FANCL

Summary: Specify the directly supported interstrand-crosslink repair contribution.

Reason: The authentic global IBD at PTN000324788 supports DNA repair; human target self-WITH is valid, and actual v19 tree/MSA data now verify the target path and displayed 375-residue sequence. The current source and the later global IBD differ by one additional Arabidopsis donor, a version boundary rather than circularity. Actual fly PMID:25205745 distinguishes Fancl crosslink sensitivity from Fancm-specific MMS/IR phenotypes; PMID:16860002 provides positive abstract-level FANCL RNAi/monoubiquitination evidence. Human FANCL performs the E3 step, directly reconstituted in PMID:19589784, and chicken PMID:17938197 separates ligase-defective mutants from intact core assembly and measures cisplatin sensitivity. GO:0036297 is the supported specific repair descendant. This does not transfer FANCM recombination/helicase work to FANCL or claim that other FANCL responses are impossible.

Proposed replacements: interstrand cross-link repair

Summary: FANCL has directly supported RING E3 ubiquitin ligase activity.

Reason: The global GO:0061630 IBD at PTN000324788 has experimental human, mouse and fly descendants; the target in WITH is legitimate. Actual v19 target tree/MSA verifies descent and the displayed 375-residue sequence; no equivalent placement/function claim is made for the 380-residue product. Human PMID:19589784 directly establishes FANCL-dependent substrate monoubiquitination. PMID:21775430 tests human RING/URD domains; PMID:24389026 resolves human RING–UBE2T binding, but its enzymatic reaction uses Xenopus FANCL/FANCD2. Mouse PMID:21229326 separately tests UBE2W-linked discharge. These preparations support the E3 interpretation without assigning a FANCL thioester intermediate or equivalent activity to every natural product.

Summary: Nuclear localization is supported by verified ancestry and target evidence.

Reason: The authentic global PAINT file contains the GO:0005634 IBD at PTN000324788 with mouse and human descendant evidence. Target self-WITH is legitimate. Fresh official PANTHER v19 tree/MSA responses place human PTN002491116 below that node and exactly match the displayed 375-residue sequence; the original intake timeouts remain historical. Independently, human HPA nuclear-body imaging and the human FA core-complex model independently support nucleus, while mouse POG/FANCL experiments report partner-dependent nuclear and nucleolar pools. Chromatin and these other nuclear pools are not collapsed into soluble nucleoplasm. The inherited PMID:17938197 quotation refers to chicken DT40 experiments.

Summary: FANCL directly participates in protein monoubiquitination as the E3.

Reason: The global GO:0006513 IBD at PTN000324788 has human and fly descendant grounding; self-WITH is correct, and the recovered v19 target tree/MSA verifies descent and the displayed 375-residue sequence. Actual human PMID:19589784 Methods/Figure 4 establish FANCL-dependent FANCI monoubiquitination with FANCL C307A and UBE2T C86A controls. FANCL performs the E3 step, unlike FANCI merely receiving ubiquitin. The single-ubiquitin substrate modification is well supported; the annotation does not assert that FANCL can never promote other ubiquitin reactions in different in-vitro preparations.

Summary: Specify FANCL ubiquitin protein ligase activity.

Reason: The combined electronic source includes the genuine IPR026848 family mapping and mouse orthology. GO:0061630 is the more specific is_a child of ubiquitin-protein transferase activity for transfer from a thioester-linked donor to a substrate amine. Actual human FANCL/UBE2T reconstitution in PMID:19589784 requires FANCL and fails with FANCL C307A or UBE2T C86A. This establishes the E3 role rather than transferring UBE2T E2 chemistry to FANCL. The human URD thioester assay in PMID:21775430 was negative, consistent with a RING E3 rather than a catalytic E2-like intermediate.

Proposed replacements: ubiquitin protein ligase activity

Summary: The combined nuclear-location mapping agrees with target evidence.

Reason: UniProt SL-0191 maps to nucleus. The actual ARBA00026330 rule contains the matching three-FunFam/Eukaryota clause, independently matched to the target record. Human HPA images show nuclear bodies, and Reactome explicitly models FANCL in the nuclear core complex. Mouse ortholog experiments additionally show partner-dependent nuclear/nucleolar localization. Retain this nuclear breadth rather than claiming every nuclear molecule is freely nucleoplasmic or assigning the HPA signal to a particular natural product.

Summary: Retain the positive cytoplasmic location as a contextual pool.

Reason: The actual SL-0086 mapping is cytoplasm and the human UniProt assertion is explicitly based on mouse Q9CR14. Mouse POG/FANCL is reported in both nucleus and cytoplasm, with partner-dependent redistribution. Independently inspected human HPA U2OS data assign vesicles as well as nuclear bodies, so replacing the broad cytoplasm term by organelle-excluding cytosol would lose that additional compartment. This is a contextual location relative to the established nuclear FA ligase role; it does not mean the cytoplasmic protein is inactive or that all cytoplasmic functions have been excluded.

Summary: FANCL supplies the E3 step in interstrand-crosslink repair.

Reason: Actual IPR026848 is the FANCL family and maps to GO:0036297; the target match is verified. Human FANCL/UBE2T substrate monoubiquitination in PMID:19589784 supplies a performed molecular step, while chicken FANCL mutants in PMID:17938197 separate defective ubiquitination/cisplatin resistance from preserved core assembly. Fly Fancl mutants in PMID:25205745 independently support crosslink resistance. The inherited PMID:19965384 quotation concerns ID2-dependent Xenopus repair and is retained as pathway context, not an isolated human FANCL assay. No incision or polymerase chemistry is assigned to FANCL.

Summary: FANCL is a component of the FA nuclear core complex.

Reason: IPR026848 maps to GO:0043240 and actually matches Q9NW38. Human BL100/CEF assembly in PMID:27986592 and the explicit Reactome assembly route support FANCL membership. FANCL contributes the E3 activity and also stabilizes the reconstituted assembly; the structural study does not make FANCL the isolated dimerization factor, and its measured architecture is kept separate from later structural models. The GO definition lists illustrative FA members rather than excluding subsequently discovered FANCL. No new scaffold annotation or all-product equivalence is proposed.

Summary: Independent electronic mappings converge on the experimentally established E3 activity.

Reason: The actual EC 2.3.2.27 definition describes a RING E3 that enables direct transfer from the charged E2 to a substrate lysine, without forming its own catalytic thioester. ARBA00028366 has a matching IPR013083/IPR016135/Mammalia clause and an independently matching three-FunFam clause in Q9NW38. Mouse orthology provides additional evidence, while actual human PMID:19589784 directly supports the chemistry. Retain GO:0061630; the checked children describe histone-specific or ubiquitin-chain activities and are not justified replacements for the demonstrated FA-substrate reaction.

Summary: The GRN (P28799) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to GRN, UniProtKB:P28799. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The CADPS (A2RRN7) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to CADPS, UniProtKB:A2RRN7. The PMID-specific IntAct validated-pair record supports this exact current partner; its historical author-release accession join remains unresolved. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: FANCL associates with SMAD4 in the tested cellular interaction system.

Reason: The exact partner Q13485 is SMAD4, a common mediator SMAD. PMID:35512704 first tests a tagged human-protein BRET library in HEK293T cells, where proximity alone does not establish isolated binary binding. The actual Data S1 Figure ivA page 4 was visually inspected: the FANCL GST-pulldown has a weaker WT-SMAD4 band and a stronger SMAD4-G386D band, with input and GST controls. Table S3B row 23 reports the SMAD4-G386D/FANCL pair positive by GST pulldown in HEK293T and NanoPCA in HCT116; it reports no endogenous-co-IP test for that pair. Thus the inherited blanket claim of exclusively mutant interaction is too strong. Verified GO:0070410 co-SMAD binding is the specific partner-class refinement. Retain the overexpression, mutant-enhancement and cell-context limits: this does not establish constitutive endogenous binding, a FANCL TGF-beta signaling role, SMAD4 ubiquitination, or a core repair function.

Proposed replacements: co-SMAD binding

Summary: Refine the pathway mapping to protein monoubiquitination.

Reason: GO_REF:0000041 maps the historical UniPathway UPA00143 protein-ubiquitination vocabulary; UniPathway is no longer maintained. The target-specific biological process is more precise: FANCL and UBE2T monoubiquitinate FA substrates, directly demonstrated for recombinant human FANCI in PMID:19589784 and supported by the preserved curated FANCD2 sources. GO:0006513 is the is_a descendant for addition of one ubiquitin. Mouse UBE2W discharge/polyubiquitin experiments are preparation-specific and are not silently promoted to a separate established human polyubiquitination pathway.

Proposed replacements: protein monoubiquitination

Summary: Mouse nuclear localization and independent human evidence support the ISS assertion.

Reason: The actual mouse Q9CR14 location assertion cites PMID:21229326. Its Methods specify mouse FANCL constructs; GFP/BiFC experiments show enrichment with UBE2W in nuclei of transfected cells. This is not an endogenous human FANCL experiment. Human HPA nuclear-body images and the curated human FA nuclear-complex model independently corroborate nuclear residence. Additional conditional nucleolar donor observations support retaining nucleus rather than forcing all evidence into nucleoplasm.

Summary: Retain the orthology-supported cytoplasmic pool with its experimental limits.

Reason: Mouse Q9CR14 is the verified donor. PMID:21229326 explicitly separates diffuse nuclear/cytoplasmic FANCL from nuclear enrichment after UBE2W coexpression, and PMID:12574169 reports partner-dependent redistribution of tagged mouse POG in HeLa cells. Human HPA additionally reports vesicular signal. The broad cytoplasmic location is supported but does not itself establish a defined FANCL cytoplasmic reaction or product-specific localization. NC denotes contextual scope, not inactivity or a failed orthology transfer.

Summary: Human PHF9/FANCL has E3 ubiquitin ligase activity.

Reason: The PMID:12973351 original author-hosted main text, Methods and figure captions were read. GST-tagged human PHF9 C-terminal fragments support in vitro autoubiquitination with E1, Ubc4 and ubiquitin; GST/non-RING fragments and C307A/C310A substitutions provide controls. HeLa depletion and EUFA868 patient-cell WT rescue connect FANCL to FANCD2 monoubiquitination and MMC resistance. The C307A cellular mutant also weakens core association, so it is not a clean separation-of-function proof by itself. Historical PHD/WD nomenclature is not substituted for the later RING/URD interpretation. Original figure pixels were not inspected and current natural products were not sequence-matched.

Summary: FANCL is the E3 ligase partner of UBE2T.

Reason: The verified PMID:16916645 abstract identifies FANCL as the ligase subunit and describes UBE2T binding and stimulated ubiquitination. The original full main was not recovered; uninspected W341G-specific conclusions are not repeated. Independent original human PMID:12973351 and purified human PMID:19589784 experiments establish E3 activity, so retain the curator-supported core function while stating the source-access limit.

Summary: FANCL supplies the E3 activity in substrate monoubiquitination.

Reason: The verified PMID:19111657 abstract describes minimal FANCL/UBE2T reconstitution and FANCI-dependent restriction to the FANCD2 acceptor lysine. The original operative main was inaccessible, so no protein-species or control details beyond that abstract are asserted for this source. Independent original human PMID:12973351 and PMID:19589784 establish FANCL E3 chemistry. Retain the curator-supported function without pretending the 2008 main was independently read.

Summary: The source-specific human FANCL chromatin assay remains unresolved.

Reason: The actual PMID:22343915 main Results and supplemental Methods/figure captions were inspected. Human FANCL is positively present in core-complex immunoprecipitations, including endogenous FAAP20 material and tagged FANCL experiments. However, main Figure 5H chromatin fractionation names FANCA, FANCG and FAAP20, with histone H2A control; the inspected supplement does not resolve a FANCL-specific chromatin readout. Independent PMID:17938197 and PMID:26149689 directly assay chicken FANCL chromatin loading. Those conserved results and human complex membership make chromatin association plausible, but do not retrospectively verify this human IDA context. Preserve the curator annotation as UNDECIDED without alleging misattribution, absence or contamination. The old quotation from PMID:17938197 remains unchanged and is not relabelled as human evidence.

Summary: FANCL contributes ubiquitin-transfer chemistry to interstrand cross-link repair.

Reason: PMID:19965384 directly studies replication-coupled interstrand cross-link repair in Xenopus egg extracts. ID2 depletion/rescue and ubiquitination-site comparisons establish pathway function; the article refers to earlier FANCL-depletion observations rather than performing a new human FANCL experiment. Retain the imported NAS annotation with that scope. Independently read human PMID:12973351 and PMID:19589784 establish FANCL's own E3 work in the pathway, beyond mere necessity. FANCL does not acquire the nuclease or translesion-polymerase activities measured downstream in the extract assay.

Summary: Human FANCL is a component of the Fanconi anemia nuclear core complex.

Reason: PMID:22343915 directly detects FANCL in human FAAP20/core-complex co-immunoprecipitation material, with endogenous FAAP20 and reciprocal tagged-core experiments. The supplemental S1 and construct/lysis Methods were inspected; complex coassociation supports membership but is not proof of a purified FANCL–FAAP20 binary interface. The EtBr experiment excludes a DNA bridge for the assayed FANCA–FAAP20 association and should not be overextended to every core pair. This positive complex evidence is distinct from the unresolved FANCL-specific chromatin IDA context of the same paper.

Summary: The human FANCL RING binds the E2 enzyme UBE2T.

Reason: The current partner Q9NPD8 is UBE2T. PMID:24389026 directly examines a human FANCL RING construct and human UBE2T, including the 2.4-angstrom complex structure, interface substitutions and E2-selectivity binding experiments. These establish the specific E2-binding function GO:0031624 more precisely than generic protein binding. The RING fragment and engineered fusion are experimental constructs, not evidence that both natural FANCL products behave identically. The paper's ubiquitination reconstitution uses Xenopus FANCL/FANCD2 with human UBE2T; that functional arm must remain distinct from the human binding arm.

Proposed replacements: ubiquitin conjugating enzyme binding

Summary: The FANCL–UBE2T pair supports substrate monoubiquitination.

Reason: Read PMID:24389026 original structural/binding Results and ubiquitination Methods. The RING–UBE2T binding experiment is human, whereas the functional assay explicitly uses Xenopus tropicalis FANCL and Xenopus laevis FANCD2 with human UBE2T. Retain that species boundary and the experimental construct limits. Conserved reconstitution plus independent purified human FANCL-dependent FANCI ubiquitination in PMID:19589784 supports the human process annotation. The term describes the E3 contribution, not intrinsic FANCL E2 activity or universal equivalence of natural products.

Summary: Retain the explicit cytosolic FANCL participant in the PKR-associated model.

Reason: Reactome:R-HSA-9835411 was traced through FA core:HSP70 input/output assemblies to human Q9NW38 entity 420789, residues 1–375, whose own compartment is cytosol. The summation attributes PKR binding/inhibition chiefly to FANCC and describes FANCA/FANCC/FANCG perturbations; these are not isolated FANCL inhibitor or kinase assays. Preserve the positive modeled location as contextual without calling this pool inactive, converting partner effects into FANCL chemistry, or extrapolating to the 380-residue product.

Summary: Purified human FANCL supports UBE2T-dependent FANCI ubiquitination.

Reason: PMID:19589784 original Methods specify human FANCL cDNA expressed as GST-FANCL in insect cells and human UBE2T expressed in bacteria. The reconstructed reaction uses E1, ATP and ubiquitin; FANCL C307A and UBE2T C86A impair activity. FANCI K523 is the principal tested site, but residual ubiquitination of K523R indicates a secondary in vitro site, so absolute site exclusivity is not claimed. These human purified-protein data directly establish the E3 function, distinct from FANCI's own DNA-binding activity.

Summary: Reactome explicitly places FANCL in nucleoplasm during FA core assembly.

Reason: Reactome:R-HSA-6785126 was independently traced to human Q9NW38 entity 419520, coordinates 1–375, with its own GO:0005654 compartment. FANCL 419520 is a direct input and a component of the DNA-associated output. This supports complex membership and location, not autonomous DNA binding by every subunit. These linked model events are not independent localization experiments. The modeled 375-residue sequence is not evidence that the natural 380-residue splice product has identical activity or distribution.

Summary: Reactome explicitly places FANCL in nucleoplasm during ID2/UBE2T recruitment.

Reason: Reactome:R-HSA-6785342 was independently traced to human Q9NW38 entity 419520, coordinates 1–375, with its own GO:0005654 compartment. FANCL remains in the core-containing input and output. The summation assigns UBE2T recruitment to FANCL; actual human RING–UBE2T binding is independently supported by PMID:21775430 and PMID:24389026. These linked model events are not independent localization experiments. The modeled 375-residue sequence is not evidence that the natural 380-residue splice product has identical activity or distribution.

Summary: Reactome explicitly places FANCL in nucleoplasm during ID2 monoubiquitination.

Reason: Reactome:R-HSA-6785361 was independently traced to human Q9NW38 entity 419520, coordinates 1–375, with its own GO:0005654 compartment. FANCL is reached through the composite catalyst as well as input/output assemblies. Here its E3 role is independently supported by human PMID:19589784; FANCI/FANCD2 are substrates and UBE2T is the E2. These linked model events are not independent localization experiments. The modeled 375-residue sequence is not evidence that the natural 380-residue splice product has identical activity or distribution.

Summary: Reactome explicitly places FANCL in nucleoplasm during nuclease recruitment.

Reason: Reactome:R-HSA-6785732 was independently traced to human Q9NW38 entity 419520, coordinates 1–375, with its own GO:0005654 compartment. FANCL persists in the core-containing input and nuclease-loaded output. The recruited nucleases and ubiquitinated FANCD2 provide the named downstream contacts; complex membership does not establish isolated FANCL–nuclease binding. These linked model events are not independent localization experiments. The modeled 375-residue sequence is not evidence that the natural 380-residue splice product has identical activity or distribution.

Summary: Reactome explicitly places FANCL in nucleoplasm during ICL unhooking.

Reason: Reactome:R-HSA-6785986 was independently traced to human Q9NW38 entity 419520, coordinates 1–375, with its own GO:0005654 compartment. FANCL is present in the input, output and composite catalyst. FAN1 and the other named nucleases perform incision; FANCL is not assigned nuclease activity by its inclusion in that assembly. These linked model events are not independent localization experiments. The modeled 375-residue sequence is not evidence that the natural 380-residue splice product has identical activity or distribution.

Summary: Reactome explicitly places FANCL in nucleoplasm during POLN recruitment.

Reason: Reactome:R-HSA-6786155 was independently traced to human Q9NW38 entity 419520, coordinates 1–375, with its own GO:0005654 compartment. FANCL is a component of the core-containing input and POLN-associated output. The summation describes POLN interaction with FANCD2/PCNA, not direct FANCL polymerase recruitment. These linked model events are not independent localization experiments. The modeled 375-residue sequence is not evidence that the natural 380-residue splice product has identical activity or distribution.

Summary: Reactome explicitly places FANCL in nucleoplasm during POLN translesion synthesis.

Reason: Reactome:R-HSA-6786166 was independently traced to human Q9NW38 entity 419520, coordinates 1–375, with its own GO:0005654 compartment. FANCL is present in input/output and composite catalyst routes, but POLN performs DNA synthesis. The location assertion does not confer polymerase activity on FANCL. These linked model events are not independent localization experiments. The modeled 375-residue sequence is not evidence that the natural 380-residue splice product has identical activity or distribution.

Summary: Reactome explicitly places FANCL in nucleoplasm during FANCD2 deubiquitination.

Reason: Reactome:R-HSA-6786171 was independently traced to human Q9NW38 entity 419520, coordinates 1–375, with its own GO:0005654 compartment. FANCL remains in substrate-associated and output core assemblies. USP1:WDR48 performs deubiquitination; FANCL retains its distinct E3 role. These linked model events are not independent localization experiments. The modeled 375-residue sequence is not evidence that the natural 380-residue splice product has identical activity or distribution.

Summary: Reactome explicitly places FANCL in nucleoplasm during ATR–ATRIP recruitment.

Reason: Reactome:R-HSA-6788385 was independently traced to human Q9NW38 entity 419520, coordinates 1–375, with its own GO:0005654 compartment. FANCL remains in the core-containing input and output. The event reports an ATRIP–FANCL contact, but the cited primary contact assay was not independently reread here; no new binding or checkpoint annotation is proposed. These linked model events are not independent localization experiments. The modeled 375-residue sequence is not evidence that the natural 380-residue splice product has identical activity or distribution.

Summary: Reactome explicitly places FANCL in nucleoplasm during ATR phosphorylation.

Reason: Reactome:R-HSA-6788392 was independently traced to human Q9NW38 entity 419520, coordinates 1–375, with its own GO:0005654 compartment. FANCL appears within input, output and composite catalyst assemblies. ATR phosphorylates the listed substrates; FANCL is neither assigned kinase chemistry nor assumed to be one of those phosphorylation substrates. These linked model events are not independent localization experiments. The modeled 375-residue sequence is not evidence that the natural 380-residue splice product has identical activity or distribution.

Summary: Human FANCL is a component of the Fanconi anemia nuclear core complex.

Reason: PMID:22343915 directly detects FANCL in human FAAP20/core-complex co-immunoprecipitation material, with endogenous FAAP20 and reciprocal tagged-core experiments. The supplemental S1 and construct/lysis Methods were inspected; complex coassociation supports membership but is not proof of a purified FANCL–FAAP20 binary interface. The EtBr experiment excludes a DNA bridge for the assayed FANCA–FAAP20 association and should not be overextended to every core pair. This positive complex evidence is distinct from the unresolved FANCL-specific chromatin IDA context of the same paper.

Summary: FANCL supplies the E3 ligase step of ubiquitin transfer.

Reason: The imported broad ubiquitin-protein transferase term covers the established activity but GO:0061630 specifies FANCL's E3 role. PMID:16916645 has a verified positive abstract; its operative full main was not recovered, so specific uninspected mutant panels or protein-species assignments are not asserted. Independent original PMID:12973351 human PHF9/FANCL autoubiquitination and cellular rescue experiments, and PMID:19589784 purified human FANCL/UBE2T-dependent FANCI ubiquitination, establish the target's catalytic role. UBE2T is the E2, not an activity to transfer to FANCL. This is a refinement of an imported row, not a new redundant annotation.

Proposed replacements: ubiquitin protein ligase activity

Summary: FANCL supplies the E3 ligase step of ubiquitin transfer.

Reason: The imported broad ubiquitin-protein transferase term covers the established activity but GO:0061630 specifies FANCL's E3 role. PMID:19111657 has a verified positive abstract; its operative full main was not recovered, so specific uninspected mutant panels or protein-species assignments are not asserted. Independent original PMID:12973351 human PHF9/FANCL autoubiquitination and cellular rescue experiments, and PMID:19589784 purified human FANCL/UBE2T-dependent FANCI ubiquitination, establish the target's catalytic role. UBE2T is the E2, not an activity to transfer to FANCL. This is a refinement of an imported row, not a new redundant annotation.

Proposed replacements: ubiquitin protein ligase activity

Summary: Refine the supported broad process to FANCL-mediated interstrand cross-link repair.

Reason: DNA repair and DNA damage response remain valid parent processes. Human FANCL/PHF9 depletion and patient-cell complementation in PMID:12973351 connect FANCL to MMC-induced chromosome damage, FANCD2 monoubiquitination and cross-link resistance; purified human FANCL/UBE2T chemistry in PMID:19589784 establishes its performed E3 step. GO:0036297 is therefore the supported specific descendant, consistent with the DNA-repair IBA refinement. The PMID:16916645 abstract's chromosome phenotype concerns UBE2T-depleted cells, and that paper's operative full main remains uninspected; this refinement rests on independently read FANCL experiments, without reassigning the UBE2T phenotype or claiming a generic checkpoint-sensor activity.

Proposed replacements: interstrand cross-link repair

Summary: FANCL catalytically contributes to protein monoubiquitination.

Reason: PMID:16916645 has a positive verified abstract describing UBE2T binding to FANCL and FANCD2 monoubiquitination in vivo. Its full operative experiments were not recovered; the abstract alone does not establish the species and constructs of every assay. Independent original human PHF9/FANCL evidence in PMID:12973351 and purified human FANCL/UBE2T-dependent FANCI ubiquitination in PMID:19589784 establish the target's work in this process. FANCL is the E3 participant rather than merely the ubiquitination substrate.

Summary: Refine the supported broad process to FANCL-mediated interstrand cross-link repair.

Reason: DNA repair and DNA damage response remain valid parent processes. Human FANCL/PHF9 depletion and patient-cell complementation in PMID:12973351 connect FANCL to MMC-induced chromosome damage, FANCD2 monoubiquitination and cross-link resistance; purified human FANCL/UBE2T chemistry in PMID:19589784 establishes its performed E3 step. GO:0036297 is therefore the supported specific descendant, consistent with the DNA-repair IBA refinement. The PMID:16916645 abstract's chromosome phenotype concerns UBE2T-depleted cells, and that paper's operative full main remains uninspected; this refinement rests on independently read FANCL experiments, without reassigning the UBE2T phenotype or claiming a generic checkpoint-sensor activity.

Proposed replacements: interstrand cross-link repair

Summary: FANCL binds the E2 UBE2T, supporting the E2-binding term.

Reason: PMID:16916645 explicitly states UBE2T binding to FANCL in the verified abstract, but the original operative main was inaccessible. Independent human RING–UBE2T structure, mutagenesis and binding/selectivity experiments in PMID:24389026 establish the interaction directly. The imported partner Q9NPD8 is an E2; current GO:0031625 denotes binding an E3, whereas GO:0031624 denotes binding an E2. Refine accordingly without asserting that uninspected W341G panels were read.

Proposed replacements: ubiquitin conjugating enzyme binding

Summary: The UBE2T partnership is best represented as E2 binding.

Reason: The exact partner is UBE2T/Q9NPD8. PMID:17938197 original Methods/Results use chicken DT40 FANCL and UBE2T, with FANCL C305A/C357A mutants: core assembly and chromatin recruitment persist while FANCD2 ubiquitination and resistance phenotypes are impaired. UBE2T chromatin loading is separable, and a transient E2–E3 engagement is the mechanistic interpretation; these results are not a purified human binary binding assay. Independent human PMID:24389026 supplies the directly measured RING–UBE2T interaction. GO:0031624 correctly specifies the E2 partner; no other-species experiment is called human.

Proposed replacements: ubiquitin conjugating enzyme binding

Summary: The source-specific UBE2W interaction remains unresolved.

Reason: This current context names UBE2W/Q96B02, distinct from the UBE2T context of the same PMID. PMID:19111657 is verified, but its operative full main/supplement could not be recovered through the retained finite publisher/author routes. Its abstract positively describes UBE2T/FANCL reconstitution and does not resolve the UBE2W assay. The curated UniProt statement supports the plausibility of UBE2W association; it is not an independent reading of this original target experiment. Retain UNDECIDED without calling the experimental IPI false or assigning UBE2T-specific structural data to UBE2W. If confirmed, the partner class would require E2 binding rather than E3 binding.

Summary: Refine the orthology-derived transferase term to the established E3 activity.

Reason: Mouse Q9CR14 is Fancl, and its IDA source PMID:21229326 directly reports FANCL-dependent stimulation of ubiquitin discharge from UBE2W in vitro. Its truncation/autoubiquitination tests and human-cell UBE2W perturbations are distinct experiments. Independent recombinant human FANCL/UBE2T assays in PMID:19589784 establish substrate monoubiquitination, supporting GO:0061630 instead of its broader transferase parent. No equivalence of the two natural human products is inferred.

Proposed replacements: ubiquitin protein ligase activity

Summary: Human FANCL is recovered with the Fanconi anemia core complex.

Reason: PMID:20347428 original Methods and Results recover human FANCL with FANCM-associated nuclear material from HeLa cells, using mass spectrometry/immunoblots and reciprocal MHF1-associated material. These target-level positive data support core-complex membership. The majority of MHF/FANCM is separable from core-complex material, so this does not imply all molecules form one constitutive stoichiometric assembly or that FANCL inherits MHF DNA-binding activity.

Summary: Retain conserved ELF-domain ubiquitin binding as the inherited ISS proposal.

Reason: Retain the existing GO:0043130 proposal with corrected evidence scope. PMID:26149689 directly measures Drosophila FANCL/ELF binding to free ubiquitin (ITC dissociation constant 42 ± 12 micromolar), maps the ubiquitin Ile44-facing surface by NMR and tests a folded binding-defective ELF mutant. This is not the only species evidence: Xenopus tropicalis FANCL binds ubiquitin, with N72R impairing binding, and chicken DT40 TAP-FANCL binds WT ubiquitin with dependence on its Ile44 patch; ELF-interface mutants lose this association and impair/delay FANCD2/FANCI monoubiquitination while core association and chromatin loading persist. Human soluble FANCL was problematic and no direct human binding measurement was established. ISS therefore remains appropriate for the inferred conserved human activity; it must not become human IDA. ELF ubiquitin recognition is distinct from RING-mediated E2 recruitment and catalysis: the assayed ELF defect does not abolish purified E2 binding/discharge or in vitro FANCD2 monoubiquitination. This is a molecular binding proposal, not a new process inferred from necessity. Generic imported protein-binding rows are retained as their own experimental contexts; no additional ancestor or descendant ubiquitin-binding proposal is added. Both historical quotations remain at their original paths and reference associations.

Summary: The TFCP2 (Q12800) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to TFCP2, UniProtKB:Q12800. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The RBM45 (Q8IUH3) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to RBM45, UniProtKB:Q8IUH3. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The IHO1 (Q8IYA8) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to IHO1, UniProtKB:Q8IYA8. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The DOCK8 (Q8NF50-2) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to DOCK8, UniProtKB:Q8NF50-2. The PMID-specific IntAct validated-pair record supports this exact current partner; its historical author-release accession join remains unresolved. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The LZTS2 (Q9BRK4) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to LZTS2, UniProtKB:Q9BRK4. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The KIFC3 (Q9BVG8) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to KIFC3, UniProtKB:Q9BVG8. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The EIF4ENIF1 (Q9NRA8) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to EIF4ENIF1, UniProtKB:Q9NRA8. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The CHCHD3 (Q9NX63) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to CHCHD3, UniProtKB:Q9NX63. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The RIMBP3 (Q9UFD9) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to RIMBP3, UniProtKB:Q9UFD9. The PMID-specific IntAct validated-pair record supports this exact current partner; its historical author-release accession join remains unresolved. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The IKZF3 (Q9UKT9) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to IKZF3, UniProtKB:Q9UKT9. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The SSX2IP (Q9Y2D8) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to SSX2IP, UniProtKB:Q9Y2D8. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The METTL15 (A6NJ78-4) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to METTL15, UniProtKB:A6NJ78-4. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The CYSRT1 (A8MQ03) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to CYSRT1, UniProtKB:A8MQ03. The PMID-specific IntAct validated-pair record supports this exact current partner; its historical author-release accession join remains unresolved. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The ARHGEF9 (O43307) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to ARHGEF9, UniProtKB:O43307. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The DDAH2 (O95865) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to DDAH2, UniProtKB:O95865. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The HOXD4 (P09016) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to HOXD4, UniProtKB:P09016. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The GATA1 (P15976-2) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to GATA1, UniProtKB:P15976-2. The PMID-specific IntAct validated-pair record supports this exact current partner; its historical author-release accession join remains unresolved. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The PSMB3 (P49720) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to PSMB3, UniProtKB:P49720. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The ID2 (Q02363) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to ID2, UniProtKB:Q02363. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”. ID2 here is inhibitor of DNA binding 2 (Q02363), distinct from the FANCI–FANCD2 repair complex.

Summary: The ANKRD55 (Q3KP44) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to ANKRD55, UniProtKB:Q3KP44. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The KRTAP19-6 (Q3LI70) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to KRTAP19-6, UniProtKB:Q3LI70. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The KRTAP13-2 (Q52LG2) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to KRTAP13-2, UniProtKB:Q52LG2. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The ACTMAP (Q5BKX5-3) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to ACTMAP, UniProtKB:Q5BKX5-3. The PMID-specific IntAct validated-pair record supports this exact current partner; its historical author-release accession join remains unresolved. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The CERCAM (Q5T4B2) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to CERCAM, UniProtKB:Q5T4B2. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The TTC23 (Q5W5X9-3) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to TTC23, UniProtKB:Q5W5X9-3. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The CYB5R2 (Q6BCY4-2) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to CYB5R2, UniProtKB:Q6BCY4-2. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The UFSP1 (Q6NVU6) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to UFSP1, UniProtKB:Q6NVU6. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The ZNF774 (Q6NX45) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to ZNF774, UniProtKB:Q6NX45. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The MORN3 (Q6PF18) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to MORN3, UniProtKB:Q6PF18. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The KRTAP11-1 (Q8IUC1) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to KRTAP11-1, UniProtKB:Q8IUC1. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The SRGAP3 (Q8IXS7) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to SRGAP3, UniProtKB:Q8IXS7. The PMID-specific IntAct validated-pair record supports this exact current partner; its historical author-release accession join remains unresolved. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The SNF8 (Q96H20) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to SNF8, UniProtKB:Q96H20. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The ANTKMT (Q9BQD7) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to ANTKMT, UniProtKB:Q9BQD7. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The HDHD3 (Q9BSH5) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to HDHD3, UniProtKB:Q9BSH5. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The KIFC3 (Q9BVG8-5) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to KIFC3, UniProtKB:Q9BVG8-5. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The SCNM1 (Q9BWG6) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to SCNM1, UniProtKB:Q9BWG6. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The CTDSP1 (Q9GZU7) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to CTDSP1, UniProtKB:Q9GZU7. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The CHCHD3 (Q9NX63) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to CHCHD3, UniProtKB:Q9NX63. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The ZNF224 (Q9NZL3) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to ZNF224, UniProtKB:Q9NZL3. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The ZNF581 (Q9P0T4) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to ZNF581, UniProtKB:Q9P0T4. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The ZMAT5 (Q9UDW3) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to ZMAT5, UniProtKB:Q9UDW3. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: The RNF11 (Q9Y3C5) screen interaction is retained as non-core.

Reason: Human-protein Y2H supports FANCL binding to RNF11, UniProtKB:Q9Y3C5. The PMID-specific IntAct validated-pair record and author-release FANCL pair records support this partner; a base-accession match does not establish current isoform identity. Retain as non-core experimental binding; shared screen methods and physiological limits are in FANCL-source-guide.md, “Screen evidence boundaries”.

Summary: Partner-dependent mouse FANCL redistribution is positive, but exact nuclear-envelope localization remains unresolved.

Reason: The mouse Q9CR14 donor traces to PMID:12574169 and GGN/PR:Q80WJ1. The recovered original Methods, Results and Figure 6 caption show tagged mouse POG/FANCL co-localizing with coexpressed GGN1 in a perinuclear pattern in HeLa cells. This is positive conditional localization evidence. However, the Discussion infers GGN1 nuclear-membrane topology from sequence and localization; it does not experimentally distinguish the nuclear envelope from nearby structures. GGN1 colocalization therefore does not independently resolve that compartment. GO:0005635 requires the nuclear envelope, while a replacement with GO:0048471 would specifically assert cytoplasm, also unresolved here. Keep the precise human orthology inference undecided, without rejecting the donor experiment or requiring FANCL itself to span a membrane. Endogenous human localization, natural-product equivalence and figure pixels remain unverified; complete operative text is available and was read.

Summary: The separate UBE2T context supports specific E2 binding.

Reason: The exact current partner Q9NPD8 is UBE2T, distinct from UBE2W/Q96B02 in current77. PMID:19111657 has a verified positive reconstitution abstract, but its full operative source was not recovered. Independently read human PMID:24389026 directly establishes FANCL RING–UBE2T binding. The verified GO:0031624 definition names E2 binding, while imported GO:0031625 names E3 binding. This positive human corroboration supports refinement for this context without resolving the separate UBE2W experiment.

Proposed replacements: ubiquitin conjugating enzyme binding