FANCL (Fanconi anemia complementation group L; also known as PHF9) is the catalytic RING-type E3 ubiquitin ligase subunit of the multiprotein Fanconi anemia (FA) core complex. Together with its dedicated E2 ubiquitin-conjugating enzyme UBE2T, FANCL catalyzes the site-specific monoubiquitination of FANCD2 (on Lys561) and FANCI (on Lys523). This monoubiquitination is the central activating step of the FA/interstrand crosslink (ICL) repair pathway: the monoubiquitinated FANCD2-FANCI (ID2) complex is recruited to chromatin at stalled replication forks and ICLs, where it coordinates nucleolytic incision, translesion synthesis and homologous-recombination-mediated repair. FANCL has a modular architecture comprising an N-terminal E2-like (ELF/UBC-like) domain, a central RWD-like (DRWD) domain, and a C-terminal RING-type zinc finger; the RING (with the essential Cys307 and Trp341) recruits and activates UBE2T, while the UBC-RWD region mediates binding to the FANCD2/FANCI substrates. FANCL assembles with FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCM in the nuclear FA core complex; the FANCB-FANCL-FAAP100 subassembly forms its catalytic module. Loss-of-function variants in FANCL cause Fanconi anemia, characterized by bone marrow failure, congenital malformations, chromosomal instability, hypersensitivity to DNA crosslinking agents and cancer predisposition.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006281 DNA repair | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) involvement in DNA repair. FANCL is genuinely a core DNA repair factor as the E3 ligase that activates the FA/ICL-repair pathway. Reason: Correct at an appropriately general level; consistent with the experimental IMP annotation from PMID:16916645 and with FANCL's established role in the FA-BRCA DNA repair pathway. Supporting Evidence: PMID:16916645 The Fanconi anemia pathway is required for the efficient repair of damaged DNA. |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of ubiquitin protein ligase activity. This is FANCL's defining core molecular function as the RING E3 of the FA core complex. Reason: Strongly supported by multiple experimental studies demonstrating RING-type E3 ligase activity dependent on the Cys307 RING residue and on UBE2T. Supporting Evidence: PMID:12973351 which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of nuclear localization/activity. FANCL functions in the nucleus as part of the FA core complex on chromatin. Reason: Consistent with UniProt subcellular location (Nucleus), with FA core complex chromatin localization, and with the site of FANCD2/FANCI monoubiquitination. Supporting Evidence: PMID:17938197 its DNA damage-induced localization to chromatin |
| GO:0006513 protein monoubiquitination | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) involvement in protein monoubiquitination. FANCL specifically catalyzes monoubiquitination (not polyubiquitination) of FANCD2 and FANCI. Reason: Well supported experimentally; FANCL/UBE2T add a single ubiquitin to FANCD2-Lys561 and FANCI-Lys523. Supporting Evidence: PMID:12973351 is essential for FANCD2 monoubiquitination in vivo |
| GO:0004842 ubiquitin-protein transferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of ubiquitin-protein transferase activity (parent of the more specific ubiquitin protein ligase activity, GO:0061630). Reason: Correct but more general than GO:0061630; retained as a valid broader molecular function term for the E3 ligase. Supporting Evidence: PMID:16916645 UBE2T binds to FANCL, the ubiquitin ligase subunit of the |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of nuclear localization, consistent with UniProt and experimental data. Reason: FANCL localizes to and functions in the nucleus as part of the FA core complex. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic assignment of cytoplasmic localization from UniProt subcellular location mapping. FANCL is nucleocytoplasmic but its catalytic FA-pathway function occurs in the nucleus/on chromatin. Reason: Consistent with UniProt (Cytoplasm; by similarity), but the cytoplasmic pool is not the site of FANCL's core E3-ligase function in ICL repair. Supporting Evidence: file:human/FANCL/FANCL-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0036297 interstrand cross-link repair | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment to interstrand cross-link repair, the pathway that FANCL activates via FANCD2/FANCI monoubiquitination. Reason: Correct core process; the FA pathway that FANCL drives is required for replication-coupled ICL repair. Supporting Evidence: PMID:19965384 FANCI-FANCD2 is required for replication-coupled ICL repair in S phase |
| GO:0043240 Fanconi anaemia nuclear complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of membership in the Fanconi anemia nuclear (core) complex. FANCL is the E3 ligase subunit of this complex. Reason: Well established experimentally; FANCL is an integral subunit of the FA core complex (FANCA/B/C/E/F/G/L/M). Supporting Evidence: file:human/FANCL/FANCL-uniprot.txt Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of ubiquitin protein ligase activity (EC:2.3.2.27), FANCL's core molecular function. Reason: Redundant with the experimental and IBA annotations of the same term; correct. Supporting Evidence: PMID:12973351 which possesses E3 ubiquitin ligase activity in vitro |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a high-throughput yeast two-hybrid interactome map (HuRI). The listed partners (e.g. GRN, TFCP2, RBM45, IHO1, RIMBP3, DDAH2, KIFC3, IKZF3, CHCHD3, EIF4ENIF1, SSX2IP) are not established functional partners of FANCL. Reason: GO:0005515 'protein binding' is uninformative per curation guidelines, and these large-scale Y2H interactions are not linked to FANCL's characterized function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic protein binding from the HuRI reference binary interactome (high-throughput Y2H). Many partners are not established FANCL functional interactors. Reason: 'protein binding' is uninformative and these systematic Y2H hits do not inform FANCL's molecular function. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a systematic screen of mutation-directed neo-PPIs in cancer (partner SMAD4). Not an established constitutive functional interaction of wild-type FANCL. Reason: 'protein binding' is uninformative and the interaction does not inform FANCL's core function. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway-based electronic assignment to protein ubiquitination, the general process to which FANCL's E3 activity contributes. Reason: Correct but general; the more specific and biologically informative process is protein monoubiquitination (GO:0006513), which is separately annotated. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-based nuclear localization (from mouse ortholog Q9CR14). Reason: Consistent with experimental and IBA nuclear localization annotations. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity-based cytoplasmic localization (from mouse ortholog Q9CR14). Reason: Consistent with UniProt, but the cytoplasmic pool is not where FANCL performs its core FA-pathway E3 function (nucleus/chromatin). |
| GO:0061630 ubiquitin protein ligase activity | EXP PMID:12973351 A novel ubiquitin ligase is deficient in Fanconi anemia. | ACCEPT | Summary: Direct experimental demonstration that FANCL/PHF9 has E3 ubiquitin ligase activity in vitro and is required for FANCD2 monoubiquitination; the RING residues Cys307/Cys310 are essential. Reason: Foundational experimental evidence establishing FANCL as the E3 ligase of the FA pathway; represents the core molecular function. Supporting Evidence: PMID:12973351 which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo |
| GO:0061630 ubiquitin protein ligase activity | EXP PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | ACCEPT | Summary: Experimental support for FANCL as the ubiquitin ligase subunit whose activity, with the E2 UBE2T, monoubiquitinates FANCD2. W341G abolishes UBE2T binding and ligase activity. Reason: Core molecular function, independently confirmed with definition of the cognate E2. Supporting Evidence: PMID:16916645 UBE2T binds to FANCL, the ubiquitin ligase subunit of the Fanconi anemia core complex, and is required for the monoubiquitination of FANCD2 in vivo |
| GO:0061630 ubiquitin protein ligase activity | EXP PMID:19111657 Mechanistic insight into site-restricted monoubiquitination ... | ACCEPT | Summary: Minimal reconstitution shows FANCL with UBE2T catalyzes FANCD2 monoubiquitination, stimulated by FANCL's conserved RWD-like domain. Reason: Directly demonstrates FANCL E3 ligase activity in a reconstituted system. Supporting Evidence: PMID:19111657 we minimally reconstitute this monoubiquitination reaction with Ube2t and the FANCL protein, revealing that monoubiquitination is stimulated by a conserved RWD-like domain in FANCL |
| GO:0000785 chromatin | IDA PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr... | ACCEPT | Summary: Direct assay localizing the FA core complex (including FANCL) to chromatin. The FA core complex is loaded onto chromatin upon DNA damage, where the active E2/E3 holoenzyme forms. Reason: FANCL's productive E3 activity depends on DNA-damage-induced chromatin localization; chromatin is the functional site of FANCD2/FANCI monoubiquitination. Supporting Evidence: PMID:17938197 the actual E3 ligase activity is not determined by the assembly of the FA core complex but rather by its DNA damage-induced localization to chromatin |
| GO:0036297 interstrand cross-link repair | NAS PMID:19965384 The Fanconi anemia pathway promotes replication-dependent DN... | ACCEPT | Summary: Non-traceable author statement placing FANCL in interstrand cross-link repair; the FA pathway it activates (via FANCD2-FANCI monoubiquitination) is required for replication-coupled ICL repair. Reason: Core biological process for FANCL, corroborated by the InterPro IEA annotation of the same term. Supporting Evidence: PMID:19965384 FANCI-FANCD2 is required for replication-coupled ICL repair in S phase |
| GO:0043240 Fanconi anaemia nuclear complex | NAS PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr... | ACCEPT | Summary: FANCL is a component of the Fanconi anemia nuclear core complex. Reason: Well established; FANCL is the E3 ligase subunit of the FA core complex. Supporting Evidence: PMID:22343915 Fanconi anemia (FA) nuclear core complex is a multiprotein complex required for the functional integrity of the FA-BRCA pathway regulating DNA repair |
| GO:0005515 protein binding | IPI PMID:24389026 Structure of the human FANCL RING-Ube2T complex reveals dete... | MARK AS OVER ANNOTATED | Summary: Protein binding annotation from the FANCL RING-UBE2T structural study (partner UBE2T, Q9NPD8). Although this is a genuine and biologically central interaction, the term 'protein binding' is uninformative; the specific E2-binding function is captured by GO:0031624 (ubiquitin conjugating enzyme binding). Reason: Per curation guidelines, GO:0005515 is too generic to be a core molecular function; the functionally meaningful FANCL-UBE2T interaction is better represented by the E2-binding term (see the modified GO:0031625 annotations). Supporting Evidence: PMID:24389026 we report the atomic structure of the FANCL RING-Ube2T complex |
| GO:0006513 protein monoubiquitination | IDA PMID:24389026 Structure of the human FANCL RING-Ube2T complex reveals dete... | ACCEPT | Summary: Direct evidence that FANCL, via its RING-UBE2T interface, mediates monoubiquitination; the specific FANCL-UBE2T pairing selects UBE2T over other E2s. Reason: Core process; monoubiquitination depends on cognate E3-E2 pairing established here. Supporting Evidence: PMID:24389026 these specific interactions are required for selection of Ube2T over other E2s by FANCL |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9835411 | KEEP AS NON CORE | Summary: Reactome-traceable cytosolic localization (from a PKR-signaling reaction involving an FA core complex:HSP70 assembly). FANCL's core E3 function is nuclear/chromatin. Reason: Consistent with a cytoplasmic/cytosolic pool of FANCL, but not the site of its central FA-pathway ubiquitin-ligase activity. |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:19589784 FANCI binds branched DNA and is monoubiquitinated by UBE2T-F... | ACCEPT | Summary: Direct demonstration that the UBE2T-FANCL pair monoubiquitinates FANCI on Lys523 in vitro, extending FANCL's E3 activity to the second ID2-complex substrate. Reason: Core molecular function; establishes FANCI (in addition to FANCD2) as a FANCL substrate. Supporting Evidence: PMID:19589784 FANCI can be ubiquitinated on Lys-523 by the UBE2T-FANCL pair in vitro |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785126 | ACCEPT | Summary: Reactome-traceable nucleoplasmic localization (FA core complex assembly at ICLs). Reason: Consistent with FANCL's nuclear localization and its function within the FA core complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785342 | ACCEPT | Summary: Reactome-traceable nucleoplasmic localization (FANCD2:FANCI and UBE2T binding ICL-DNA with the FA core complex). Reason: Consistent with FANCL's nuclear localization within the FA pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785361 | ACCEPT | Summary: Reactome-traceable nucleoplasmic localization (monoubiquitination of FANCD2:FANCI). Reason: Consistent with FANCL's nuclear localization and catalytic role in this reaction. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785732 | ACCEPT | Summary: Reactome-traceable nucleoplasmic localization (DNA nucleases bind monoubiquitinated ID2 complex). Reason: Consistent with FANCL's nuclear localization within the FA pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785986 | ACCEPT | Summary: Reactome-traceable nucleoplasmic localization (DNA nucleases unhook the ICL). Reason: Consistent with FANCL's nuclear localization within the FA pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786155 | ACCEPT | Summary: Reactome-traceable nucleoplasmic localization (POLN binds ICL-DNA). Reason: Consistent with FANCL's nuclear localization within the FA pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786166 | ACCEPT | Summary: Reactome-traceable nucleoplasmic localization (translesion synthesis across unhooked ICL by POLN). Reason: Consistent with FANCL's nuclear localization within the FA pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786171 | ACCEPT | Summary: Reactome-traceable nucleoplasmic localization (FANCD2 deubiquitination by USP1:WDR48). Reason: Consistent with FANCL's nuclear localization within the FA pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788385 | ACCEPT | Summary: Reactome-traceable nucleoplasmic localization (ATR:ATRIP recruited to ICL-DNA). Reason: Consistent with FANCL's nuclear localization within the FA pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788392 | ACCEPT | Summary: Reactome-traceable nucleoplasmic localization (ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA). Reason: Consistent with FANCL's nuclear localization within the FA pathway. |
| GO:0043240 Fanconi anaemia nuclear complex | IDA PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr... | ACCEPT | Summary: Direct assay confirming FANCL is a component of the Fanconi anemia nuclear core complex. Reason: FANCL is the RING E3 ligase subunit of the FA core complex; a core localization/complex annotation. Supporting Evidence: PMID:22343915 Fanconi anemia (FA) nuclear core complex is a multiprotein complex required for the functional integrity of the FA-BRCA pathway regulating DNA repair |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | ACCEPT | Summary: Direct experimental evidence for ubiquitin-protein transferase activity of FANCL (with UBE2T); a broader parent of the more specific ubiquitin protein ligase activity. Reason: Correct; represents the same core E3 function as GO:0061630 at a slightly more general level. Supporting Evidence: PMID:16916645 UBE2T binds to FANCL, the ubiquitin ligase subunit of the Fanconi anemia core complex |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:19111657 Mechanistic insight into site-restricted monoubiquitination ... | ACCEPT | Summary: Direct evidence for ubiquitin-protein transferase activity in the reconstituted FANCL/UBE2T FANCD2-monoubiquitination reaction. Reason: Correct; general parent of ubiquitin protein ligase activity (GO:0061630). Supporting Evidence: PMID:19111657 we minimally reconstitute this monoubiquitination reaction with Ube2t and the FANCL protein |
| GO:0006281 DNA repair | IMP PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | ACCEPT | Summary: Mutant-phenotype evidence that FANCL function is required for DNA repair; disruption of the FANCL/UBE2T-dependent FANCD2 monoubiquitination causes the abnormal chromosomes characteristic of FA. Reason: Core biological role in the FA-BRCA DNA repair pathway, experimentally supported. Supporting Evidence: PMID:16916645 The Fanconi anemia pathway is required for the efficient repair of damaged DNA |
| GO:0006513 protein monoubiquitination | IDA PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | ACCEPT | Summary: Direct evidence that FANCL, with UBE2T, is required for FANCD2 monoubiquitination in vivo. Reason: Core biological process; FANCL catalyzes the monoubiquitination central to the FA pathway. Supporting Evidence: PMID:16916645 is required for the monoubiquitination of FANCD2 in vivo |
| GO:0006974 DNA damage response | IMP PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | ACCEPT | Summary: Mutant-phenotype evidence for FANCL's involvement in the DNA damage response; the FANCL/UBE2T-dependent FANCD2 monoubiquitination is a DNA-damage-restricted event. Reason: Correct general process; FANCL acts in the S-phase/DNA-damage-activated FA pathway. Supporting Evidence: PMID:16916645 DNA damage in UBE2T-depleted cells leads to the formation of abnormal chromosomes that are a hallmark of Fanconi anemia |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | MODIFY | Summary: IPI interaction with UBE2T (Q9NPD8). UBE2T is an E2 ubiquitin-conjugating enzyme, not an E3 ubiquitin protein ligase, so the more accurate molecular function is binding to an E2 (ubiquitin conjugating enzyme binding). Reason: The interaction partner UBE2T is an E2 conjugating enzyme; GO:0031625 ('ubiquitin protein ligase binding') denotes binding to an E3. The correct term is GO:0031624 ('ubiquitin conjugating enzyme binding', defined as binding to any E2). This captures the biologically central FANCL RING-E2 interaction. Proposed replacements: ubiquitin conjugating enzyme binding Supporting Evidence: PMID:16916645 UBE2T binds to FANCL, the ubiquitin ligase subunit of the Fanconi anemia core complex |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:17938197 UBE2T, the Fanconi anemia core complex, and FANCD2 are recru... | MODIFY | Summary: IPI interaction with the E2 enzyme UBE2T (Q9NPD8). As above, the partner is an E2 conjugating enzyme, so the E2-binding term is the accurate molecular function. Reason: UBE2T is an E2, not an E3; MODIFY to GO:0031624 (ubiquitin conjugating enzyme binding), reflecting FANCL's RING-mediated E2 recruitment. Proposed replacements: ubiquitin conjugating enzyme binding Supporting Evidence: PMID:17938197 the E2 ubiquitin-conjugating enzyme UBE2T |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:19111657 Mechanistic insight into site-restricted monoubiquitination ... | MODIFY | Summary: IPI interaction with an E2 enzyme (UBE2W, Q96B02; FANCL also binds UBE2T). The partners are E2 conjugating enzymes, so the E2-binding term is more accurate than the E3-binding term. Reason: UBE2W (like UBE2T) is an E2 conjugating enzyme, not an E3 ligase; MODIFY to GO:0031624 (ubiquitin conjugating enzyme binding). Proposed replacements: ubiquitin conjugating enzyme binding Supporting Evidence: file:human/FANCL/FANCL-uniprot.txt Directly interacts (via the RING-type zinc finger) with UBE2T and UBE2W |
| GO:0004842 ubiquitin-protein transferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-based ubiquitin-protein transferase activity (from mouse ortholog Q9CR14). Reason: Correct; consistent with the experimental E3 ligase annotations (a broader parent of GO:0061630). |
| GO:0043240 Fanconi anaemia nuclear complex | IDA PMID:20347428 A histone-fold complex and FANCM form a conserved DNA-remode... | ACCEPT | Summary: Direct assay placing FANCL within the FA core complex; FANCM-MHF associates with the FA core complex and promotes FANCD2 monoubiquitination. Reason: FANCL is an integral subunit of the FA core complex; a core complex/localization annotation. Supporting Evidence: PMID:20347428 FANCM-MHF associates with the Fanconi anemia (FA) core complex |
| GO:0043130 ubiquitin binding | ISS PMID:26149689 The Fanconi Anemia DNA Repair Pathway Is Regulated by an Int... | NEW | Summary: The N-terminal E2-like fold (ELF) domain of FANCL binds free ubiquitin non-covalently via ubiquitin's canonical Ile44 patch. This binding is dispensable for core-complex recognition, UBE2T binding and in vitro FANCD2 monoubiquitination, but is required for efficient DNA-damage-induced FANCD2 monoubiquitination in vertebrate cells. Reason: Not present in GOA, but a genuine, experimentally demonstrated molecular function of FANCL from a dedicated structural/functional study. Evidence code is ISS, not IDA: the binding assays purify DROSOPHILA MELANOGASTER FANCL ELF-domain constructs, and the cellular arm is described as "vertebrate cells" rather than human, so no direct assay of the human protein is on offer. It is regulatory and non-core relative to the RING E3 ligase activity, but a real distinct MF of the ELF domain that promotes efficient in vivo FANCD2 monoubiquitination. Supporting Evidence: PMID:26149689 the ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin PMID:26149689 the ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of ubiquitin binding by FANCL in vivo |
Loading supporting content…
Download this section (compressed HTML)Q: How is FANCL's catalytic B-L-100 module (FANCB-FANCL-FAAP100) allosterically regulated within the larger FA core complex, and what conformational changes couple chromatin loading to productive FANCD2/FANCI monoubiquitination?
Q: Beyond FANCD2 and FANCI, are there other physiological substrates of FANCL, and does the reported stimulation of ubiquitin release from UBE2W reflect a distinct biological function?
Experiment: Reconstitute the B-L-100 catalytic module with UBE2T and ID2 complex on defined ICL-containing chromatin templates and use cryo-EM to capture the active E3-E2-substrate holoenzyme, mapping how the RING and UBC-RWD domains orient UBE2T toward FANCD2-Lys561.
Experiment: Systematically test FANCL patient-derived RING and URD-domain variants in a FANCL-null cell line for FANCD2/FANCI monoubiquitination, chromatin loading, and MMC sensitivity to define genotype-function relationships.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)