Fanconi anemia group I protein (FANCI) is the obligate heterodimeric partner of FANCD2, with which it forms the FANCI-FANCD2 (ID2) complex, the central effector of the Fanconi anemia (FA) DNA interstrand crosslink (ICL) repair pathway. FANCI is a large, predominantly alpha-solenoid nuclear protein that binds double-stranded DNA with a preference for branched structures (Holliday junctions, overhangs and replication forks). During S phase and following genotoxic stress, FANCI is monoubiquitinated on Lys523 by the FANCL/UBE2T ubiquitin ligase acting downstream of the multi-subunit FA core complex; this event is mutually interdependent with, and required to promote, FANCD2 monoubiquitination. Monoubiquitination converts the open, trough-like ID2 complex into a closed sliding clamp that encircles duplex DNA at stalled replication forks and ICLs, coordinating downstream repair reactions including nucleolytic incision/unhooking, translesion synthesis and homologous recombination. ATR-dependent phosphorylation of a conserved S/TQ cluster in FANCI acts as a molecular switch that activates the pathway. FANCI also contributes to replication fork protection and S/G2 checkpoint signaling. Biallelic loss-of-function mutations cause Fanconi anemia complementation group I, characterized by bone marrow failure, congenital malformations, chromosomal instability, cellular hypersensitivity to crosslinking agents, and cancer predisposition.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005654 nucleoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: FANCI is an active nuclear protein; it functions in the nucleoplasm/chromatin as part of the ID2 complex. IBA localization is appropriate and consistent with experimental data. Reason: UniProt records nuclear localization (PubMed:17412408, 17460694), and the ID2 complex acts on nuclear chromatin. Nucleoplasm is the correct compartment for FANCI's core activity. Supporting Evidence: PMID:18931676 In turn, FancD2 and FancI are both targeted to chromatin and form colocalizing foci together with the HR proteins BRCA1 and Rad51 |
| GO:0006974 DNA damage response | IBA GO_REF:0000033 | ACCEPT | Summary: FANCI is a bona fide DNA damage response factor, activated by replication stress and ICLs and phosphorylated by ATR/ATM. Broad but correct. Reason: The FA pathway responds to stalled replication forks and ICLs; FANCI is phosphorylated in response to DNA damage and participates in checkpoint signaling. Supporting Evidence: PMID:18931676 In response to DNA damage or replication fork stress, the Fanconi anemia pathway is activated, leading to monoubiquitination of FANCD2 and FANCI and their colocalization in foci. |
| GO:0031398 positive regulation of protein ubiquitination | IBA GO_REF:0000033 | ACCEPT | Summary: FANCI is required to promote the monoubiquitination of FANCD2 by FANCL/UBE2T; its phosphorylation acts as the activating switch for this event. A core FANCI function. Reason: Loss of FANCI abrogates FANCD2 monoubiquitination, and FANCI phospho-mimic mutants induce constitutive FANCD2 monoubiquitination, demonstrating FANCI positively regulates protein (FANCD2) monoubiquitination. Supporting Evidence: PMID:18931676 FANCI carrying phosphomimic mutations on the same six residues induces constitutive monoubiquitination and focus formation of FANCI and FANCD2 |
| GO:1990391 DNA repair complex | IBA GO_REF:0000033 | ACCEPT | Summary: FANCI is a subunit of the FANCI-FANCD2 (ID2) DNA repair complex. IBA complex membership is correct. Reason: FANCI forms an obligate heterodimeric DNA repair complex with FANCD2 (ID2), a GO:0032991 protein-containing DNA repair complex. Supporting Evidence: PMID:32269332 The ID complex, involving the proteins FANCI and FANCD2, is required for the repair of DNA interstrand crosslinks (ICL) and related lesions |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization mapped from the UniProt subcellular location vocabulary. Correct, though less specific than nucleoplasm. Reason: FANCI is a nuclear protein (UniProt Nucleus, PubMed:17412408, 17460694, 19465922). The broader 'nucleus' term is acceptable as an IEA mapping. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: Cytoplasm mapped from the UniProt subcellular-location vocabulary, which itself derives from a single incidental proteomic identification (PubMed:18445686). FANCI is overwhelmingly nuclear and executes its DNA-repair function on chromatin. Reason: The cytoplasm assignment traces to PubMed:18445686, an EML3-focused mitotic-spindle proteomics paper in which FANCI was an incidental hit, not a focused localization study. Any cytoplasmic pool is minor and non-functional; the compartment relevant to FANCI's activity is the nucleus/chromatin. |
| GO:0006281 DNA repair | IEA GO_REF:0000002 | ACCEPT | Summary: FANCI is a core DNA repair factor. Broad InterPro-based term is correct; the more specific interstrand cross-link repair term is captured elsewhere. Reason: InterPro family IPR026171 (FANCI) maps to DNA repair, consistent with FANCI's established role in ICL and double-strand break repair. |
| GO:0005515 protein binding | IPI PMID:17460694 FANCI is a second monoubiquitinated member of the Fanconi an... | KEEP AS NON CORE | Summary: Captures the physical interaction with FANCD2 that forms the ID2 complex. The interaction is real and central, but 'protein binding' is uninformative as a molecular function; the functional consequence (ID2 complex / DNA clamp) is captured by the complex and DNA-binding annotations. Reason: PubMed:17460694 (WITH FANCD2, Q9BXW9) documents FANCI-FANCD2 interaction. Retained as evidence of complex formation but not as a core molecular function per curation guidance to avoid 'protein binding'. Supporting Evidence: PMID:17460694 FANCI, a second monoubiquitinated component of the FA pathway |
| GO:0005515 protein binding | IPI PMID:20603015 Identification of KIAA1018/FAN1, a DNA repair nuclease recru... | KEEP AS NON CORE | Summary: Captures interaction with FAN1 (MTMR15; WITH Q9Y2M0/Q9BXW9), a nuclease recruited to the monoubiquitinated ID/FANCD2. Real interaction but uninformative MF term. Reason: PubMed:20603015 identifies FAN1 as a partner of the monoubiquitinated FANCD2/ID complex. Retained as interaction evidence, non-core; 'protein binding' is too generic for a core molecular function. Supporting Evidence: PMID:20603015 a highly conserved protein, KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2 |
| GO:0005515 protein binding | IPI PMID:31240132 CTDP1 regulates breast cancer survival and DNA repair throug... | KEEP AS NON CORE | Summary: Captures interaction with CTDP1 (WITH Q9Y5B0), a phosphatase that regulates FANCI chromatin localization and SQ-motif phosphorylation. Real interaction, uninformative MF. Reason: PubMed:31240132 documents a direct CTDP1-FANCI (BRCT) interaction regulating FANCI activity. Retained as interaction evidence, non-core. Supporting Evidence: PMID:31240132 CTDP1 was found to regulate multiple aspects of FANCI activity, including chromatin localization, interaction with Ξ³-H2AX, and SQ motif phosphorylations. |
| GO:0000785 chromatin | NAS PMID:19965384 The Fanconi anemia pathway promotes replication-dependent DN... | ACCEPT | Summary: FANCI localizes to chromatin, where the monoubiquitinated ID2 complex acts. Correct and functionally important location. Reason: Monoubiquitination targets FANCI/FANCD2 to chromatin foci; chromatin binding is required for DNA repair function. Supporting Evidence: PMID:18931676 In turn, FancD2 and FancI are both targeted to chromatin and form colocalizing foci together with the HR proteins BRCA1 and Rad51 |
| GO:0036297 interstrand cross-link repair | NAS PMID:19965384 The Fanconi anemia pathway promotes replication-dependent DN... | ACCEPT | Summary: Interstrand cross-link repair is the defining biological process of FANCI/ID2. Strong, well-supported core annotation. Reason: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase; monoubiquitinated ID2 is essential for excision, translesion synthesis and homologous recombination during ICL repair. Supporting Evidence: PMID:19965384 Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. PMID:32269332 Monoubiquitination of ID is essential for ICL repair by excision, translesion synthesis and homologous recombination |
| GO:1990391 DNA repair complex | IPI PMID:32269332 DNA clamp function of the monoubiquitinated Fanconi anaemia ... | ACCEPT | Summary: Structural (cryo-EM) demonstration that FANCI is a subunit of the ID2 DNA repair complex that clamps DNA. Core complex membership. Reason: Cryo-EM structures of the monoubiquitinated human FANCI-FANCD2 complex bound to DNA confirm FANCI as an integral subunit of this DNA repair complex. Supporting Evidence: PMID:32269332 we report a cryo-electron microscopy structure of the monoubiquitinated human ID complex bound to DNA, and reveal that it forms a closed ring that encircles the DNA |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) localizes FANCI to the nucleoplasm. Consistent with its nuclear DNA-repair function. Reason: Immunofluorescence-based nucleoplasm localization agrees with all other evidence for FANCI being a nuclear protein. |
| GO:0031398 positive regulation of protein ubiquitination | IDA PMID:18931676 FANCI phosphorylation functions as a molecular switch to tur... | ACCEPT | Summary: Experimental demonstration that FANCI (via its phosphorylation switch) positively regulates FANCD2 monoubiquitination. Core FANCI function. Reason: FANCI phospho-mimic mutants induce constitutive FANCD2 monoubiquitination while phospho-dead mutants abolish it, in both chicken DT40 and human cells, establishing FANCI as a positive regulator of protein (FANCD2) monoubiquitination. Supporting Evidence: PMID:18931676 FANCI phosphorylation exerts an evolutionarily conserved function in inducing FANCD2 monoubiqutination in human cells as well. PMID:22287633 The DNA-binding activity of FANCI is required to stimulate FANCD2 monoubiquitylation |
| GO:0005737 cytoplasm | IDA PMID:18445686 EML3 is a nuclear microtubule-binding protein required for t... | MARK AS OVER ANNOTATED | Summary: Cytoplasmic localization asserted from a proteomics screen focused on EML3 and the mitotic spindle, in which FANCI was an incidental identification. FANCI is a nuclear DNA-repair protein; a cytoplasmic pool, if present, is minor and not its functional site. Reason: PubMed:18445686 is a proteomic identification of spindle/nuclear microtubule-binding proteins centered on EML3, not a focused study of FANCI localization. All focused studies place FANCI in the nucleus/chromatin, so cytoplasm is an over-annotation. Supporting Evidence: PMID:18445686 we used a proteomic approach to selectively identify proteins of this category and revealed 50 poorly characterised human gene products, among them the echinoderm microtubule-associated-protein-like gene product, EML3. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785361 | ACCEPT | Summary: Reactome nucleoplasm localization for the FA/ICL repair reaction (Monoubiquitination of FANCD2:FANCI). Correct. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785732 | ACCEPT | Summary: Reactome nucleoplasm localization for the ID/nuclease binding step. Correct. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785986 | ACCEPT | Summary: Reactome nucleoplasm localization for the ICL unhooking step. Correct. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786155 | ACCEPT | Summary: Reactome nucleoplasm localization for the POLN-ICL binding step. Correct. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786166 | ACCEPT | Summary: Reactome nucleoplasm localization for translesion synthesis across the unhooked ICL. Correct. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786171 | ACCEPT | Summary: Reactome nucleoplasm localization for FANCD2 deubiquitination by USP1:WDR48. Correct. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788392 | ACCEPT | Summary: Reactome nucleoplasm localization for ATR phosphorylation of RPA2, FANCI, FANCD2, FANCM at ICL-DNA. Correct. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | REMOVE | Summary: Membrane localization derives from a bulk NK-cell membrane-fraction mass-spectrometry survey. FANCI has no transmembrane region and is a soluble nuclear DNA-repair protein; this is a co-purification artifact of membrane-fraction proteomics. Reason: FANCI has no predicted or observed transmembrane domain (UniProt) and no biological role at membranes. The source paper itself states that only ~40% of identified proteins are plausible membrane proteins and the remainder are cellular-process proteins transiently associated with membranes; FANCI falls in the latter, non-membrane class. The annotation is demonstrably incorrect as a subcellular location. Supporting Evidence: PMID:19946888 approximately 40% of the identified proteins were predicted as plausible membrane proteins. The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes. |
| GO:0070182 DNA polymerase binding | IPI PMID:19995904 DNA polymerase POLN participates in cross-link repair and ho... | KEEP AS NON CORE | Summary: FANCI physically and functionally interacts with the translesion/HR polymerase POLN. A specific, informative binding term, but this interaction is peripheral to FANCI's core clamp/ubiquitination functions. Reason: PubMed:19995904 (WITH POLN, Q7Z5Q5) documents FANCI-POLN interaction linking the FA pathway to translesion synthesis/HR. The term is accurate but reflects a downstream/ accessory partnership rather than FANCI's defining activity. Supporting Evidence: PMID:19995904 we obtained evidence for physical and functional interaction of POLN with factors belonging to the Fanconi anemia pathway, a master regulator of cross-link repair |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785342 | ACCEPT | Summary: Reactome nucleoplasm localization for FANCD2:FANCI + UBE2T binding ICL-DNA. Correct. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785594 | ACCEPT | Summary: Reactome nucleoplasm localization for the FANCD2 binds FANCI step. Correct. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788385 | ACCEPT | Summary: Reactome nucleoplasm localization for recruitment of ATR:ATRIP to ICL-DNA. Correct. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6797712 | ACCEPT | Summary: Reactome nucleoplasm localization for CDK12 stimulation of DNA-repair gene expression. Location correct for FANCI. Reason: FANCI acts in the nucleoplasm; consistent with all other localization evidence. |
| GO:0000217 DNA secondary structure binding | IDA PMID:32269332 DNA clamp function of the monoubiquitinated Fanconi anaemia ... | NEW | Summary: Structure-selective DNA binding is FANCI's defining biochemical activity and is absent from the GOA export even though UniProt carries the DNA-binding keyword. FANCI (within ID2) binds duplex DNA with a preference for branched structures and, when monoubiquitinated, clamps around dsDNA. Reason: Structural and biochemical studies show FANCI binds DNA with a documented preference for branched structures - Holliday junctions, overhangs and replication forks - and the monoubiquitinated ID2 complex encircles duplex DNA as a sliding clamp. Bare GO:0003677 DNA binding under-represents that evidence, so GO:0000217 DNA secondary structure binding is used instead. GO:0000400 four-way junction DNA binding (used elsewhere in this cohort for RAD51C and XRCC2) is its child and covers only the Holliday-junction part of the quoted preference, so the parent is the accurate fit for the full substrate set. The paralog FANCD2 correspondingly carries the specific GO:0003697. Supporting Evidence: PMID:32269332 FANCI and FANCD2 are paralogs that bind to DNA with preference for branched structures including Holliday junction, overhang and replication fork DNA PMID:32269332 the monoubiquitinated ID complex loses its preference for ICL and related branched DNA structures, and becomes a sliding DNA clamp that can coordinate the subsequent repair reactions PMID:19589784 We show that FANCI and its C-terminal fragment possess a DNA binding activity that prefers branched structures. PMID:27694619 The DNA binding activity of FANCI is required for the I-D complex-mediated stabilization of the RAD51-DNA filament. |
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