:
    summary: >-
      SLX4 colocalizes with / is a component of a Holliday-junction resolvase
      activity, contributed by the SLX1-SLX4 module.
    action: ACCEPT
    reason: >-
      The SLX1-SLX4 module is a bona fide Holliday-junction resolvase; the
      colocalizes_with assignment to the resolvase complex is experimentally
      supported.
    supported_by:
    - reference_id: PMID:19596235
      supporting_text: >-
        identifying SLX1-SLX4 as a HJ resolvase
- term:
    id: GO:0048476
    label: Holliday junction resolvase complex
  evidence_type: IDA
  original_reference_id: PMID:19596235
  qualifier: colocalizes_with
  review:
    summary: >-
      SLX4 associates with a Holliday-junction resolvase complex (the SLX1-SLX4
      module).
    action: ACCEPT
    reason: >-
      Experimentally supported; SLX1-SLX4 promotes symmetrical HJ cleavage.
    supported_by:
    - reference_id: PMID:19596235
      supporting_text: >-
        the SLX1-SLX4 module promotes symmetrical cleavage of static and migrating
        Holliday junctions (HJs), identifying SLX1-SLX4 as a HJ resolvase
- term:
    id: GO:0048476
    label: Holliday junction resolvase complex
  evidence_type: IDA
  original_reference_id: PMID:19596236
  qualifier: colocalizes_with
  review:
    summary: >-
      SLX4 associates with Holliday-junction resolvase activity displayed by the
      SLX1-SLX4 complex.
    action: ACCEPT
    reason: Experimentally supported HJ-resolvase association.
    supported_by:
    - reference_id: PMID:19596236
      supporting_text: >-
        Human SLX1-SLX4 displays robust Holliday junction resolvase activity
- term:
    id: GO:0070522
    label: ERCC4-ERCC1 complex
  evidence_type: IDA
  original_reference_id: PMID:19595721
  qualifier: colocalizes_with
  review:
    summary: >-
      SLX4 colocalizes with / associates with the ERCC4(XPF)-ERCC1 endonuclease
      complex, one of its partner nucleases.
    action: ACCEPT
    reason: >-
      Experimentally supported association; SLX4 binds and stimulates XPF-ERCC1.
      colocalizes_with is appropriate since SLX4 is a regulatory partner rather than
      a stable structural subunit of ERCC4-ERCC1.
    supported_by:
    - reference_id: PMID:19595721
      supporting_text: >-
        SLX4 enhances the nuclease activity of SLX1, MUS81, and XPF
- term:
    id: GO:0070522
    label: ERCC4-ERCC1 complex
  evidence_type: IDA
  original_reference_id: PMID:19596235
  qualifier: colocalizes_with
  review:
    summary: SLX4 associates with the ERCC4(XPF)-ERCC1 endonuclease complex.
    action: ACCEPT
    reason: >-
      Experimentally supported; SLX4 binds XPF-ERCC1 as part of its nuclease toolkit.
    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:0070522
    label: ERCC4-ERCC1 complex
  evidence_type: IDA
  original_reference_id: PMID:19596236
  qualifier: colocalizes_with
  review:
    summary: SLX4 associates with the ERCC4(XPF)-ERCC1 endonuclease complex.
    action: ACCEPT
    reason: Experimentally supported XPF-ERCC1 association.
    supported_by:
    - reference_id: PMID:19596236
      supporting_text: >-
        SLX4 binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1
        endonucleases
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:19596236
  qualifier: enables
  review:
    summary: >-
      SLX4 functions as a molecular adaptor/docking platform that physically bridges
      multiple structure-specific endonucleases (SLX1, XPF-ERCC1, MUS81-EME1),
      bringing them together on branched DNA.
    action: NEW
    reason: >-
      This scaffold/adaptor role is the most informative molecular-function
      description of SLX4 and is directly stated by the primary literature, yet it is
      not captured by any existing GOA molecular-function term (which are limited to
      DNA binding, enzyme activator activity and the uninformative protein binding).
      Added to reflect the core adaptor activity used in core_functions.
    supported_by:
    - reference_id: PMID:19596236
      supporting_text: >-
        We propose that SLX4 acts as a docking platform for multiple
        structure-specific endonucleases
    - reference_id: PMID:19595721
      supporting_text: >-
        human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and
        SLX1
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IMP
  original_reference_id: PMID:21240275
  qualifier: involved_in
  review:
    summary: >-
      SLX4 is required for DNA interstrand crosslink (ICL) repair; biallelic SLX4
      loss causes Fanconi anemia (FANCP) with cellular hypersensitivity to
      crosslinking agents, and SLX4-coordinated XPF-ERCC1/MUS81 incisions unhook ICLs.
    action: NEW
    reason: >-
      Interstrand cross-link repair is the central process underlying SLX4's disease
      role (FANCP), demonstrated by loss-of-function and complementation, but is not
      represented among the existing GOA process terms (which capture the broader
      "DNA repair" and specific DSB/telomere sub-processes). Added as the core ICL
      process referenced by core_functions.
    supported_by:
    - reference_id: PMID:21240275
      supporting_text: >-
        biallelic mutations in SLX4/FANCP cause a new subtype of Fanconi anemia, FA-P
    - reference_id: PMID:19596236
      supporting_text: >-
        SLX4 binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1
        endonucleases and is required for DNA interstrand crosslink repair
    - reference_id: PMID:24726325
      supporting_text: >-
        the 3' flap endonuclease XPF-ERCC1 cooperates with SLX4/FANCP to carry
        out the unhooking incisions
- term:
    id: GO:0061665
    label: SUMO ligase activity
  evidence_type: IDA
  original_reference_id: PMID:25533188
  qualifier: enables
  review:
    summary: >-
      Beyond its nuclease-scaffold role, the SLX4 complex acts as a SUMO E3
      ligase that SUMOylates SLX4 itself and the XPF subunit of XPF-ERCC1; this
      activity is mediated by a specific SLX4-UBC9 interaction and requires
      SLX4's SUMO-interaction motifs and BTB domain.
    action: NEW
    reason: >-
      This is a genuine, biochemically-demonstrated molecular function of SLX4
      that is distinct from (and additional to) its nuclease-activator/adaptor
      role, and is not represented among the existing GOA molecular-function
      terms. It is retained as non-core because the SLX4 SIMs (and hence the SUMO
      E3 ligase activity) are dispensable for interstrand crosslink repair; the
      activity is instead important to prevent mitotic catastrophe at common
      fragile sites. SLX4 being nuclease-dead does not preclude this separate
      SUMO-transfer catalytic function.
    supported_by:
    - reference_id: PMID:25533188
      supporting_text: >-
        the SLX4 complex is a SUMO E3 ligase that SUMOylates SLX4 itself and the
        XPF subunit of the DNA repair/recombination XPF-ERCC1 endonuclease
core_functions:
- description: >-
    Molecular adaptor/scaffold that assembles structure-specific endonucleases —
    SLX1, XPF-ERCC1 (ERCC4-ERCC1) and MUS81-EME1 — into a modular DNA-repair
    toolkit (the SLX-MUS complex), physically bridging the catalytic nucleases and
    positioning them on branched DNA intermediates during interstrand crosslink
    repair and homologous-recombination-mediated double-strand break repair. SLX4
    itself is nuclease-dead and provides the docking platform, not the catalysis.
  supported_by:
  - reference_id: PMID:19596236
    supporting_text: >-
      We propose that SLX4 acts as a docking platform for multiple structure-specific
      endonucleases
  - reference_id: PMID:19595721
    supporting_text: >-
      human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and SLX1
  - reference_id: PMID:24726325
    supporting_text: >-
      the 3' flap endonuclease XPF-ERCC1 cooperates with SLX4/FANCP to carry
      out the unhooking incisions
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  directly_involved_in:
  - id: GO:0036297
    label: interstrand cross-link repair
  - id: GO:0000724
    label: double-strand break repair via homologous recombination
  locations:
  - id: GO:0005654
    label: nucleoplasm
  - id: GO:0000785
    label: chromatin
  in_complex:
    id: GO:0033557
    label: Slx1-Slx4 complex
- description: >-
    Regulatory (enzyme-activator) subunit that stimulates the nucleolytic activity
    of its bound structure-specific endonucleases, enhancing SLX1-, MUS81- and
    XPF-catalyzed cleavage of branched DNA; through the SLX1-SLX4 module it
    contributes to symmetrical Holliday-junction resolution (crossover-junction
    endodeoxyribonuclease activity of the complex), which SLX4 activates but does
    not itself catalyze.
  supported_by:
  - reference_id: PMID:19595721
    supporting_text: >-
      SLX4 enhances the nuclease activity of SLX1, MUS81, and XPF
  - reference_id: PMID:19596235
    supporting_text: >-
      the SLX1-SLX4 module promotes symmetrical cleavage of static and migrating
      Holliday junctions (HJs), identifying SLX1-SLX4 as a HJ resolvase
  - reference_id: PMID:24726326
    supporting_text: >-
      Recombinant mini-SLX4 enhances XPF-ERCC1 nuclease activity up to 100-fold,
      directing specificity toward DNA forks
  molecular_function:
    id: GO:0008047
    label: enzyme activator activity
  contributes_to_molecular_function:
    id: GO:0008821
    label: crossover junction DNA endonuclease activity
  directly_involved_in:
  - id: GO:0036297
    label: interstrand cross-link repair
  - id: GO:0000724
    label: double-strand break repair via homologous recombination
  in_complex:
    id: GO:0033557
    label: Slx1-Slx4 complex
proposed_new_terms: []
suggested_questions:
- question: >-
    Which of SLX4's three partner nucleases (SLX1, XPF-ERCC1, MUS81-EME1) is most
    critical for interstrand crosslink unhooking in vivo, and does this differ
    between somatic and germline/hematopoietic compartments?
- question: >-
    What is the precise role of SLX4 SUMOylation and its SUMO-interaction motifs in
    coordinating the timing of nuclease activation at replication forks and telomeres?
suggested_experiments:
- description: >-
    Separation-of-function complementation of FANCP patient cells with SLX4 alleles
    that selectively disrupt SLX1-, MUS81- or XPF-binding, to dissect which
    nuclease-coordination activity rescues crosslink sensitivity.
  hypothesis: >-
    Distinct partner-nuclease interactions of SLX4 make non-redundant contributions
    to interstrand crosslink resistance.
- description: >-
    Reconstituted biochemical assays measuring the fold-stimulation of SLX1, MUS81
    and XPF cleavage by wild-type versus BTB- or UBZ-mutant SLX4 on defined branched
    substrates, to quantify the enzyme-activator function domain by domain.
  hypothesis: >-
    The BTB and UBZ domains of SLX4 are required for maximal stimulation of its
    partner endonucleases.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  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:19595721
  title: Coordination of structure-specific nucleases by human SLX4/BTBD12 is required
    for DNA repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary paper identifying human SLX4 as a scaffold for XPF-ERCC1, MUS81-EME1
      and SLX1 and showing SLX4 enhances their nuclease activity; supporting quotes
      verified verbatim against the cached record.
- id: PMID:19595722
  title: Drosophila MUS312 and the vertebrate ortholog BTBD12 interact with DNA structure-specific
    endonucleases in DNA repair and recombination.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes orthology of BTBD12/SLX4 to MUS312/Slx4 and its role directing
      HJ resolution and ICL repair; quotes verified.
- 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: >-
      Defines the SLX4 multiprotein complex and the SLX1-SLX4 HJ resolvase; source
      of the enzyme activator activity and complex-membership annotations. Quotes
      verified verbatim.
- id: PMID:19596236
  title: Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA
    repair/recombination endonucleases.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Independently identifies SLX4 as a docking platform for XPF-ERCC1, MUS81-EME1
      and SLX1 required for ICL repair; quotes verified.
- id: PMID:23361013
  title: FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell
    death following replication stress.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: >-
      Cited by MGI for the SLX4 GO:0072429 (intra-S checkpoint) annotation, but the
      cached abstract concerns FBH1 and MUS81, not SLX4, and full text is
      unavailable; SLX4-specific support could not be verified.
- id: PMID:24012755
  title: SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases
    with telomeres.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Source of the telomere-maintenance / t-circle / D-loop annotations; shows the
      SLX4-TRF2 scaffold bridges SLX1/XPF/MUS81 to telomeres. Quotes verified.
- id: PMID:25852190
  title: Integrative analysis of kinase networks in TRAIL-induced apoptosis provides
    a source of potential targets for combination therapy.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput kinase-network study; source of a generic PLK1 protein-binding
      IPI, uninformative for SLX4 molecular function.
- id: PMID:29892012
  title: An interactome perturbation framework prioritizes damaging missense mutations
    for developmental disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome dataset; generic protein-binding IPI only.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI proteome-scale two-hybrid map; generic protein-binding IPI only.
- id: PMID:32707033
  title: Kinase Interaction Network Expands Functional and Disease Roles of Human
    Kinases.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale kinase interaction network; generic protein-binding IPI only.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex proteome-scale AP-MS network; generic protein-binding IPI only.
- id: PMID:34804132
  title: Exploring the Structures and Functions of Macromolecular SLX4-Nuclease Complexes
    in Genome Stability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Review of SLX4-nuclease complexes; cited (NAS) for a broad DNA replication
      annotation that over-annotates SLX4's replication-associated repair role.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map foundation dataset; generic protein-binding IPI only.
- id: PMID:21240275
  title: Mutations of the SLX4 gene in Fanconi anemia.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes biallelic SLX4 mutations as a Fanconi anemia subtype (FANCP) and
      that SLX4 loss does not affect FANCD2 monoubiquitination; full text verified.
- id: PMID:21240277
  title: SLX4, a coordinator of structure-specific endonucleases, is mutated in a
    new Fanconi anemia subtype.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Companion FANCP-defining paper describing the first individuals with biallelic
      SLX4 mutations; abstract verified.
- id: PMID:24726325
  title: XPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with
    FANCD2 and FANCP/SLX4.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Xenopus egg-extract reconstitution showing XPF-ERCC1 cooperates with
      SLX4/FANCP to perform the unhooking incisions of replication-coupled ICL
      repair, and that XPF-ERCC1/SLX4 recruitment depends on ubiquitylated
      FANCD2. Provides the mechanistic basis for SLX4's core ICL-repair role;
      supporting quote verified verbatim against the cached full text.
- id: PMID:24726326
  title: Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease
    XPF-ERCC1 in DNA crosslink repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Demonstrates that the N-terminal mini-SLX4 (XPF-ERCC1-binding only) is
      sufficient for crosslink resistance and enhances XPF-ERCC1 nuclease
      activity up to 100-fold, directing fork specificity and stimulating dual
      incisions at a crosslink. Directly quantifies SLX4's enzyme-activator
      function; quote verified verbatim against the cached full text.
- id: PMID:25533188
  title: The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome
    and genome stability.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary biochemical/cell-biological evidence that the SLX4 complex is a
      SUMO E3 ligase (SUMOylating SLX4 and XPF via a specific SLX4-UBC9
      interaction, SIMs and BTB domain). Source of the NEW SUMO ligase activity
      annotation; SIMs are dispensable for ICL repair but the activity prevents
      mitotic catastrophe at common fragile sites. Quote verified verbatim
      against the cached abstract.
- id: Reactome:R-HSA-5686475
  title: SLX1A:SLX4 binds MUS81:EME1,(MUS81:EME2)
  findings: []
- id: Reactome:R-HSA-5693584
  title: Cleavage of Holliday junctions by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)
  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: []