Existing Annotations Review

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

Core Functions

RING-type E3 ubiquitin ligase that, in partnership with the cognate E2 enzyme UBE2T, catalyzes site-specific monoubiquitination of FANCD2 (Lys561) and FANCI (Lys523) as the catalytic subunit of the Fanconi anemia core complex, activating the interstrand crosslink (ICL) repair pathway on chromatin.

Molecular Function:

ubiquitin protein ligase activity

Directly Involved In:

protein monoubiquitination interstrand cross-link repair

Cellular Locations:

chromatin nucleus

In Complex:

Fanconi anaemia nuclear complex

Substrates:

FANCD2 FANCI

Supporting Evidence:

PMID:12973351
which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo
PMID:19589784
FANCI can be ubiquitinated on Lys-523 by the UBE2T-FANCL pair in vitro

Recruits and activates the dedicated E2 ubiquitin-conjugating enzyme UBE2T via its C-terminal RING-type zinc finger, selecting UBE2T over other E2s to enable FANCD2/FANCI monoubiquitination.

Molecular Function:

ubiquitin conjugating enzyme binding

Directly Involved In:

protein monoubiquitination

Cellular Locations:

nucleus

In Complex:

Fanconi anaemia nuclear complex

Supporting Evidence:

PMID:24389026
these specific interactions are required for selection of Ube2T over other E2s by FANCL
PMID:16916645
UBE2T binds to FANCL, the ubiquitin ligase subunit of the Fanconi anemia core complex

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:12973351

A novel ubiquitin ligase is deficient in Fanconi anemia.

PMID:16916645

UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation.

PMID:17938197

UBE2T, the Fanconi anemia core complex, and FANCD2 are recruited independently to chromatin: a basis for the regulation of FANCD2 monoubiquitination.

PMID:19111657

Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI.

PMID:19589784

FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL.

PMID:19965384

The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.

PMID:20347428

A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability.

PMID:22343915

FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein required for functional integrity of the FA-BRCA DNA repair pathway.

PMID:24389026

Structure of the human FANCL RING-Ube2T complex reveals determinants of cognate E3-E2 selection.

PMID:26149689

The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:35512704

Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.

Reactome:R-HSA-6785126

FA core complex assembles at DNA interstrand crosslinks (ICLs)

Reactome:R-HSA-6785342

FANCD2:FANCI complex and UBE2T bind ICL-DNA associated with the FA core complex

Reactome:R-HSA-6785361

Monoubiquitination of FANCD2:FANCI

Reactome:R-HSA-6785732

DNA nucleases bind monoubiquitinated ID2 complex

Reactome:R-HSA-6785986

DNA nucleases unhook the interstrand crosslink (ICL)

Reactome:R-HSA-6786155

POLN binds ICL-DNA

Reactome:R-HSA-6786166

Translesion synthesis across unhooked ICL by POLN

Reactome:R-HSA-6786171

FANCD2 deubiquitination by USP1:WDR48

Reactome:R-HSA-6788385

The complex of ATR and ATRIP is recruited to ICL-DNA

Reactome:R-HSA-6788392

ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA

Reactome:R-HSA-9835411

FA core complex:HSP70s binds PKR

PMID:12724401

A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.

Suggested Experiments

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.

Deep Research

Affinage

(FANCL-deep-research-affinage.md)

Affinage mechanistic annotation for FANCL (human) Affinage Affinage (Claude Sonnet reading pass + Opus synthesis pass) 22 citations

Affinage mechanistic annotation for FANCL (human)

Current model (mechanistic narrative)

FANCL is the catalytic RING-type E3 ubiquitin ligase subunit of the Fanconi anemia core complex, partnering with the E2 enzyme UBE2T to monoubiquitinate FANCD2 and FANCI and thereby drive homologous-recombination repair of DNA interstrand crosslinks [PMID:19111657, PMID:17352736]. Its crystal structure resolves a tripartite architecture in which the central DRWD/URD domain binds the FANCD2/FANCI substrate dimer while the C-terminal RING domain mediates E2 recruitment, and an extensive electrostatic/hydrophobic RING–UBE2T interface confers selective recruitment of UBE2T over other E2 enzymes [PMID:20154706, PMID:24389026]. Reconstitution shows FANCL and UBE2T are sufficient to monoubiquitinate FANCD2, with FANCI both stimulating the reaction and restricting modification to the correct lysine (K561 on FANCD2; K523 on FANCI) [PMID:19111657, PMID:19589784]; the N-terminal ELF domain additionally binds free ubiquitin via the Ile44 patch to promote efficient damage-induced FANCD2 monoubiquitination in cells PMID:26149689. FANCL-dependent monoubiquitination is required for FANCD2 chromatin and nuclear-matrix association and for HR repair of induced chromosomal breaks, an epistatic relationship conserved from Drosophila to vertebrates [PMID:14712086, PMID:17352736, PMID:16860002]. A catalytic-cysteine knock-in mouse establishes that loss of RING E3 ligase activity alone reproduces all major Fanconi anemia phenotypes, and FANCL variants causing protein destabilization or cytoplasmic mislocalization underlie premature ovarian insufficiency [PMID:41259745, PMID:32048394]. Beyond DNA repair, FANCL extends K11-linked non-proteolytic ubiquitin chains on β-catenin to enhance Wnt target transcription in hematopoietic stem/progenitor cells PMID:22653977, supports Parkin-mediated mitophagy through a ubiquitin ligase-independent mitochondrial function PMID:35644338, and is required for primordial germ cell proliferation and oocyte survival through meiosis [PMID:12417526, PMID:20661450].

Affinage mechanism profile (Affinage's own GO/Reactome grounding)

molecular_activity: GO:0016874 ligase activity, GO:0140096 catalytic activity, acting on a protein, GO:0031386 protein tag activity
localization: GO:0005634 nucleus, GO:0000228 nuclear chromosome, GO:0005739 mitochondrion
pathway (Reactome): R-HSA-73894 DNA Repair, R-HSA-392499 Metabolism of proteins, R-HSA-162582 Signal Transduction, R-HSA-9612973 Autophagy, R-HSA-1474165 Reproduction
partners: UBE2T, FANCD2, FANCI, UBE2W, CTNNB1, GGN, AXIN1
complexes: Fanconi anemia core complex

Dated findings (citation-anchored)

Year	Confidence	Finding	PMIDs	Journal
2008	High	FANCL acts as an E3 ubiquitin ligase that, together with the E2-conjugating enzyme Ube2t, is sufficient to monoubiquitinate FANCD2 in a minimal reconstituted system. A conserved RWD-like domain in FANCL stimulates monoubiquitination, and addition of FANCI enhances the reaction and restricts it to the correct in vivo lysine residue on FANCD2 (K561).	PMID:19111657	Molecular cell
2004	Medium	FANCL (PHF9), but not BRCA1, is the likely E3 ubiquitin ligase responsible for FANCD2 monoubiquitination. In FANCL-mutant cells, monoubiquitinated FANCD2 is absent from chromatin and nuclear matrix fractions, whereas non-ubiquitinated FANCD2 resides in the soluble fraction, demonstrating that FANCL-dependent monoubiquitination is required for FANCD2 chromatin association.	PMID:14712086	Cell cycle (Georgetown, Tex.)
2010	High	Crystal structure of FANCL at 3.2 Å reveals three domains: an N-terminal E2-like fold (ELF domain), a novel double-RWD (DRWD) domain, and a C-terminal RING domain. Binding assays show the DRWD domain (not ELF) is responsible for substrate (FANCD2/FANCI) binding, while the RING domain mediates E2 (Ube2T) interaction.	PMID:20154706	Nature structural & molecular biology
2014	High	Crystal structure of the FANCL RING domain in complex with Ube2T reveals an extensive network of specific electrostatic and hydrophobic interactions beyond the generic E3–E2 interface, and mutagenesis shows these specific interactions are required for selective recruitment of Ube2T over other E2 enzymes by FANCL.	PMID:24389026	Structure (London, England : 1993)
2011	High	Structure of the central (DRWD/URD) domain of human FANCL confirms conservation with Drosophila FANCL. Mutational analysis identifies residues in the DRWD domain required for binding FANCD2 and FANCI substrates, and a separate region required for Ube2T binding.	PMID:21775430	The Journal of biological chemistry
2006	High	The WD40 repeats (not the PHD/RING domain) of FANCL are required for interaction with other FA core complex subunits. The PHD domain is dispensable for core complex incorporation but is required for FANCD2 monoubiquitination; a conserved tryptophan in the PHD analogous to the c-CBL RING finger is required for in vitro auto-ubiquitination and in vivo FANCD2 monoubiquitination.	PMID:16474167	The Journal of biological chemistry
2007	High	FANCL physically interacts with FANCD2 via its PHD domain (co-immunoprecipitation in 293T cells and yeast two-hybrid). FANCL is required for FANCD2 monoubiquitination and focus formation in DT40 cells, and loss of FANCL (or FANCD2 monoubiquitination) causes quantitatively identical defects in homologous recombination repair of I-SceI-induced chromosomal breaks.	PMID:17352736	Genes to cells : devoted to molecular & cellular mechanisms
2009	High	The UBE2T–FANCL pair can monoubiquitinate FANCI on Lys-523 in vitro. FANCI binds branched DNA structures through its C-terminal fragment, a binding activity that likely positions it as a substrate.	PMID:19589784	The Journal of biological chemistry
2010	Medium	UBE2W interacts with the PHD domain of FANCL (the PHD domain is necessary and sufficient for this interaction) and catalyzes monoubiquitination of the FANCL PHD domain in vitro. UBE2W overexpression promotes FANCD2 monoubiquitination in cells, and UBE2W knockdown reduces UV-induced (but not MMC-induced) FANCD2 monoubiquitination, indicating UBE2W regulates FANCD2 monoubiquitination through FANCL by a mechanism distinct from UBE2T.	PMID:21229326	Molecules and cells
2015	High	The N-terminal ELF domain of FANCL mediates a non-covalent interaction with ubiquitin via the canonical Ile44 patch on ubiquitin. This interaction is not required for FANCD2 monoubiquitination in vitro, nor for core complex recognition or Ube2T binding, but is required for efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, indicating a regulatory in vivo function for ubiquitin binding by the ELF domain.	PMID:26149689	The Journal of biological chemistry
2012	Medium	FANCL ubiquitinates β-catenin with atypical lysine-11 ubiquitin chain extension (non-proteolytic), enhancing β-catenin nuclear activity and transcription of Wnt targets c-Myc and Cyclin D1. FANCL-deficient cells show diminished β-catenin activation, and suppression of FANCL in human CD34+ stem/progenitor cells reduces β-catenin-active cells and inhibits multilineage progenitor expansion.	PMID:22653977	Blood
2013	Medium	FANCL protein is constitutively targeted for proteasomal degradation via K48-linked polyubiquitination. The ELF (E2-like fold) domain may direct this polyubiquitination. FANCL is stabilized in a complex with axin1 when GSK-3β is overexpressed, and constitutively active Akt (myristoylated) increases FANCL steady-state levels by reducing K48-linked polyubiquitination. Phosphorylated (acidic) forms of FANCL are not subject to polyubiquitination.	PMID:23783032	Molecular biology of the cell
2017	Medium	Arsenite (As3+) binds directly to the PHD/RING finger domain of FANCL both in vitro and in cells. This binding compromises FANCL-mediated FANCD2 ubiquitination in cells, reduces FANCD2 chromatin recruitment to DNA damage sites, and renders cells more sensitive to DNA interstrand cross-linking agents.	PMID:28535027	ACS chemical biology
2019	Medium	A small-molecule inhibitor identified by high-throughput screening inhibits UBE2T/FANCL-mediated FANCD2 monoubiquitylation and sensitizes cells to the DNA cross-linking agent carboplatin, validating the UBE2T–FANCL catalytic pair as a druggable target in the FA pathway.	PMID:31525021	ACS chemical biology
2022	Medium	FANCL protein localizes to mitochondria (in both basal and mitochondrial stress conditions), and its ubiquitin ligase activity is not required for this mitochondrial localization. CRISPR/Cas9 knockout of FANCL in parkin-overexpressing HeLa cells impairs clearance of damaged mitochondria (mitophagy) upon oligomycin/antimycin treatment; this defect is rescued by reintroduction of either wild-type FANCL or the catalytically dead FANCL(C307A) mutant, demonstrating a ubiquitin ligase-independent role in supporting Parkin-mediated mitophagy.	PMID:35644338	Biochimica et biophysica acta. Molecular basis of disease
2006	Medium	In Drosophila, FANCL is necessary for monoubiquitination of FANCD2, and epistasis analysis places FANCL upstream of FANCD2 in a linear DNA repair pathway. Knockdown of either FANCL or FANCD2 confers hypersensitivity to cross-linking agents.	PMID:16860002	DNA repair
2002	Medium	Mouse Pog (the ortholog of FANCL) is necessary for primordial germ cell (PGC) proliferation between E9.5 and E10.25 dpc. Deletion of Pog causes the germ-cell-deficient (gcd) phenotype with reduced PGC numbers and adult sterility; the proliferation defect rather than aberrant migration is responsible.	PMID:12417526	Human molecular genetics
2003	Medium	POG (FANCL ortholog) interacts with GGN1 and GGN3 (gametogenetin isoforms) via yeast two-hybrid and co-expression in HeLa cells. Co-expression of POG with GGN1 or GGN3 relocalizes POG to the perinuclear region or nucleoli, respectively, and Pog-deficient mice show impaired meiosis during spermatogenesis.	PMID:12574169	The Journal of biological chemistry
2010	High	In zebrafish, fancl is expressed in developing germ cells at the critical time of sexual fate determination. Loss of fancl causes Tp53-mediated germ cell apoptosis (demonstrated by caspase-3 immunoassay), compromises oocyte survival through meiosis, and results in female-to-male sex reversal. Introduction of a tp53 mutation into fancl mutants rescues sex reversal by reducing germ cell apoptosis.	PMID:20661450	PLoS genetics
2020	Medium	Two heterozygous frameshift mutations in FANCL (c.1048_1051delGTCT and c.739dupA) identified in POI patients cause cytoplasmic retention of mutant FANCL protein (whereas wild-type FANCL is nuclear), impaired ubiquitin-ligase activity, and compromised DNA repair after mitomycin C treatment.	PMID:32048394	Human mutation
2026	High	A murine FanclTATΔ allele removing the catalytic cysteine in the RING domain generates a core complex that retains structural integrity but lacks FANCD2 monoubiquitination activity. Homozygous mice phenocopy human FA (infertility, craniofacial anomalies, DNA damage hypersensitivity, progressive HSC loss). CRISPR-Cas9 or prime editing correction of the mutation restores FANCD2 monoubiquitination and DNA damage resistance in myeloid cells, demonstrating that loss of RING E3 ligase activity alone explains all major FA phenotypes.	PMID:41259745	Blood advances
2020	Medium	Analysis of 17 FANCL URD-domain variants from patient cancer cells shows that mutations I136V, L154S, W212A, L214A, R221W, R221C, and V287G destabilize FANCL, while E217K, T224K, M247V, and the hydrophobic patch mutants (L248A, F252A, L254A, I265A) impair catalytic function without destabilizing the fold. N270K and E289Q specifically destabilize the C-terminal helices of the URD domain. These functional defects correlate with cellular sensitivity to an interstrand cross-linking agent.	PMID:32420600	Bioscience reports

Citations

PMID:12417526
PMID:12574169
PMID:14712086
PMID:16474167
PMID:16860002
PMID:17352736
PMID:19111657
PMID:19589784
PMID:20154706
PMID:20661450
PMID:21229326
PMID:21775430
PMID:22653977
PMID:23783032
PMID:24389026
PMID:26149689
PMID:28535027
PMID:31525021
PMID:32048394
PMID:32420600
PMID:35644338
PMID:41259745

📚 Additional Documentation

Notes

(FANCL-notes.md)

FANCL (Q9NW38) review notes

Human Fanconi anemia complementation group L. HGNC:20748. Synonym PHF9. 375 aa.

Core biology (synthesis)

FANCL is the catalytic RING-type E3 ubiquitin ligase subunit of the multiprotein
Fanconi anemia (FA) core complex. Working with the dedicated E2 conjugating enzyme
UBE2T, FANCL monoubiquitinates FANCD2 (on Lys561) and FANCI (on Lys523), the key
activating step of the FA/interstrand-crosslink (ICL) repair pathway. The
monoubiquitinated FANCD2–FANCI (ID2) complex is recruited to chromatin at stalled
replication forks / ICLs and coordinates nucleolytic incision, translesion synthesis
and homologous recombination.

Domain architecture (UniProt Q9NW38): N-terminal E2-like/ELF (UBC-like) domain,
central "DRWD"/RWD-like domain, and a C-terminal RING-type zinc finger (residues
307–363, degenerate, binds 2 Zn). The UBC-RWD region (URD, ~104–294) mediates
interaction with FANCI and FANCD2; the RING binds the E2 (UBE2T). Cys307 is essential
for ligase activity (C307A abolishes activity). Trp341 is required for UBE2T binding.

Note the UniProt CAUTION: originally reported as a PHD-type zinc finger (PubMed:12724401)
but it is actually a RING-type zinc finger; PHD fingers have no ubiquitin ligase activity.

Key evidence / provenance

E3 ubiquitin ligase activity; essential for FANCD2 monoubiquitination:
PMID:12973351. Also defines involvement in FA (disease), catalytic activity, and C307/C310 mutagenesis abolishing activity.
UBE2T is the cognate E2 that binds FANCL (E2/E3 pair):
PMID:16916645. W341G abolishes UBE2T binding and ligase activity.
E3 activity determined by chromatin localization, forms active E2/E3 holoenzyme on chromatin:
PMID:17938197;
PMID:17938197.
Minimal reconstitution: Ube2t + FANCL monoubiquitinate FANCD2, stimulated by RWD-like domain; FANCI restricts site-specificity:
PMID:19111657;
PMID:19111657.
FANCL also monoubiquitinates FANCI (Lys523):
PMID:19589784.
Structure of FANCL RING–Ube2T; specific E3–E2 selection:
PMID:24389026;
PMID:24389026.
FA nuclear core complex membership / chromatin:
PMID:22343915.
PMID:20347428.
UniProt SUBUNIT: FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM.
ICL repair pathway (downstream of FANCD2/FANCI monoubiquitination):
PMID:19965384.

Curation decisions

MF ubiquitin protein ligase activity (GO:0061630): core, ACCEPT (IBA/IEA/EXP/IDA).
MF ubiquitin-protein transferase activity (GO:0004842): parent of 0061630; correct but more
general; ACCEPT (IEA/IDA/ISS).
BP protein monoubiquitination (GO:0006513): core, ACCEPT.
BP interstrand cross-link repair (GO:0036297): core pathway, ACCEPT.
CC Fanconi anaemia nuclear complex (GO:0043240): core location/complex, ACCEPT.
CC chromatin (GO:0000785): site of active E3 holoenzyme, ACCEPT.
CC nucleus/nucleoplasm/cytosol/cytoplasm: ACCEPT nucleus/nucleoplasm; cytoplasm/cytosol
KEEP_AS_NON_CORE (FANCL acts in nucleus/chromatin; cytoplasmic pool by similarity/ISS).
MF protein binding (GO:0005515): uninformative; MARK_AS_OVER_ANNOTATED. Most are
high-throughput Y2H (HuRI PMID:25416956/32296183; neo-PPI PMID:35512704). The
functionally meaningful one (PMID:24389026, partner UBE2T Q9NPD8) is better captured by
the E2-binding term.
MF ubiquitin protein ligase binding (GO:0031625, IPI with UBE2T/UBE2W which are E2s):
the partners UBE2T (Q9NPD8) and UBE2W (Q96B02) are E2 conjugating enzymes, not E3 ligases;
MODIFY to GO:0031624 ubiquitin conjugating enzyme binding (verified QuickGO/AmiGO:
"Binding to a ubiquitin conjugating enzyme, any of the E2 proteins").
BP DNA repair (GO:0006281), DNA damage response (GO:0006974), protein ubiquitination
(GO:0016567): correct general terms, ACCEPT.
MF ubiquitin binding (GO:0043130): NEW (not in GOA). ELF (E2-like fold) domain binds
free ubiquitin non-covalently via the Ile44 patch; dispensable in vitro but required for
efficient DNA-damage-induced FANCD2 monoubiquitination in vivo. Regulatory/non-core.
PMID:26149689; PMID:26149689. Verified GO:0043130 is a
molecular_function via QuickGO (not obsolete). Added during Affinage reconciliation.

Affinage reconciliation (2026-07)

Affinage record (run 2026-06-09, 22 discoveries, self-eval win) is a PMID-dense narrative
fully consistent with AIGR on the core biology. Its mechanism_profile GO layer is coarse
(GO:0016874 ligase activity, GO:0140096 catalytic activity acting on protein, GO:0031386
protein tag activity; nucleus/nuclear chromosome/mitochondrion) — do not import directly;
AIGR's GO:0061630 + GO:0031624 + specific locations are more precise. Incorporated
PMID:26149689 (ELF ubiquitin binding, above) as the one genuine MF the review lacked.
Affinage's moonlighting claims — K11-linked β-catenin/Wnt (PMID:22653977), ligase-independent
Parkin mitophagy (PMID:35644338), germ-cell/reproduction phenotypes (PMID:12417526,
PMID:20661450) — are single-study and/or non-human organism/tissue phenotypes; AIGR correctly
scopes them out of the human GO core-function set. Not added as annotations.

📄 View Raw YAML

id: Q9NW38
gene_symbol: FANCL
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: '1'
  id: Q9NW38-1
- name: '2'
  id: Q9NW38-2
  sequence_note: VSP_041727
existing_annotations:
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:16916645
        supporting_text: The Fanconi anemia pathway is required for the efficient repair of damaged DNA.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Strongly supported by multiple experimental studies demonstrating RING-type E3
      ligase activity dependent on the Cys307 RING residue and on UBE2T.
    supported_by:
      - reference_id: PMID:12973351
        supporting_text: which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment of nuclear localization/activity. FANCL functions in
      the nucleus as part of the FA core complex on chromatin.
    action: ACCEPT
    reason: >-
      Consistent with UniProt subcellular location (Nucleus), with FA core complex
      chromatin localization, and with the site of FANCD2/FANCI monoubiquitination.
    supported_by:
      - reference_id: PMID:17938197
        supporting_text: its DNA damage-induced localization to chromatin
- term:
    id: GO:0006513
    label: protein monoubiquitination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) involvement in protein monoubiquitination. FANCL specifically
      catalyzes monoubiquitination (not polyubiquitination) of FANCD2 and FANCI.
    action: ACCEPT
    reason: >-
      Well supported experimentally; FANCL/UBE2T add a single ubiquitin to FANCD2-Lys561
      and FANCI-Lys523.
    supported_by:
      - reference_id: PMID:12973351
        supporting_text: is essential for FANCD2 monoubiquitination in vivo
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of ubiquitin-protein transferase activity (parent of the more
      specific ubiquitin protein ligase activity, GO:0061630).
    action: ACCEPT
    reason: >-
      Correct but more general than GO:0061630; retained as a valid broader molecular
      function term for the E3 ligase.
    supported_by:
      - reference_id: PMID:16916645
        supporting_text: UBE2T binds to FANCL, the ubiquitin ligase subunit of the
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of nuclear localization, consistent with UniProt and experimental data.
    action: ACCEPT
    reason: FANCL localizes to and functions in the nucleus as part of the FA core complex.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: file:human/FANCL/FANCL-uniprot.txt
        supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-based electronic assignment to interstrand cross-link repair, the pathway
      that FANCL activates via FANCD2/FANCI monoubiquitination.
    action: ACCEPT
    reason: >-
      Correct core process; the FA pathway that FANCL drives is required for
      replication-coupled ICL repair.
    supported_by:
      - reference_id: PMID:19965384
        supporting_text: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: >-
      InterPro-based electronic assignment of membership in the Fanconi anemia nuclear
      (core) complex. FANCL is the E3 ligase subunit of this complex.
    action: ACCEPT
    reason: >-
      Well established experimentally; FANCL is an integral subunit of the FA core complex
      (FANCA/B/C/E/F/G/L/M).
    supported_by:
      - reference_id: file:human/FANCL/FANCL-uniprot.txt
        supporting_text: Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of ubiquitin protein ligase activity (EC:2.3.2.27), FANCL's core molecular function.
    action: ACCEPT
    reason: Redundant with the experimental and IBA annotations of the same term; correct.
    supported_by:
      - reference_id: PMID:12973351
        supporting_text: which possesses E3 ubiquitin ligase activity in vitro
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 'protein binding' is uninformative per curation guidelines, and these
      large-scale Y2H interactions are not linked to FANCL's characterized function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from the HuRI reference binary interactome (high-throughput
      Y2H). Many partners are not established FANCL functional interactors.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'protein binding' is uninformative and these systematic Y2H hits do not inform
      FANCL's molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35512704
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: '''protein binding'' is uninformative and the interaction does not inform FANCL''s core function.'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based electronic assignment to protein ubiquitination, the general
      process to which FANCL's E3 activity contributes.
    action: ACCEPT
    reason: >-
      Correct but general; the more specific and biologically informative process is
      protein monoubiquitination (GO:0006513), which is separately annotated.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based nuclear localization (from mouse ortholog Q9CR14).
    action: ACCEPT
    reason: Consistent with experimental and IBA nuclear localization annotations.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based cytoplasmic localization (from mouse ortholog Q9CR14).
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with UniProt, but the cytoplasmic pool is not where FANCL performs its
      core FA-pathway E3 function (nucleus/chromatin).
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:12973351
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Foundational experimental evidence establishing FANCL as the E3 ligase of the FA
      pathway; represents the core molecular function.
    supported_by:
      - reference_id: PMID:12973351
        supporting_text: which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:16916645
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Core molecular function, independently confirmed with definition of the cognate E2.
    supported_by:
      - reference_id: PMID:16916645
        supporting_text: UBE2T binds to FANCL, the ubiquitin ligase subunit of the Fanconi anemia core complex, and is required for the monoubiquitination of FANCD2 in vivo
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:19111657
  qualifier: enables
  review:
    summary: >-
      Minimal reconstitution shows FANCL with UBE2T catalyzes FANCD2 monoubiquitination,
      stimulated by FANCL's conserved RWD-like domain.
    action: ACCEPT
    reason: Directly demonstrates FANCL E3 ligase activity in a reconstituted system.
    supported_by:
      - reference_id: PMID:19111657
        supporting_text: 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
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IDA
  original_reference_id: PMID:22343915
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: >-
      FANCL's productive E3 activity depends on DNA-damage-induced chromatin localization;
      chromatin is the functional site of FANCD2/FANCI monoubiquitination.
    supported_by:
      - reference_id: PMID:17938197
        supporting_text: 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
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: NAS
  original_reference_id: PMID:19965384
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Core biological process for FANCL, corroborated by the InterPro IEA annotation of the same term.
    supported_by:
      - reference_id: PMID:19965384
        supporting_text: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: NAS
  original_reference_id: PMID:22343915
  qualifier: part_of
  review:
    summary: FANCL is a component of the Fanconi anemia nuclear core complex.
    action: ACCEPT
    reason: Well established; FANCL is the E3 ligase subunit of the FA core complex.
    supported_by:
      - reference_id: PMID:22343915
        supporting_text: Fanconi anemia (FA) nuclear core complex is a multiprotein complex required for the functional integrity of the FA-BRCA pathway regulating DNA repair
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24389026
  qualifier: enables
  review:
    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).
    action: MARK_AS_OVER_ANNOTATED
    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).
    supported_by:
      - reference_id: PMID:24389026
        supporting_text: we report the atomic structure of the FANCL RING-Ube2T complex
- term:
    id: GO:0006513
    label: protein monoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:24389026
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence that FANCL, via its RING-UBE2T interface, mediates monoubiquitination;
      the specific FANCL-UBE2T pairing selects UBE2T over other E2s.
    action: ACCEPT
    reason: Core process; monoubiquitination depends on cognate E3-E2 pairing established here.
    supported_by:
      - reference_id: PMID:24389026
        supporting_text: these specific interactions are required for selection of Ube2T over other E2s by FANCL
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9835411
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with a cytoplasmic/cytosolic pool of FANCL, but not the site of its
      central FA-pathway ubiquitin-ligase activity.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:19589784
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Core molecular function; establishes FANCI (in addition to FANCD2) as a FANCL substrate.
    supported_by:
      - reference_id: PMID:19589784
        supporting_text: FANCI can be ubiquitinated on Lys-523 by the UBE2T-FANCL pair in vitro
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785126
  qualifier: located_in
  review:
    summary: Reactome-traceable nucleoplasmic localization (FA core complex assembly at ICLs).
    action: ACCEPT
    reason: Consistent with FANCL's nuclear localization and its function within the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785342
  qualifier: located_in
  review:
    summary: Reactome-traceable nucleoplasmic localization (FANCD2:FANCI and UBE2T binding ICL-DNA with the FA core complex).
    action: ACCEPT
    reason: Consistent with FANCL's nuclear localization within the FA pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785361
  qualifier: located_in
  review:
    summary: Reactome-traceable nucleoplasmic localization (monoubiquitination of FANCD2:FANCI).
    action: ACCEPT
    reason: Consistent with FANCL's nuclear localization and catalytic role in this reaction.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785732
  qualifier: located_in
  review:
    summary: Reactome-traceable nucleoplasmic localization (DNA nucleases bind monoubiquitinated ID2 complex).
    action: ACCEPT
    reason: Consistent with FANCL's nuclear localization within the FA pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785986
  qualifier: located_in
  review:
    summary: Reactome-traceable nucleoplasmic localization (DNA nucleases unhook the ICL).
    action: ACCEPT
    reason: Consistent with FANCL's nuclear localization within the FA pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786155
  qualifier: located_in
  review:
    summary: Reactome-traceable nucleoplasmic localization (POLN binds ICL-DNA).
    action: ACCEPT
    reason: Consistent with FANCL's nuclear localization within the FA pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786166
  qualifier: located_in
  review:
    summary: Reactome-traceable nucleoplasmic localization (translesion synthesis across unhooked ICL by POLN).
    action: ACCEPT
    reason: Consistent with FANCL's nuclear localization within the FA pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786171
  qualifier: located_in
  review:
    summary: Reactome-traceable nucleoplasmic localization (FANCD2 deubiquitination by USP1:WDR48).
    action: ACCEPT
    reason: Consistent with FANCL's nuclear localization within the FA pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788385
  qualifier: located_in
  review:
    summary: Reactome-traceable nucleoplasmic localization (ATR:ATRIP recruited to ICL-DNA).
    action: ACCEPT
    reason: Consistent with FANCL's nuclear localization within the FA pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788392
  qualifier: located_in
  review:
    summary: Reactome-traceable nucleoplasmic localization (ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA).
    action: ACCEPT
    reason: Consistent with FANCL's nuclear localization within the FA pathway.
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:22343915
  qualifier: part_of
  review:
    summary: Direct assay confirming FANCL is a component of the Fanconi anemia nuclear core complex.
    action: ACCEPT
    reason: FANCL is the RING E3 ligase subunit of the FA core complex; a core localization/complex annotation.
    supported_by:
      - reference_id: PMID:22343915
        supporting_text: Fanconi anemia (FA) nuclear core complex is a multiprotein complex required for the functional integrity of the FA-BRCA pathway regulating DNA repair
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:16916645
  qualifier: enables
  review:
    summary: >-
      Direct experimental evidence for ubiquitin-protein transferase activity of FANCL
      (with UBE2T); a broader parent of the more specific ubiquitin protein ligase activity.
    action: ACCEPT
    reason: >-
      Correct; represents the same core E3 function as GO:0061630 at a slightly more
      general level.
    supported_by:
      - reference_id: PMID:16916645
        supporting_text: UBE2T binds to FANCL, the ubiquitin ligase subunit of the Fanconi anemia core complex
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:19111657
  qualifier: enables
  review:
    summary: Direct evidence for ubiquitin-protein transferase activity in the reconstituted FANCL/UBE2T FANCD2-monoubiquitination reaction.
    action: ACCEPT
    reason: Correct; general parent of ubiquitin protein ligase activity (GO:0061630).
    supported_by:
      - reference_id: PMID:19111657
        supporting_text: we minimally reconstitute this monoubiquitination reaction with Ube2t and the FANCL protein
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IMP
  original_reference_id: PMID:16916645
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Core biological role in the FA-BRCA DNA repair pathway, experimentally supported.
    supported_by:
      - reference_id: PMID:16916645
        supporting_text: The Fanconi anemia pathway is required for the efficient repair of damaged DNA
- term:
    id: GO:0006513
    label: protein monoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:16916645
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence that FANCL, with UBE2T, is required for FANCD2 monoubiquitination in
      vivo.
    action: ACCEPT
    reason: Core biological process; FANCL catalyzes the monoubiquitination central to the FA pathway.
    supported_by:
      - reference_id: PMID:16916645
        supporting_text: is required for the monoubiquitination of FANCD2 in vivo
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IMP
  original_reference_id: PMID:16916645
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Correct general process; FANCL acts in the S-phase/DNA-damage-activated FA pathway.
    supported_by:
      - reference_id: PMID:16916645
        supporting_text: DNA damage in UBE2T-depleted cells leads to the formation of abnormal chromosomes that are a hallmark of Fanconi anemia
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:16916645
  qualifier: enables
  review:
    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).
    action: MODIFY
    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_replacement_terms:
      - id: GO:0031624
        label: ubiquitin conjugating enzyme binding
    supported_by:
      - reference_id: PMID:16916645
        supporting_text: UBE2T binds to FANCL, the ubiquitin ligase subunit of the Fanconi anemia core complex
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:17938197
  qualifier: enables
  review:
    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.
    action: MODIFY
    reason: >-
      UBE2T is an E2, not an E3; MODIFY to GO:0031624 (ubiquitin conjugating enzyme
      binding), reflecting FANCL's RING-mediated E2 recruitment.
    proposed_replacement_terms:
      - id: GO:0031624
        label: ubiquitin conjugating enzyme binding
    supported_by:
      - reference_id: PMID:17938197
        supporting_text: the E2 ubiquitin-conjugating enzyme UBE2T
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:19111657
  qualifier: enables
  review:
    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.
    action: MODIFY
    reason: >-
      UBE2W (like UBE2T) is an E2 conjugating enzyme, not an E3 ligase; MODIFY to GO:0031624
      (ubiquitin conjugating enzyme binding).
    proposed_replacement_terms:
      - id: GO:0031624
        label: ubiquitin conjugating enzyme binding
    supported_by:
      - reference_id: file:human/FANCL/FANCL-uniprot.txt
        supporting_text: Directly interacts (via the RING-type zinc finger) with UBE2T and UBE2W
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity-based ubiquitin-protein transferase activity (from mouse ortholog Q9CR14).
    action: ACCEPT
    reason: Correct; consistent with the experimental E3 ligase annotations (a broader parent of GO:0061630).
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:20347428
  qualifier: part_of
  review:
    summary: >-
      Direct assay placing FANCL within the FA core complex; FANCM-MHF associates with the
      FA core complex and promotes FANCD2 monoubiquitination.
    action: ACCEPT
    reason: FANCL is an integral subunit of the FA core complex; a core complex/localization annotation.
    supported_by:
      - reference_id: PMID:20347428
        supporting_text: FANCM-MHF associates with the Fanconi anemia (FA) core complex
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: ISS
  original_reference_id: PMID:26149689
  qualifier: enables
  review:
    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.
    action: NEW
    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.
    supported_by:
      - reference_id: PMID:26149689
        supporting_text: the ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin
      - reference_id: PMID:26149689
        supporting_text: 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
core_functions:
- description: >-
    RING-type E3 ubiquitin ligase that, in partnership with the cognate E2 enzyme UBE2T,
    catalyzes site-specific monoubiquitination of FANCD2 (Lys561) and FANCI (Lys523) as
    the catalytic subunit of the Fanconi anemia core complex, activating the interstrand
    crosslink (ICL) repair pathway on chromatin.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  directly_involved_in:
  - id: GO:0006513
    label: protein monoubiquitination
  - id: GO:0036297
    label: interstrand cross-link repair
  locations:
  - id: GO:0000785
    label: chromatin
  - id: GO:0005634
    label: nucleus
  in_complex:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  substrates:
  - id: UniProtKB:Q9BXW9
    label: FANCD2
  - id: UniProtKB:Q9NVI1
    label: FANCI
  supported_by:
  - reference_id: PMID:12973351
    supporting_text: which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo
  - reference_id: PMID:19589784
    supporting_text: FANCI can be ubiquitinated on Lys-523 by the UBE2T-FANCL pair in vitro
- description: >-
    Recruits and activates the dedicated E2 ubiquitin-conjugating enzyme UBE2T via its
    C-terminal RING-type zinc finger, selecting UBE2T over other E2s to enable
    FANCD2/FANCI monoubiquitination.
  molecular_function:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  directly_involved_in:
  - id: GO:0006513
    label: protein monoubiquitination
  locations:
  - id: GO:0005634
    label: nucleus
  in_complex:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  supported_by:
  - reference_id: PMID:24389026
    supporting_text: these specific interactions are required for selection of Ube2T over other E2s by FANCL
  - reference_id: PMID:16916645
    supporting_text: UBE2T binds to FANCL, the ubiquitin ligase subunit of the Fanconi anemia core complex
proposed_new_terms: []
suggested_questions:
- question: >-
    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?
- question: >-
    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?
suggested_experiments:
- description: >-
    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.
- description: >-
    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.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12973351
  title: A novel ubiquitin ligase is deficient in Fanconi anemia.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Discovery paper identifying FANCL/PHF9 as the E3 ubiquitin ligase of the FA core
      complex, essential for FANCD2 monoubiquitination; establishes the core molecular
      function. Abstract verified against PubMed; supports EC:2.3.2.27 and RING mutagenesis.
- id: PMID:16916645
  title: UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes UBE2T as the cognate E2 that binds FANCL and is required for FANCD2
      monoubiquitination; underpins the E3-ligase, E2-binding, DNA-repair and
      monoubiquitination annotations. Verified against PubMed.
- id: PMID:17938197
  title: 'UBE2T, the Fanconi anemia core complex, and FANCD2 are recruited independently
    to chromatin: a basis for the regulation of FANCD2 monoubiquitination.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Shows FANCL E3 activity is governed by DNA-damage-induced chromatin localization and
      formation of an active E2/E3 holoenzyme; supports chromatin and E2-binding
      annotations. Verified against PubMed.
- id: PMID:19111657
  title: Mechanistic insight into site-restricted monoubiquitination of FANCD2 by
    Ube2t, FANCL, and FANCI.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Minimal reconstitution of FANCD2 monoubiquitination with FANCL and UBE2T; identifies
      the RWD-like domain as stimulatory and FANCI as conferring site specificity. Verified
      against PubMed.
- id: PMID:19589784
  title: FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct demonstration that UBE2T-FANCL monoubiquitinates FANCI on Lys523, establishing
      FANCI as a second FANCL substrate. Verified against PubMed.
- id: PMID:19965384
  title: The Fanconi anemia pathway promotes replication-dependent DNA interstrand
    cross-link repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes that monoubiquitinated FANCI-FANCD2 is required for replication-coupled
      ICL repair; supports the interstrand cross-link repair process annotation. Verified
      against PubMed.
- id: PMID:20347428
  title: A histone-fold complex and FANCM form a conserved DNA-remodeling complex
    to maintain genome stability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Characterizes FANCM-MHF and its association with the FA core complex (of which FANCL
      is a subunit) to promote FANCD2 monoubiquitination; supports FA core complex
      membership. Verified against PubMed.
- id: PMID:22343915
  title: 'FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein required
    for functional integrity of the FA-BRCA DNA repair pathway.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Characterizes the FA nuclear core complex and its chromatin function; used by
      ComplexPortal/UniProt for FANCL complex-membership and chromatin annotations. Verified
      against PubMed.
- id: PMID:24389026
  title: Structure of the human FANCL RING-Ube2T complex reveals determinants of cognate
    E3-E2 selection.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Atomic structure of the FANCL RING-UBE2T complex defining specific E3-E2 selection;
      supports the E2-binding molecular function and monoubiquitination process. Verified
      against PubMed.
- id: PMID:26149689
  title: The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between
    Ubiquitin and the E2-like Fold Domain of FANCL.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Dedicated structural/functional study (Walden lab) showing the FANCL N-terminal ELF
      domain binds ubiquitin non-covalently via the Ile44 patch; dispensable for FANCD2
      monoubiquitination in vitro but required for efficient DNA-damage-induced FANCD2
      monoubiquitination in vertebrate cells. Full text (PMC4543658) verified. Adds a
      regulatory ubiquitin-binding molecular function absent from the curated GOA
      annotations.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      High-throughput yeast two-hybrid interactome (HuRI); source of numerous generic
      'protein binding' (GO:0005515) annotations that are not linked to FANCL's
      characterized function.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      HuRI reference binary interactome (high-throughput Y2H); source of generic 'protein
      binding' annotations not informative for FANCL's molecular function.
- id: PMID:35512704
  title: Systematic discovery of mutation-directed neo-protein-protein interactions
    in cancer.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Systematic neo-PPI screen (partner SMAD4); a generic 'protein binding' interaction
      not representing a constitutive functional interaction of wild-type FANCL.
- id: Reactome:R-HSA-6785126
  title: FA core complex assembles at DNA interstrand crosslinks (ICLs)
  findings: []
- id: Reactome:R-HSA-6785342
  title: FANCD2:FANCI complex and UBE2T bind ICL-DNA associated with the FA core complex
  findings: []
- id: Reactome:R-HSA-6785361
  title: Monoubiquitination of FANCD2:FANCI
  findings: []
- id: Reactome:R-HSA-6785732
  title: DNA nucleases bind monoubiquitinated ID2 complex
  findings: []
- id: Reactome:R-HSA-6785986
  title: DNA nucleases unhook the interstrand crosslink (ICL)
  findings: []
- id: Reactome:R-HSA-6786155
  title: POLN binds ICL-DNA
  findings: []
- id: Reactome:R-HSA-6786166
  title: Translesion synthesis across unhooked ICL by POLN
  findings: []
- id: Reactome:R-HSA-6786171
  title: FANCD2 deubiquitination by USP1:WDR48
  findings: []
- id: Reactome:R-HSA-6788385
  title: The complex of ATR and ATRIP is recruited to ICL-DNA
  findings: []
- id: Reactome:R-HSA-6788392
  title: ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA
  findings: []
- id: Reactome:R-HSA-9835411
  title: FA core complex:HSP70s binds PKR
  findings: []
- id: PMID:12724401
  title: A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Identified FANCL in the BRAFT complex; originally described a PHD-type zinc finger,
      later corrected to a RING-type zinc finger (UniProt CAUTION). Background/context.

FANCL

Gene Description