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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000712 resolution of meiotic recombination intermediates | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) inference that SLX4 resolves recombination intermediates, framed in the meiotic context of orthologs such as fly MUS312. 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. Supporting Evidence: PMID:19596236 including fly MUS312, essential for meiotic recombination, and human BTBD12 |
| GO:0033557 Slx1-Slx4 complex | IBA GO_REF:0000033 | ACCEPT | Summary: SLX4 is a defining subunit of the SLX1-SLX4 structure-specific endonuclease complex; supported by phylogenetic inference and abundant experimental data. 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. Supporting Evidence: PMID:19595721 human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and SLX1 |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | 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. 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. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: SLX4 is a nuclear protein that relocalizes to sites of DNA damage. Reason: Consistent with experimentally-determined nuclear localization (nucleoplasm, chromatin, nuclear chromosome, telomeric foci). Correct, if unspecific. Supporting Evidence: PMID:19596235 SLX4 assembles a modular toolkit for repair of specific |
| GO:0006260 DNA replication | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro-based inference that SLX4 is involved in DNA replication. 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. |
| GO:0006281 DNA repair | IEA GO_REF:0000002 | ACCEPT | Summary: Broad DNA repair process, well supported: SLX4 coordinates nucleases in crosslink repair, DSB repair and recombination-intermediate processing. 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. Supporting Evidence: PMID:19595721 Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair |
| GO:0032206 positive regulation of telomere maintenance | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning inference that SLX4 positively regulates telomere maintenance; the same term is also asserted by IDA (PMID:24012755). 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. Supporting Evidence: PMID:24012755 the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple endonucleases with telomeres for recombination-based telomere maintenance |
| GO:0033557 Slx1-Slx4 complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based inference of Slx1-Slx4 complex membership. Reason: Duplicate of the well-supported Slx1-Slx4 complex assignment; correct and core. Supporting Evidence: PMID:19595721 human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and SLX1 |
| GO:0005515 protein binding | IPI PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotations to SLX4 interaction partners (endonuclease subunits, MSH2, PLK1, TERF2/TERF2IP, SLX4IP) from the Svendsen et al. complex purification. 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. Supporting Evidence: PMID:19596235 Human SLX4 forms a multiprotein complex with the ERCC4(XPF)-ERCC1, MUS81-EME1, and SLX1 endonucleases |
| GO:0005515 protein binding | IPI PMID:19596236 Human SLX4 is a Holliday junction resolvase subunit that bin... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from Fekairi et al., documenting SLX4 binding to XPF(ERCC4) and MUS81 endonuclease subunits. 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. Supporting Evidence: PMID:19596236 SLX4 binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1 endonucleases |
| GO:0005515 protein binding | IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo... | MARK AS OVER ANNOTATED | Summary: Protein-binding annotation with PLK1 derived from a high-throughput kinase interaction study (TRAIL-induced apoptosis network). 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. |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | MARK AS OVER ANNOTATED | Summary: Protein-binding annotation from a systematic interactome-perturbation framework for developmental-disorder missense variants. Reason: Uninformative high-throughput "protein binding" call; no specific molecular function conveyed. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Protein-binding annotation from the HuRI reference map of the human binary interactome. Reason: Generic protein-binding term from a proteome-scale two-hybrid map; uninformative for molecular function. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MARK AS OVER ANNOTATED | Summary: Protein-binding annotation from a large-scale kinase interaction network study. Reason: Uninformative high-throughput protein-binding call. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Protein-binding annotation from the BioPlex dual proteome-scale interactome networks. Reason: Generic protein-binding term from a proteome-scale AP-MS dataset; uninformative for molecular function. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Protein-binding annotation from a multimodal cell-map foundation dataset. Reason: Uninformative high-throughput protein-binding call; no specific molecular function conveyed. |
| GO:0090656 t-circle formation | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic inference that SLX4 is involved in t-circle (telomeric circle) formation, mirroring the mouse ortholog and the human IMP data. 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. Supporting Evidence: PMID:24012755 SLX4 assembles an endonuclease toolkit that negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures |
| GO:1904431 positive regulation of t-circle formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-based electronic transfer (from the mouse ortholog) that SLX4 positively regulates t-circle formation. Reason: Consistent with SLX4's telomere-trimming role via SLX1-catalyzed resolution; genuine but specialized/non-core. Supporting Evidence: PMID:24012755 negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures |
| GO:0000228 nuclear chromosome | IDA PMID:19596236 Human SLX4 is a Holliday junction resolvase subunit that bin... | ACCEPT | Summary: Direct-assay localization of SLX4 to the nuclear chromosome, consistent with its chromatin/DNA-repair role. Reason: Experimental localization by ComplexPortal curation; consistent with chromatin and DNA-damage-site localization reported for SLX4. |
| GO:0000724 double-strand break repair via homologous recombination | IDA PMID:19596236 Human SLX4 is a Holliday junction resolvase subunit that bin... | ACCEPT | Summary: SLX4 participates in homologous-recombination-mediated DSB repair by coordinating structure-specific endonucleases that process recombination intermediates. Reason: Well supported experimentally; SLX4 depletion reduces DSB-induced HR and the SLX1-SLX4 resolvase processes Holliday junctions arising in HR. Core process. Supporting Evidence: PMID:19595721 Depletion of SLX4 causes a decrease in DSB-induced homologous recombination |
| GO:0006260 DNA replication | NAS PMID:34804132 Exploring the Structures and Functions of Macromolecular SLX... | MARK AS OVER ANNOTATED | Summary: Non-traceable author statement associating SLX4 with DNA replication in a review of SLX4-nuclease complexes. 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. |
| GO:0033557 Slx1-Slx4 complex | IPI PMID:19596236 Human SLX4 is a Holliday junction resolvase subunit that bin... | ACCEPT | Summary: Physical-interaction evidence for the SLX1-SLX4 structure-specific endonuclease complex. Reason: Directly demonstrated complex membership; correct and core. Supporting Evidence: PMID:19596236 Human SLX1-SLX4 displays robust Holliday junction resolvase activity in addition to 5' flap endonuclease activity |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence localization of SLX4 to the nucleoplasm (HPA). Reason: Consistent with SLX4's established nuclear/nucleoplasmic localization. |
| GO:0000781 chromosome, telomeric region | IDA PMID:24012755 SLX4 assembles a telomere maintenance toolkit by bridging mu... | ACCEPT | Summary: SLX4 localizes to telomeres, where the SLX4-TRF2 complex recruits structure-specific endonucleases. Reason: Experimentally supported telomeric localization via the SLX4-TRF2 interaction; consistent with the telomere-maintenance role. Supporting Evidence: PMID:24012755 SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres |
| GO:0032206 positive regulation of telomere maintenance | IDA PMID:24012755 SLX4 assembles a telomere maintenance toolkit by bridging mu... | KEEP AS NON CORE | Summary: Direct-assay evidence that SLX4 regulates telomere maintenance/length homeostasis through nucleolytic resolution of telomeric structures. 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. Supporting Evidence: PMID:24012755 the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple endonucleases with telomeres for recombination-based telomere maintenance |
| GO:0061820 telomeric D-loop disassembly | IMP PMID:24012755 SLX4 assembles a telomere maintenance toolkit by bridging mu... | KEEP AS NON CORE | Summary: SLX4-directed nuclease activity resolves telomeric D-loop/t-loop structures, contributing to telomere trimming. Reason: Specific and experimentally supported telomere function; a specialized aspect of the scaffold's telomere role rather than the core somatic function. Supporting Evidence: PMID:24012755 negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures |
| GO:0005515 protein binding | IPI PMID:24012755 SLX4 assembles a telomere maintenance toolkit by bridging mu... | MARK AS OVER ANNOTATED | Summary: Protein-binding annotations to telomeric partners (TRF2/TERF2) and endonucleases from the SLX4 telomere-toolkit study. 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. Supporting Evidence: PMID:24012755 SLX4 also interacts with telomeric protein TRF2 in human cells |
| GO:0033557 Slx1-Slx4 complex | TAS PMID:24012755 SLX4 assembles a telomere maintenance toolkit by bridging mu... | ACCEPT | Summary: Traceable-author statement of SLX1-SLX4 complex membership. Reason: Correct, well-established complex; core. |
| GO:0090656 t-circle formation | IMP PMID:24012755 SLX4 assembles a telomere maintenance toolkit by bridging mu... | KEEP AS NON CORE | Summary: SLX4 depletion/mutation experiments show SLX4 is required for formation of extrachromosomal telomeric circles (t-circles). Reason: Experimentally supported telomere-trimming output; specialized/non-core. Supporting Evidence: PMID:24012755 SLX4 assembles an endonuclease toolkit that negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures |
| GO:1904357 negative regulation of telomere maintenance via telomere lengthening | IMP PMID:24012755 SLX4 assembles a telomere maintenance toolkit by bridging mu... | KEEP AS NON CORE | Summary: SLX4 negatively regulates telomere lengthening by resolving telomeric structures (telomere trimming). Reason: Consistent with the demonstrated negative regulation of telomere length via SLX1-catalyzed resolution; genuine but specialized/non-core. Supporting Evidence: PMID:24012755 negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures |
| GO:0090656 t-circle formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer (from the mouse ortholog) of the t-circle formation role. Reason: Duplicate telomere-trimming function supported by ISS and by human IMP; specialized/non-core. |
| GO:1904431 positive regulation of t-circle formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of positive regulation of t-circle formation from the mouse ortholog. Reason: Specialized telomere role; genuine but non-core. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686475 | ACCEPT | Summary: Reactome-curated nucleoplasmic localization (SLX1A:SLX4 binds MUS81:EME1). Reason: Consistent with established nucleoplasmic localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693584 | ACCEPT | Summary: Reactome-curated nucleoplasmic localization (Holliday-junction cleavage by SLX1A:SLX4:MUS81:EME1). Reason: Consistent with established nucleoplasmic localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785732 | ACCEPT | Summary: Reactome-curated nucleoplasmic localization (DNA nucleases bind monoubiquitinated ID2 complex). Reason: Consistent with established nucleoplasmic localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785986 | ACCEPT | Summary: Reactome-curated nucleoplasmic localization (DNA nucleases unhook the interstrand crosslink). Reason: Consistent with established nucleoplasmic localization. |
| GO:0072429 response to intra-S DNA damage checkpoint signaling | IMP PMID:23361013 FBH1 co-operates with MUS81 in inducing DNA double-strand br... | UNDECIDED | 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. 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). |
| GO:0000724 double-strand break repair via homologous recombination | IMP PMID:19595721 Coordination of structure-specific nucleases by human SLX4/B... | ACCEPT | Summary: SLX4 depletion decreases DSB-induced homologous recombination, establishing a functional role in HR-mediated DSB repair. Reason: Directly demonstrated by loss-of-function; core process for SLX4 as a coordinator of nucleases that process recombination intermediates. Supporting Evidence: PMID:19595721 Depletion of SLX4 causes a decrease in DSB-induced homologous recombination |
| GO:0000724 double-strand break repair via homologous recombination | IMP PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | ACCEPT | Summary: SLX4 depletion reduces the efficiency of DSB repair; the SLX1-SLX4 resolvase acts on Holliday junctions formed during HR. Reason: Experimentally supported role in HR-mediated DSB repair; core. Supporting Evidence: PMID:19596235 Depletion of SLX4 causes sensitivity to mitomycin C and camptothecin and reduces the efficiency of DSB repair in vivo |
| GO:0000781 chromosome, telomeric region | IDA PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | ACCEPT | Summary: SLX4 colocalizes with the telomeric region, consistent with its association with the TERF2(TRF2)-TERF2IP(RAP1) telomere-binding complex. Reason: Experimentally observed telomeric colocalization; consistent with the SLX4-TRF2 interaction. Supporting Evidence: PMID:19596235 telomere binding complex TERF2(TRF2)-TERF2IP(RAP1) |
| GO:0000785 chromatin | IDA PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | ACCEPT | Summary: SLX4 localizes to chromatin. Reason: Experimentally determined chromatin localization, consistent with its recruitment to DNA-damage sites on chromatin. |
| GO:0005515 protein binding | IPI PMID:19595721 Coordination of structure-specific nucleases by human SLX4/B... | MARK AS OVER ANNOTATED | Summary: Physical-interaction evidence (Munoz et al.) for SLX4 binding endonuclease partners including MUS81 and SLX1. Reason: Real, functionally-important interactions, but the generic "protein binding" term is uninformative; captured by molecular adaptor and enzyme activator activity in core_functions. Supporting Evidence: PMID:19595721 human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and SLX1 |
| GO:0005515 protein binding | IPI PMID:19595722 Drosophila MUS312 and the vertebrate ortholog BTBD12 interac... | MARK AS OVER ANNOTATED | Summary: Physical-interaction evidence (Andersen et al.) for BTBD12/SLX4 interaction with structure-specific endonucleases (e.g. MUS81). Reason: Documented interaction but uninformative as "protein binding"; scaffold function captured in core_functions. Supporting Evidence: PMID:19595722 MUS312 and BTBD12 direct Holliday junction resolution by at least two distinct endonucleases in different recombination and repair contexts |
| GO:0006281 DNA repair | IMP PMID:19595722 Drosophila MUS312 and the vertebrate ortholog BTBD12 interac... | ACCEPT | Summary: Loss-of-function evidence that BTBD12/SLX4 is required for DNA repair (including interstrand crosslink repair). Reason: Experimentally supported high-level repair process; correct and core. Supporting Evidence: PMID:19595722 MEI-9-independent role in interstrand crosslink (ICL) repair |
| GO:0006289 nucleotide-excision repair | IMP PMID:19596236 Human SLX4 is a Holliday junction resolvase subunit that bin... | KEEP AS NON CORE | Summary: IMP annotation to nucleotide-excision repair, reflecting SLX4's association with the XPF-ERCC1 endonuclease (the NER incision nuclease). 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. Supporting Evidence: PMID:19596236 SLX4 binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1 endonucleases and is required for DNA interstrand crosslink repair |
| GO:0008047 enzyme activator activity | IDA PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | ACCEPT | Summary: Direct biochemical evidence that SLX4 stimulates the nuclease activity of its partner endonucleases (SLX1, MUS81, XPF). 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. Supporting Evidence: PMID:19595721 SLX4 enhances the nuclease activity of SLX1, MUS81, and XPF PMID:24726326 Recombinant mini-SLX4 enhances XPF-ERCC1 nuclease activity up to 100-fold, directing specificity toward DNA forks |
| GO:0010792 DNA double-strand break processing involved in repair via single-strand annealing | IMP PMID:19595721 Coordination of structure-specific nucleases by human SLX4/B... | ACCEPT | Summary: SLX4 depletion impairs DSB processing in the single-strand annealing pathway, consistent with SLX4-directed XPF-ERCC1 cleavage of 3'-flaps during SSA. Reason: Experimentally supported; SLX4/XPF-ERCC1 removes 3' non-homologous flaps during SSA. A specific but genuine repair role supported by IMP. Supporting Evidence: PMID:19595721 human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and SLX1 |
| GO:0033557 Slx1-Slx4 complex | IDA PMID:19595721 Coordination of structure-specific nucleases by human SLX4/B... | ACCEPT | Summary: Direct-assay evidence of SLX1-SLX4 complex membership. Reason: Directly demonstrated; correct and core. Supporting Evidence: PMID:19595721 human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and SLX1 |
| GO:0033557 Slx1-Slx4 complex | IDA PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | ACCEPT | Summary: Direct-assay evidence of SLX1-SLX4 complex membership. Reason: Directly demonstrated; correct and core. Supporting Evidence: PMID:19596235 Human SLX4 forms a multiprotein complex with the ERCC4(XPF)-ERCC1, MUS81-EME1, and SLX1 endonucleases |
| GO:0033557 Slx1-Slx4 complex | IDA PMID:19596236 Human SLX4 is a Holliday junction resolvase subunit that bin... | ACCEPT | Summary: Direct-assay evidence of SLX1-SLX4 complex membership. Reason: Directly demonstrated; correct and core. Supporting Evidence: PMID:19596236 Human SLX1-SLX4 displays robust Holliday junction resolvase activity |
| GO:0048476 Holliday junction resolvase complex | IDA PMID:19595721 Coordination of structure-specific nucleases by human SLX4/B... | ACCEPT | Summary: SLX4 colocalizes with / is a component of a Holliday-junction resolvase activity, contributed by the SLX1-SLX4 module. Reason: The SLX1-SLX4 module is a bona fide Holliday-junction resolvase; the colocalizes_with assignment to the resolvase complex is experimentally supported. Supporting Evidence: PMID:19596235 identifying SLX1-SLX4 as a HJ resolvase |
| GO:0048476 Holliday junction resolvase complex | IDA PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | ACCEPT | Summary: SLX4 associates with a Holliday-junction resolvase complex (the SLX1-SLX4 module). Reason: Experimentally supported; SLX1-SLX4 promotes symmetrical HJ cleavage. Supporting Evidence: PMID:19596235 the SLX1-SLX4 module promotes symmetrical cleavage of static and migrating Holliday junctions (HJs), identifying SLX1-SLX4 as a HJ resolvase |
| GO:0048476 Holliday junction resolvase complex | IDA PMID:19596236 Human SLX4 is a Holliday junction resolvase subunit that bin... | ACCEPT | Summary: SLX4 associates with Holliday-junction resolvase activity displayed by the SLX1-SLX4 complex. Reason: Experimentally supported HJ-resolvase association. Supporting Evidence: PMID:19596236 Human SLX1-SLX4 displays robust Holliday junction resolvase activity |
| GO:0070522 ERCC4-ERCC1 complex | IDA PMID:19595721 Coordination of structure-specific nucleases by human SLX4/B... | ACCEPT | Summary: SLX4 colocalizes with / associates with the ERCC4(XPF)-ERCC1 endonuclease complex, one of its partner nucleases. 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. Supporting Evidence: PMID:19595721 SLX4 enhances the nuclease activity of SLX1, MUS81, and XPF |
| GO:0070522 ERCC4-ERCC1 complex | IDA PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | ACCEPT | Summary: SLX4 associates with the ERCC4(XPF)-ERCC1 endonuclease complex. Reason: Experimentally supported; SLX4 binds XPF-ERCC1 as part of its nuclease toolkit. Supporting Evidence: PMID:19596235 Human SLX4 forms a multiprotein complex with the ERCC4(XPF)-ERCC1, MUS81-EME1, and SLX1 endonucleases |
| GO:0070522 ERCC4-ERCC1 complex | IDA PMID:19596236 Human SLX4 is a Holliday junction resolvase subunit that bin... | ACCEPT | Summary: SLX4 associates with the ERCC4(XPF)-ERCC1 endonuclease complex. Reason: Experimentally supported XPF-ERCC1 association. Supporting Evidence: PMID:19596236 SLX4 binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1 endonucleases |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:19596236 Human SLX4 is a Holliday junction resolvase subunit that bin... | NEW | 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. 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. Supporting Evidence: PMID:19596236 We propose that SLX4 acts as a docking platform for multiple structure-specific endonucleases PMID:19595721 human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and SLX1 |
| GO:0036297 interstrand cross-link repair | IMP PMID:21240275 Mutations of the SLX4 gene in Fanconi anemia. | NEW | 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. 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. Supporting Evidence: PMID:21240275 biallelic mutations in SLX4/FANCP cause a new subtype of Fanconi anemia, FA-P PMID:19596236 SLX4 binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1 endonucleases and is required for DNA interstrand crosslink repair PMID:24726325 the 3' flap endonuclease XPF-ERCC1 cooperates with SLX4/FANCP to carry out the unhooking incisions |
| GO:0061665 SUMO ligase activity | IDA PMID:25533188 The SLX4 complex is a SUMO E3 ligase that impacts on replica... | NEW | 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. 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. Supporting Evidence: PMID:25533188 the SLX4 complex is a SUMO E3 ligase that SUMOylates SLX4 itself and the XPF subunit of the DNA repair/recombination XPF-ERCC1 endonuclease |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
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