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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006312 mitotic recombination | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:22547097 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. |
| GO:1990599 3' overhang single-stranded DNA endonuclease activity | IBA GO_REF:0000033 | ACCEPT | Summary: Structure-specific endonuclease activity on 3' single-stranded overhangs; experimentally demonstrated at telomeres and phylogenetically conserved. 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. Supporting Evidence: PMID:14690602 ERCC1/XPF-deficient cells retained the telomeric overhang after TRF2 inhibition, identifying this nucleotide excision repair endonuclease as the culprit in overhang removal. |
| GO:1901255 nucleotide-excision repair involved in interstrand cross-link repair | IBA GO_REF:0000033 | ACCEPT | Summary: Role in the incision (unhooking) step of interstrand crosslink repair, phylogenetically inferred and experimentally confirmed. 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. Supporting Evidence: PMID:32034146 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. PMID:23623386 the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair. |
| GO:0000110 nucleotide-excision repair factor 1 complex | IBA GO_REF:0000033 | ACCEPT | Summary: Membership in NER factor 1 (the ERCC1-XPF heterodimer), the 5'-incision nuclease of NER. Reason: NEF1 is the ERCC1-XPF complex; XPF is a defining subunit. Correct and well supported. |
| GO:0000712 resolution of meiotic recombination intermediates | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred meiotic role (yeast Rad1, fly Mei-9 resolve heteroduplex/recombination intermediates); mouse Xpf is upregulated in meiotic spermatogenic cells. Reason: A conserved but specialized meiotic application of the endonuclease; not the primary somatic DNA-repair function of human XPF. Supporting Evidence: PMID:10644440 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. |
| GO:0000724 double-strand break repair via homologous recombination | IBA GO_REF:0000033 | ACCEPT | Summary: Role in homology-directed double-strand break repair, chiefly single-strand annealing where XPF-ERCC1 trims 3' non-homologous flaps. 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). Supporting Evidence: PMID:14734547 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. |
| GO:0003684 damaged DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Binds damaged DNA / DNA-damage sites, consistent with its recruitment to lesions and localization to sites of DNA damage. Reason: Supported by localization of XPF to chromatin damage sites and by its structure-specific substrate recognition; a correct supporting molecular function. Supporting Evidence: PMID:11790111 XPF forms a heterodimeric complex with ERCC1 and is required for the repair of DNA interstrand cross-links. |
| GO:0003697 single-stranded DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Binds single-stranded DNA; the XPF HhH motifs contact the ssDNA arm at ss/ds junctions. Reason: Directly supported biochemically (XPF binds DNA without ERCC1) and structurally (XPF-ssDNA complex); a real, specific supporting function. Supporting Evidence: PMID:22483113 A positively charged region within the second helix of the first HhH motif contacts the ssDNA phosphate backbone. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: General DNA-binding activity inferred from the ERCC4/XPF InterPro domain. Reason: Correct but general; the more informative ssDNA/damaged-DNA/junction binding is captured by other annotations. Acceptable as a broad electronic annotation. |
| GO:0003697 single-stranded DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: ssDNA binding inferred from InterPro (XPF domain). Reason: Consistent with experimental and structural evidence for ssDNA binding by XPF; a correct electronic annotation. |
| GO:0004520 DNA endonuclease activity | IEA GO_REF:0000002 | ACCEPT | Summary: DNA endonuclease activity inferred from the XPF InterPro nuclease domain. Reason: Correct core catalytic activity, matching abundant experimental evidence. Could be refined to structure-specific/ssDNA endodeoxyribonuclease, but the general term is not wrong. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization (UniProt subcellular location mapping). Reason: XPF is a nuclear DNA-repair enzyme; consistent with experimental localization. |
| GO:0005694 chromosome | IEA GO_REF:0000044 | ACCEPT | Summary: Chromosome/chromatin localization (UniProt subcellular location mapping). Reason: XPF localizes to chromatin sites of DNA damage; consistent with experimental data. |
| GO:0006281 DNA repair | IEA GO_REF:0000120 | ACCEPT | Summary: General DNA repair, the parent process for XPF's NER/ICL/recombination roles. Reason: Correct though broad; more specific processes (NER, ICL repair) are annotated separately. Acceptable as a high-level electronic annotation. |
| GO:0009411 response to UV | IEA GO_REF:0000117 | ACCEPT | Summary: Response to UV, reflecting XPF's role in repair of UV photolesions via NER. Reason: Consistent with XP-F photosensitivity and the requirement of XPF nuclease activity for repair of UV-induced damage. |
| GO:0005515 protein binding | IPI PMID:16338413 The structure of the human ERCC1/XPF interaction domains rev... | MARK AS OVER ANNOTATED | Summary: IntAct-curated binary interaction with ERCC1 (P07992), the obligate partner in the XPF-ERCC1 heterodimer. Reason: 'protein binding' is uninformative; the functionally meaningful ERCC1 association is captured by the ERCC4-ERCC1 complex (GO:0070522) annotations. |
| GO:0005515 protein binding | IPI PMID:17289582 Identification of FAAP24, a Fanconi anemia core complex prot... | MARK AS OVER ANNOTATED | Summary: IntAct-curated binary interaction (with ERCC1, P07992). Reason: Uninformative generic term; complex membership is captured by GO:0070522. |
| GO:0005515 protein binding | IPI PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction with SLX4/BTBD12 (Q8IY92), which scaffolds XPF-ERCC1 with other structure-specific nucleases. Reason: Generic term is uninformative; the SLX4-coordinated function is reflected in the ICL-repair and recombination process annotations. 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: IntAct-curated interaction with SLX4 (Q8IY92). Reason: Uninformative generic term; SLX4 coordination is captured functionally elsewhere. |
| GO:0005515 protein binding | IPI PMID:24780295 Importance of EGFR/ERCC1 interaction following radiation-ind... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction (with ERCC1, P07992). Reason: Uninformative generic term; not a core function statement. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome interaction (with ERCC1, P07992). Reason: Generic term from a large-scale interactome screen; uninformative for function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: High-throughput binary interactome interaction (with TACC1 isoform, O75410-7). Reason: Generic term from a proteome-scale two-hybrid map; not functionally interpretable here. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome interactions (ERCC1 P07992; SLX4 Q8IY92). Reason: Generic term from a large-scale interactome study; uninformative for function. |
| GO:0042802 identical protein binding | IPI PMID:22483113 The structure of the XPF-ssDNA complex underscores the disti... | MARK AS OVER ANNOTATED | Summary: IntAct self-interaction (XPF-XPF, Q92889) recorded from the XPF-ssDNA structural study. 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. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nucleoplasmic localization by immunofluorescence (HPA). Reason: Consistent with a soluble nuclear DNA-repair enzyme. |
| GO:0016604 nuclear body | IDA GO_REF:0000052 | ACCEPT | Summary: Localization to nuclear bodies/foci, consistent with damage-induced XPF nuclear foci. Reason: XPF is recruited into damage-induced nuclear foci; nuclear body localization is consistent with this behavior. Supporting Evidence: PMID:12571280 FANCA and the known DNA repair protein XPF localize to the same nuclear foci. |
| GO:0006289 nucleotide-excision repair | IDA PMID:22547097 Multiple DNA binding domains mediate the function of the ERC... | ACCEPT | Summary: Direct role in NER as the 5'-incising nuclease; ComplexPortal annotation of the ERCC1-XPF endonuclease. Reason: Core function. Recruited to lesions via XPA and incises 5' to the damage. Supporting Evidence: PMID:22547097 In NER, ERCC1-XPF is recruited to DNA lesions by interaction with XPA and incises the DNA 5' to the lesion. |
| GO:0070522 ERCC4-ERCC1 complex | IPI PMID:16076955 Crystal structure and DNA binding functions of ERCC1, a subu... | ACCEPT | Summary: Member of the ERCC1-XPF (ERCC4-ERCC1) structure-specific endonuclease heterodimer. Reason: The definitive physiological complex for XPF; established structurally and biochemically. Core. Supporting Evidence: PMID:16076955 Human XPF-ERCC1 is a DNA endonuclease that incises a damaged DNA strand on the 5' side of a lesion during nucleotide excision repair |
| GO:0005634 nucleus | EXP PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | ACCEPT | Summary: Experimental nuclear localization; XPF/ERCC4 functions as part of the nuclear SLX4-coordinated structure-specific nuclease machinery. Reason: Consistent with a nuclear DNA-repair enzyme; XPF acts within nuclear DNA-repair complexes. Supporting Evidence: PMID:19596235 Human SLX4 forms a multiprotein complex with the ERCC4(XPF)-ERCC1, MUS81-EME1, and SLX1 endonucleases |
| GO:0005694 chromosome | EXP PMID:11790111 Contribution of XPF functional domains to the 5' and 3' inci... | ACCEPT | Summary: Experimental chromosome/chromatin localization; localizes to sites of DNA damage. Reason: Chromatin association at damage sites is consistent with UniProt's note that XPF localizes to sites of DNA damage. |
| GO:0006303 double-strand break repair via nonhomologous end joining | IMP PMID:14690602 ERCC1/XPF removes the 3' overhang from uncapped telomeres an... | KEEP AS NON CORE | Summary: At uncapped telomeres, XPF-mediated removal of the 3' overhang is a prerequisite for NHEJ-mediated end fusion. 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). Supporting Evidence: PMID:14690602 overhang processing is a prerequisite for NHEJ of telomeres. |
| GO:1990599 3' overhang single-stranded DNA endonuclease activity | IMP PMID:14690602 ERCC1/XPF removes the 3' overhang from uncapped telomeres an... | ACCEPT | Summary: Removes the telomeric 3' single-stranded overhang from uncapped telomeres. Reason: Directly demonstrated: XPF-deficient cells retain the 3' overhang after TRF2 inhibition, identifying XPF as the overhang-removing nuclease. Supporting Evidence: PMID:14690602 ERCC1/XPF-deficient cells retained the telomeric overhang after TRF2 inhibition, identifying this nucleotide excision repair endonuclease as the culprit in overhang removal. |
| GO:0006289 nucleotide-excision repair | IDA PMID:10413517 Domain mapping of the DNA binding, endonuclease, and ERCC1 b... | ACCEPT | Summary: Direct role in NER; the XPF/ERCC1 complex makes one of the two NER incisions. Reason: Core function, biochemically established with purified protein. Supporting Evidence: PMID:10413517 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. |
| GO:0006289 nucleotide-excision repair | IMP PMID:14728600 Defining the function of xeroderma pigmentosum group F prote... | ACCEPT | Summary: XPF-deficient cells show defective repair; XPF required for NER incision. Reason: Core function; XPF nuclear extract and cellular repair assays establish its NER requirement. Supporting Evidence: PMID:14728600 the XPF nuclear extract is normal in introducing dual incisions during the nucleotide excision repair process. |
| GO:0006289 nucleotide-excision repair | IDA PMID:32034146 Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex as... | ACCEPT | Summary: XPF-ERCC1 endonuclease essential for NER; acetylation-regulated complex assembly is required for repair. Reason: Core function; loss of XPF acetylation impairs NER. Supporting Evidence: PMID:32034146 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. |
| GO:0034644 cellular response to UV | IDA PMID:32034146 Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex as... | ACCEPT | Summary: Cellular response to UV; TIP60-mediated acetylation of XPF is induced by UV and required for repair. Reason: Consistent with UV-induced regulation of XPF-ERCC1 assembly and the essential role of XPF in repairing UV lesions. Supporting Evidence: PMID:32034146 TIP60, also known as KAT5, a haplo-insufficient tumor suppressor, directly acetylates XPF at Lys911 following UV irradiation |
| GO:0070522 ERCC4-ERCC1 complex | IDA PMID:32034146 Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex as... | ACCEPT | Summary: Member of the XPF-ERCC1 heterodimer; assembly regulated by Lys911 acetylation. Reason: Directly demonstrated complex assembly. Core. Supporting Evidence: PMID:32034146 this acetylation is required for XPF-ERCC1 complex assembly and subsequent activation. |
| GO:1901255 nucleotide-excision repair involved in interstrand cross-link repair | IDA PMID:32034146 Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex as... | ACCEPT | Summary: Direct role in interstrand crosslink repair by the XPF-ERCC1 endonuclease. Reason: Core function; XPF-ERCC1 is essential for ICL repair and loss of XPF acetylation causes ICL repair defects. Supporting Evidence: PMID:32034146 loss of XPF acetylation impairs the damage-induced XPF-ERCC1 interaction, resulting in defects in both NER and ICL repair. |
| GO:0061819 telomeric DNA-containing double minutes formation | IMP PMID:14690602 ERCC1/XPF removes the 3' overhang from uncapped telomeres an... | KEEP AS NON CORE | Summary: XPF represses formation of Telomeric DNA-containing Double Minute chromosomes (TDMs); ERCC1/XPF-deficient mouse cells accumulate TDMs. 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. Supporting Evidence: PMID:14690602 ERCC1/XPF-deficient mouse cells had a novel telomere phenotype, characterized by Telomeric DNA-containing Double Minute chromosomes (TDMs). |
| GO:0000781 chromosome, telomeric region | IDA PMID:14690602 ERCC1/XPF removes the 3' overhang from uncapped telomeres an... | ACCEPT | Summary: Localizes to telomeres as a component of the telomeric TRF2 complex. Reason: ERCC1/XPF was identified as a component of the telomeric TRF2 complex, supporting telomeric-region localization. Supporting Evidence: PMID:14690602 ERCC1/XPF was also identified as a component of the telomeric TRF2 complex. |
| GO:0005515 protein binding | IPI PMID:18812185 Human XPF controls TRF2 and telomere length maintenance thro... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction (with ERCC1, P07992) from the TRF2/telomere study. Reason: Uninformative generic term; not a core function statement. |
| GO:0005515 protein binding | IPI PMID:24012755 SLX4 assembles a telomere maintenance toolkit by bridging mu... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction with SLX4 (Q8IY92) in the telomere-maintenance toolkit. Reason: Generic term; the SLX4-bridged telomeric function is captured by process annotations. Supporting Evidence: PMID:24012755 SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. |
| GO:0010521 telomerase inhibitor activity | IDA NOT PMID:18812185 Human XPF controls TRF2 and telomere length maintenance thro... | ACCEPT | Summary: XPF controls telomere length via TRF2 regulation and a nuclease-independent mechanism, NOT by inhibiting telomerase; the negated annotation is informative. Reason: The negation correctly records that XPF's effect on telomere length is not mediated by telomerase inhibition; retain as a valid NOT annotation. Supporting Evidence: PMID:18812185 XPF-ERCC1 controls TRF2 and telomere length maintenance through two distinctive mechanisms, with the former requiring its nuclease activity. |
| GO:0070522 ERCC4-ERCC1 complex | IDA PMID:14690602 ERCC1/XPF removes the 3' overhang from uncapped telomeres an... | ACCEPT | Summary: Member of the ERCC1-XPF heterodimer (here acting at telomeres). Reason: Established complex membership. Core. |
| GO:1904357 negative regulation of telomere maintenance via telomere lengthening | IDA PMID:18812185 Human XPF controls TRF2 and telomere length maintenance thro... | KEEP AS NON CORE | Summary: XPF-ERCC1 acts as a negative mediator of telomere length; XPF overexpression induces telomere shortening. Reason: Well-documented but specialized telomeric regulatory role, distinct from the core DNA-repair endonuclease function. Supporting Evidence: PMID:18812185 overexpression of XPF induces telomere shortening in XPF-proficient cells whereas XPF complementation suppresses telomere lengthening in XPF-deficient cells. |
| GO:1905765 negative regulation of protection from non-homologous end joining at telomere | IMP PMID:14690602 ERCC1/XPF removes the 3' overhang from uncapped telomeres an... | KEEP AS NON CORE | Summary: By removing the protective 3' overhang from uncapped telomeres, XPF antagonizes the protection of telomeres from NHEJ. Reason: A precise but highly specialized telomere phenotype supported by the IMP data; retained as non-core. Supporting Evidence: PMID:14690602 TRF2 prevents NHEJ at telomeres through protection of the telomeric overhang from ERCC1/XPF. |
| GO:0000723 telomere maintenance | IGI PMID:17055345 XPF with mutations in its conserved nuclease domain is defec... | KEEP AS NON CORE | Summary: Functions with TRF2 in telomere-length regulation; required for TRF2-promoted telomere shortening. Reason: Genuine telomere role established by genetic interaction with TRF2, but secondary to the core repair function. Supporting Evidence: PMID:17055345 TRF2-induced telomere shortening is abrogated in human cells deficient in XPF, demonstrating that XPF-ERCC1 is required for TRF2-promoted telomere shortening. |
| GO:0004520 DNA endonuclease activity | IMP PMID:17055345 XPF with mutations in its conserved nuclease domain is defec... | ACCEPT | Summary: Nuclease-domain point mutants are repair-defective, demonstrating the requirement for XPF endonuclease activity. Reason: Core catalytic function; nuclease-inactive XPF fails to repair UV damage. Could be refined to the structure-specific/ssDNA endonuclease level. Supporting Evidence: PMID:17055345 the nuclease-inactive XPF proteins fail to do so, indicating that the nuclease activity of XPF is essential for nucleotide excision repair. |
| GO:0005515 protein binding | IPI PMID:17055345 XPF with mutations in its conserved nuclease domain is defec... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction (with ERCC1, P07992). Reason: Uninformative generic term; ERCC1 partnership is captured by GO:0070522. |
| GO:0006281 DNA repair | IGI PMID:17055345 XPF with mutations in its conserved nuclease domain is defec... | ACCEPT | Summary: General DNA repair, established through genetic interaction with TRF2 and repair assays. Reason: Correct though broad; specific NER role is annotated separately. |
| GO:0034644 cellular response to UV | IGI PMID:17055345 XPF with mutations in its conserved nuclease domain is defec... | ACCEPT | Summary: XPF nuclease activity required for repair of UV-induced DNA damage. Reason: Consistent with XPF's role in NER of UV photolesions; wild-type but not nuclease-dead XPF complements repair of UV damage. Supporting Evidence: PMID:17055345 wild type XPF can complement XPF-deficient cells for repair of UV-induced DNA damage |
| GO:0070522 ERCC4-ERCC1 complex | IDA PMID:17055345 XPF with mutations in its conserved nuclease domain is defec... | ACCEPT | Summary: Member of the XPF-ERCC1 structure-specific endonuclease. Reason: Established complex membership. Core. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-109955 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; formation of the ERCC1:XPF complex). Reason: Consistent with nuclear localization of the repair enzyme. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686657 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; ERCC1:XPF cleaves SSA flaps). Reason: Consistent nuclear localization; redundant with other nucleoplasm annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686663 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; completion of SSA). Reason: Consistent nuclear localization; redundant Reactome annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5690213 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; GG-NER). Reason: Consistent nuclear localization; redundant Reactome annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5690988 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; 3'-incision by XPG in GG-NER). Reason: Consistent nuclear localization; redundant Reactome annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5690990 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; 5'-incision by ERCC1:ERCC4 in GG-NER). Reason: Consistent nuclear localization; this step is XPF's own 5' incision in NER. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5690991 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; binding of ERCC1:ERCC4 to GG-NER pre-incision complex). Reason: Consistent nuclear localization; redundant Reactome annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6782141 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; ERCC1:ERCC4 binding in TC-NER). Reason: Consistent nuclear localization; redundant Reactome annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6782204 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; 5' incision by ERCC1:ERCC4 in TC-NER). Reason: Consistent nuclear localization; XPF's 5' incision in TC-NER. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6782211 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; TC-NER). Reason: Consistent nuclear localization; redundant Reactome annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6782224 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; 3' incision by XPG in TC-NER). Reason: Consistent nuclear localization; redundant Reactome annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785732 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; DNA nucleases bind monoubiquitinated ID2 in FA pathway). Reason: Consistent nuclear localization; redundant Reactome annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785986 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; DNA nucleases unhook the ICL). Reason: Consistent nuclear localization; this is XPF's ICL unhooking step. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9980006 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; ERCC1:XPF binds DSBs with SSA overhangs/flaps). Reason: Consistent nuclear localization; redundant Reactome annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9980021 | ACCEPT | Summary: Nucleoplasmic localization (Reactome; LIG1 binds SSA sites). Reason: Consistent nuclear localization; redundant Reactome annotation. |
| GO:0000110 nucleotide-excision repair factor 1 complex | IDA PMID:10413517 Domain mapping of the DNA binding, endonuclease, and ERCC1 b... | ACCEPT | Summary: Component of NER factor 1 (ERCC1-XPF), directly demonstrated by domain-mapping/interaction. Reason: XPF C-terminal domain binds ERCC1 to form NEF1. Core complex membership. Supporting Evidence: PMID:10413517 the C-terminal 214 residues are capable of binding specifically to ERCC1. |
| GO:0005515 protein binding | IPI PMID:19595721 Coordination of structure-specific nucleases by human SLX4/B... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction with SLX4 (Q8IY92). Reason: Uninformative generic term; SLX4 coordination captured by process annotations. |
| GO:0005515 protein binding | IPI PMID:19595722 Drosophila MUS312 and the vertebrate ortholog BTBD12 interac... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction with SLX4/BTBD12 (Q8IY92). Reason: Uninformative generic term; SLX4 coordination captured functionally elsewhere. |
| GO:0006281 DNA repair | IMP PMID:19596235 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvas... | ACCEPT | Summary: Required for efficient DNA repair as part of the SLX4-coordinated nuclease toolkit. Reason: Correct though broad; the specific NER/ICL functions are annotated separately. Supporting Evidence: PMID:19596235 Depletion of SLX4 causes sensitivity to mitomycin C and camptothecin and reduces the efficiency of DSB repair in vivo. |
| GO:0000723 telomere maintenance | IMP PMID:14690602 ERCC1/XPF removes the 3' overhang from uncapped telomeres an... | KEEP AS NON CORE | Summary: Regulates telomere integrity by processing the telomeric 3' overhang. Reason: Genuine telomere role, but a specialized application of the endonuclease rather than the core repair function. Supporting Evidence: PMID:14690602 these data reveal an unanticipated involvement of the ERCC1/XPF NER endonuclease in the regulation of telomere integrity |
| GO:0005515 protein binding | IPI PMID:14690602 ERCC1/XPF removes the 3' overhang from uncapped telomeres an... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interactions (TRF2, Q15554; and RAP1/TERF2IP, Q9NYB0) in the telomeric TRF2 complex. Reason: Uninformative generic term; telomeric-complex association is captured by localization/process annotations. |
| GO:0000724 double-strand break repair via homologous recombination | IMP PMID:14728600 Defining the function of xeroderma pigmentosum group F prote... | ACCEPT | Summary: Role in homology-directed repair, consistent with XPF-ERCC1 function in single-strand annealing and recombination. Reason: Core recombination function of the XPF-family nuclease (dual excision-repair and recombination roles); XPF is required for homology-dependent DSB repair. |
| GO:0003677 DNA binding | IDA PMID:14734547 Physical and functional interaction between the XPF/ERCC1 en... | ACCEPT | Summary: DNA binding by the XPF/ERCC1 structure-specific endonuclease. Reason: Correct but general; more specific ssDNA/junction binding is annotated elsewhere. Retained as a supporting activity. |
| GO:0004520 DNA endonuclease activity | IDA PMID:8797827 Xeroderma pigmentosum group F caused by a defect in a struct... | ACCEPT | Summary: Catalytic endonuclease that makes the 5' incision in DNA repair; the XPF-ERCC1 complex is a structure-specific endonuclease. Reason: Core catalytic function established by purification of the XPF-ERCC1 structure-specific endonuclease responsible for the 5' incision. Supporting Evidence: PMID:8797827 This complex is a structure-specific endonuclease responsible for the 5' incision during repair. |
| GO:0004520 DNA endonuclease activity | IDA PMID:14734547 Physical and functional interaction between the XPF/ERCC1 en... | ACCEPT | Summary: Structure-specific endonuclease activity, stimulated by hRad52 during recombinational repair. Reason: Core catalytic activity; complex formation with hRad52 stimulates the XPF/ERCC1 endonuclease. Supporting Evidence: PMID:14734547 Complex formation between hRad52 and XPF/ERCC1 concomitantly stimulates the DNA structure-specific endonuclease activity of XPF/ERCC1 |
| GO:0005515 protein binding | IPI PMID:14734547 Physical and functional interaction between the XPF/ERCC1 en... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction with hRAD52 (P43351). Reason: Generic term is uninformative; the functionally relevant RAD52 stimulation of the endonuclease is captured by the endonuclease-activity and recombination annotations. |
| GO:0006289 nucleotide-excision repair | IMP PMID:8797827 Xeroderma pigmentosum group F caused by a defect in a struct... | ACCEPT | Summary: XP-F cells are NER-defective; XPF corrects the repair defect, establishing its essential NER role. Reason: Core function; classic genetic/biochemical evidence for XPF in NER. Supporting Evidence: PMID:8797827 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. |
| GO:0032205 negative regulation of telomere maintenance | IMP PMID:17055345 XPF with mutations in its conserved nuclease domain is defec... | KEEP AS NON CORE | Summary: Negatively regulates telomere maintenance via TRF2-mediated telomere shortening. Reason: Specialized telomeric regulatory role established genetically; not the gene's core repair function. Supporting Evidence: PMID:17055345 XPF-ERCC1 is required for TRF2-promoted telomere shortening. |
| GO:0003684 damaged DNA binding | IMP PMID:11790111 Contribution of XPF functional domains to the 5' and 3' inci... | ACCEPT | Summary: Binds damaged DNA / DNA-damage sites (localizes to the site of a psoralen interstrand crosslink). Reason: Consistent with XPF's recruitment to damage and its structure-specific substrate recognition at lesion sites. Supporting Evidence: PMID:11790111 it is involved in production of the 5' incision at the site of a psoralen interstrand cross-link as well as the 3' incision. |
| GO:0003697 single-stranded DNA binding | IDA PMID:10413517 Domain mapping of the DNA binding, endonuclease, and ERCC1 b... | ACCEPT | Summary: Binds DNA (including ssDNA) independently of ERCC1, via its N-terminal domain. Reason: Directly demonstrated: recombinant XPF binds DNA in the absence of the ERCC1 subunit, and the N-terminal region binds and hydrolyzes DNA. Supporting Evidence: PMID:10413517 the N-terminal 378 amino acids of XPF are capable of binding and hydrolyzing DNA |
| GO:0004520 DNA endonuclease activity | IDA PMID:10413517 Domain mapping of the DNA binding, endonuclease, and ERCC1 b... | ACCEPT | Summary: Intrinsic endonuclease activity; recombinant XPF is an endonuclease that binds and hydrolyzes DNA even without ERCC1. Reason: Core catalytic function directly demonstrated with purified recombinant XPF; XPF is the catalytic subunit. Mg2+-dependent (EC 3.1.-.-). Supporting Evidence: PMID:10413517 determined that it is an endonuclease and can bind DNA in the absence of the ERCC1 subunit. |
| GO:0006289 nucleotide-excision repair | IMP PMID:11790111 Contribution of XPF functional domains to the 5' and 3' inci... | ACCEPT | Summary: Required for the incisions in nucleotide excision repair and ICL repair. Reason: Core function; XPF functional domains determine the 5' and 3' repair incisions. Supporting Evidence: PMID:11790111 XPF forms a heterodimeric complex with ERCC1 and is required for the repair of DNA interstrand cross-links. |
| GO:0005515 protein binding | IPI PMID:12571280 Nonerythroid alphaII spectrin is required for recruitment of... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interactions with FANCA (O15360) and nonerythroid alphaII-spectrin/SPTAN1 (Q13813). Reason: Uninformative generic term; the ICL-repair foci relationship with FANCA/spectrin is captured by the nuclear-body localization and ICL-repair annotations. |
| GO:0005634 nucleus | IDA PMID:12571280 Nonerythroid alphaII spectrin is required for recruitment of... | ACCEPT | Summary: Nuclear localization; XPF forms damage-induced nuclear foci at interstrand crosslinks. Reason: Consistent with XPF's nuclear DNA-repair function. Supporting Evidence: PMID:12571280 FANCA and the known DNA repair protein XPF localize to the same nuclear foci. |
| GO:0009411 response to UV | IMP PMID:16678501 gamma-H2AX formation in response to interstrand crosslinks r... | ACCEPT | Summary: Required for the DNA-damage signaling response to crosslinking agents (gamma-H2AX formation); XPF-deficient cells fail to mount this response. Reason: Consistent with XPF's role in processing UV/crosslink damage; ectopic XPF restores the damage response. Supporting Evidence: PMID:16678501 XPF is required to form gamma-H2AX and likely double strand breaks in response to interstrand crosslinks in human cells. |
| GO:0005515 protein binding | IPI PMID:9722633 Mapping of interaction domains between human repair proteins... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction with ERCC1 (P07992); mapping of ERCC1-XPF interaction domains. Reason: Uninformative generic term; ERCC1 partnership captured by GO:0070522. |
| GO:0005515 protein binding | IPI PMID:7559382 Purification and characterization of the XPF-ERCC1 complex o... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction with ERCC1 (P07992); purification of the XPF-ERCC1 excision nuclease. Reason: Uninformative generic term; ERCC1 partnership captured by GO:0070522. |
| GO:0000109 nucleotide-excision repair complex | IDA PMID:10644440 Characterization of the mouse Xpf DNA repair gene and differ... | ACCEPT | Summary: Component of a nucleotide-excision repair complex (the XPF/ERCC1 endonuclease). Reason: Correct, more general parent of the ERCC1-XPF (NEF1) complex; XPF is an essential subunit of the NER excision machinery. Supporting Evidence: PMID:10644440 The human XPF protein, an endonuclease subunit essential for DNA excision repair, may also function in homologous recombination. |
| GO:0006289 nucleotide-excision repair | IDA PMID:10644440 Characterization of the mouse Xpf DNA repair gene and differ... | ACCEPT | Summary: Role in nucleotide excision repair (XPF is an endonuclease subunit essential for excision repair). Reason: Core function; the qualifier reflects the older annotation style but the NER involvement is correct. Supporting Evidence: PMID:10644440 The human XPF protein, an endonuclease subunit essential for DNA excision repair, may also function in homologous recombination. |
| GO:0000014 single-stranded DNA endodeoxyribonuclease activity | IDA PMID:22483113 The structure of the XPF-ssDNA complex underscores the disti... | NEW | 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. 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. Supporting Evidence: PMID:22483113 Human XPF/ERCC1 is a structure-specific DNA endonuclease that nicks the damaged DNA strand at the 5' end during nucleotide excision repair. PMID:10413517 determined that it is an endonuclease and can bind DNA in the absence of the ERCC1 subunit. |
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