{"gene":"CCNF","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2016,"finding":"Cyclin F is a component of an SCF(Cyclin F) E3 ubiquitin-protein ligase complex; expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and an SCF(Cyclin F) substrate, implicating protein homeostasis disruption in neurodegeneration.","method":"Transfection of mutant CCNF in neuronal cells, ubiquitination assays, identification of ubiquitinated substrates","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional assay in neuronal cells, substrate identification, replicated across multiple subsequent studies","pmids":["27080313"],"is_preprint":false},{"year":2017,"finding":"ALS/FTD-causing mutant cyclin F (S621G) causes increased Lys48-specific ubiquitylation in neuronal cells, and proteomic analysis identified p62/SQSTM1 and autophagy-related proteins as elevated Lys48-ubiquitylated substrates; mutant cyclin F impairs autophagosome-lysosome fusion and cyclin F physically interacts with p62.","method":"Transfection in Neuro-2A and SH-SY5Y cells, Lys48-specific ubiquitylation assays, immunoprecipitation of Lys48-ubiquitylated proteins, proteomics, autophagy marker analysis (p62, LC3, Lamp2)","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, Co-IP, autophagy markers), single lab","pmids":["28852778"],"is_preprint":false},{"year":2017,"finding":"Cyclin F (FBXO1) physically interacts with HIV-1 Vif protein and mediates its ubiquitination and proteasomal degradation through the SCF(Cyclin F) E3 ligase machinery, thereby restoring APOBEC3G expression and reducing progeny virion infectivity; a cyclin F-specific C-terminal motif in Vif is required for this interaction.","method":"Co-immunoprecipitation, gene overexpression and knockdown, ubiquitination assays, mutational analysis of Vif degron motif, APOBEC3G expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutational analysis of binding motif, and functional ubiquitination assay in single lab with multiple orthogonal methods","pmids":["28184007"],"is_preprint":false},{"year":2017,"finding":"ALS-linked CCNF mutations disrupt cellular pathways including caspase-3-mediated apoptosis; mutant CCNF expression in zebrafish caused increased activated caspase-3, increased spinal cord cell death, shortened primary motor axons, and aberrant axonal branching.","method":"Proteomic analysis of in vitro models, transient overexpression of human CCNF in zebrafish embryos, immunostaining for cleaved caspase-3, motor axon morphology assessment, photomotor response assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo zebrafish model with multiple readouts and in vitro proteomics, single lab","pmids":["28444311"],"is_preprint":false},{"year":2017,"finding":"Two novel ALS-associated CCNF missense mutations (p.S222P and p.S532R) result in dysfunction of the cyclin F-mediated ubiquitin-proteasome pathway in vitro.","method":"In vitro functional studies of ubiquitin-proteasome pathway activity with mutant CCNF constructs","journal":"Neurobiology of aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited methodological detail in abstract","pmids":["29102476"],"is_preprint":false},{"year":2019,"finding":"Cyclin F binds to VCP (valosin-containing protein) via its N-terminal region and colocalizes with VCP in the nucleus; VCP is not ubiquitylated by SCF(Cyclin F) but instead its ATPase activity is enhanced by Cyclin F in vitro; ALS-associated CCNF mutations increase Cyclin F binding to VCP, enhance VCP ATPase activity, cause cytoplasmic mislocalization of Cyclin F, and promote cytoplasmic TDP-43 aggregation.","method":"Co-immunoprecipitation, deletion mapping, in vitro ATPase assay, subcellular fractionation/localization, transfection experiments, TDP-43 aggregation assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ATPase assay combined with Co-IP, deletion mapping, and localization studies; multiple orthogonal methods in single study","pmids":["31577344"],"is_preprint":false},{"year":2021,"finding":"Cyclin F is targeted for proteasomal degradation by FBXL8 and FZR1 E3 ligases (both pull down CCNF; double knockdown causes CCNF accumulation); CCNF itself pulls down RRM2 and CCNF overexpression reduces RRM2 protein levels, indicating RRM2 is a substrate of SCF(Cyclin F).","method":"Pulldown assays, double knockdown experiments, overexpression studies, protein level analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pulldown and knockdown with functional protein level readouts, single lab, two orthogonal methods","pmids":["34201347"],"is_preprint":false},{"year":2021,"finding":"Multiple ALS-linked CCNF mutations (K97R, S195R, S509P, R574Q, S621G) activate apoptosis pathways in HEK293 cells and iPSC-derived cells, as revealed by label-free quantitative proteomics and validated by immunoblot.","method":"Label-free quantitative proteomics of HEK293 cells and patient-derived iPSCs, immunoblot validation","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus immunoblot validation, two cell models, single lab","pmids":["33986643"],"is_preprint":false},{"year":2023,"finding":"ALS-linked CCNF S621G mutation causes ubiquitin-proteasome system dysfunction in iPSC-derived motor neurons; both wild-type and S621G CCNF overexpression alter free ubiquitin levels; double mutants designed to abolish E3 ligase complex formation improved UPS function and increased free monomeric ubiquitin, demonstrating that SCF(Cyclin F) ligase activity is required for normal ubiquitin homeostasis.","method":"iPSC-derived motor neuron model, proteasome activity assays, ubiquitin level measurement, overexpression of E3 ligase-dead double mutants in NSC-34 cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSC-derived neurons plus mechanistic mutagenesis rescue experiments, single lab","pmids":["37220877"],"is_preprint":false},{"year":2023,"finding":"FBXO1 (Cyclin F) binds E2F1, E2F2, and E2F3a through R/I and R/V degron motifs in their dimerization domains and mediates K48-linked ubiquitination and proteasomal degradation of these transcription factors; MEK/ERK signaling-mediated phosphorylation of threonine residues near these motifs regulates the FBXO1-E2F interaction and E2F protein stability, thereby controlling G1/S cell cycle transition.","method":"Co-immunoprecipitation, ubiquitination assays, half-life measurement, binding domain/degron mutagenesis (RI/AA, RV/AA), specific kinase inhibitor analysis, FBXO1 knockdown, cell cycle analysis","journal":"Archives of pharmacal research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination assay, mutagenesis, half-life, cell cycle readout), single lab but rigorous mechanistic dissection","pmids":["36607545"],"is_preprint":false},{"year":2024,"finding":"Loss of ccnf in zebrafish (CRISPR/TALEN knockout) causes abnormal motor neuron development and axonal outgrowth defects, and ccnf-deficient zebrafish are specifically sensitized to endoplasmic reticulum stress, identifying a role for CCNF in motor neuron development and ER stress response.","method":"CRISPR/Cas9 and TALEN-mediated genome editing in zebrafish, motor neuron morphology analysis, stress response assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function model with defined cellular phenotype and stress-pathway readout, single lab","pmids":["38474336"],"is_preprint":false},{"year":2026,"finding":"Endogenous knock-in CcnfS621G mice (generated by CRISPR/Cas9) show no motor decline or neuronal loss at 18 months but display increased hippocampal astrocyte ramification; CCNFS621G iPSC-derived astrocytes exhibit impaired mitochondrial membrane potential and altered network morphology; CCNFS621G astrocytes suppress repetitive motor neuron firing, reduce voltage-gated sodium currents, and increase the proportion of neurons unable to fire action potentials when co-cultured with motor neurons, demonstrating a non-cell-autonomous astrocyte-driven mechanism.","method":"CRISPR/Cas9 knock-in mouse model, immunohistochemistry, proteomics, iPSC-derived astrocyte and motor neuron co-culture, mitochondrial membrane potential assay, electrophysiology (action potential and voltage-gated sodium current recording)","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — endogenous knock-in model plus iPSC-derived cells, multiple orthogonal methods including electrophysiology and proteomics, single lab","pmids":["42069601"],"is_preprint":false},{"year":1994,"finding":"CCNF encodes a new member of the cyclin family (Cyclin F) located on chromosome 16p13.3; it is related to A- and B-type cyclins by sequence; its function was not determined at this time.","method":"cDNA sequencing, exon-intron boundary determination, Northern blot analysis","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — characterization of transcript structure only, no functional mechanism established","pmids":["7896286"],"is_preprint":false}],"current_model":"Cyclin F (CCNF/FBXO1) is the substrate-recognition subunit of the SCF(Cyclin F) E3 ubiquitin ligase complex, which mediates K48-linked ubiquitination and proteasomal degradation of substrates including E2F1/2/3a (regulated by MEK/ERK-mediated phosphorylation of degron motifs) and viral Vif protein; it also enhances VCP ATPase activity through direct N-terminal binding and colocalizes with VCP in the nucleus; ALS/FTD-associated mutations cause cytoplasmic mislocalization of Cyclin F, elevated VCP ATPase activity, disrupted Lys48 ubiquitylation homeostasis (including impaired autophagosome-lysosome fusion), UPS dysfunction, caspase-3-mediated apoptosis, and—via a non-cell-autonomous astrocyte mechanism—suppression of motor neuron excitability."},"narrative":{"mechanistic_narrative":"Cyclin F (CCNF/FBXO1) is the substrate-recognition subunit of an SCF(Cyclin F) E3 ubiquitin ligase that controls protein homeostasis through K48-linked ubiquitination and proteasomal turnover of its substrates [PMID:27080313, PMID:36607545]. It binds the E2F1/E2F2/E2F3a transcription factors via R/I and R/V degron motifs in their dimerization domains and targets them for K48-linked degradation, with MEK/ERK-mediated phosphorylation near these degrons regulating the interaction and thereby gating the G1/S cell cycle transition [PMID:36607545]; it also recognizes RRM2 as a substrate [PMID:34201347] and, in an antiviral role, binds and degrades HIV-1 Vif through a Vif C-terminal motif to restore APOBEC3G and suppress virion infectivity [PMID:28184007]. Beyond its ligase activity, Cyclin F directly binds VCP through its N-terminal region and colocalizes with VCP in the nucleus, enhancing VCP ATPase activity without ubiquitylating it [PMID:31577344]. Cyclin F is itself a degradation target of the FBXL8 and FZR1 ligases [PMID:34201347]. ALS/FTD-associated CCNF mutations (notably S621G) disrupt this homeostatic machinery: they drive cytoplasmic mislocalization of Cyclin F, increase VCP ATPase activity, promote cytoplasmic TDP-43 aggregation, and perturb Lys48-ubiquitylation and free-ubiquitin balance in a manner requiring intact SCF ligase activity [PMID:27080313, PMID:31577344, PMID:37220877]. Mutant Cyclin F impairs autophagosome-lysosome fusion and physically interacts with p62/SQSTM1 [PMID:28852778], activates caspase-3-mediated apoptosis [PMID:28444311, PMID:33986643], and—through a non-cell-autonomous astrocyte mechanism—suppresses motor neuron excitability and sodium currents [PMID:42069601], establishing CCNF as a causative gene in ALS/FTD pathogenesis.","teleology":[{"year":1994,"claim":"Established CCNF as a distinct cyclin-family gene, defining the molecule whose function would later be dissected.","evidence":"cDNA sequencing and Northern blot mapping CCNF to chromosome 16p13.3","pmids":["7896286"],"confidence":"Low","gaps":["No functional mechanism established","No substrates or complex membership defined"]},{"year":2016,"claim":"Connected CCNF to neurodegeneration by showing mutant Cyclin F disrupts ubiquitination homeostasis, addressing how an SCF subunit could drive disease.","evidence":"Transfection of mutant CCNF in neuronal cells with ubiquitination and substrate-accumulation assays","pmids":["27080313"],"confidence":"High","gaps":["Did not resolve which degradation steps are directly impaired","Causal substrate spectrum not fully defined"]},{"year":2017,"claim":"Defined the consequences of mutant Cyclin F on autophagy and on a viral substrate, broadening the substrate landscape of SCF(Cyclin F).","evidence":"Lys48-ubiquitylation proteomics, Co-IP with p62 and autophagy-marker analysis (Neuro-2A/SH-SY5Y); Co-IP, degron mutagenesis, and ubiquitination assays for HIV-1 Vif; zebrafish caspase-3 and motor-axon readouts","pmids":["28852778","28184007","28444311","29102476"],"confidence":"Medium","gaps":["Mechanistic link between autophagy block and ligase activity not isolated","Vif degradation not validated beyond a single lab","Apoptosis readouts correlative in some models"]},{"year":2019,"claim":"Identified a ligase-independent function of Cyclin F as a VCP ATPase enhancer and tied mutation-driven mislocalization to TDP-43 aggregation.","evidence":"Co-IP, deletion mapping, in vitro ATPase assay, subcellular fractionation, and TDP-43 aggregation assays","pmids":["31577344"],"confidence":"High","gaps":["Physiological role of VCP enhancement in vivo unclear","How elevated VCP activity causes TDP-43 mislocalization not mechanistically resolved"]},{"year":2021,"claim":"Placed Cyclin F within its own regulatory turnover circuit and added RRM2 as a substrate, clarifying upstream control of Cyclin F levels.","evidence":"Pulldown and double-knockdown of FBXL8/FZR1, plus RRM2 pulldown and overexpression protein-level analysis","pmids":["34201347"],"confidence":"Medium","gaps":["Direct ubiquitination of Cyclin F by FBXL8/FZR1 not shown","RRM2 ubiquitination not directly demonstrated"]},{"year":2021,"claim":"Generalized mutation-driven apoptosis activation across multiple ALS variants and patient-derived cells.","evidence":"Label-free quantitative proteomics in HEK293 and iPSC-derived cells with immunoblot validation","pmids":["33986643"],"confidence":"Medium","gaps":["Causal chain from UPS disruption to apoptosis not defined","Single lab"]},{"year":2023,"claim":"Demonstrated that SCF(Cyclin F) ligase activity is required for ubiquitin homeostasis and mapped the E2F degron mechanism, linking Cyclin F to both proteostasis and cell-cycle control.","evidence":"iPSC-derived motor neurons with ligase-dead rescue mutants and proteasome/free-ubiquitin assays; Co-IP, degron mutagenesis, half-life, kinase-inhibitor and cell-cycle analyses for E2F1/2/3a","pmids":["37220877","36607545"],"confidence":"High","gaps":["In vivo relevance of E2F regulation in neurons not established","How MEK/ERK signaling intersects disease mutations unknown"]},{"year":2024,"claim":"Established an endogenous developmental requirement for CCNF in motor neurons and a specific sensitivity to ER stress via loss-of-function.","evidence":"CRISPR/TALEN ccnf knockout in zebrafish with motor neuron morphology and stress-response assays","pmids":["38474336"],"confidence":"Medium","gaps":["Molecular link between Cyclin F and ER stress pathway unresolved","Relationship of loss-of-function to gain-of-function mutant phenotypes unclear"]},{"year":2026,"claim":"Revealed a non-cell-autonomous astrocyte mechanism by which the S621G mutation suppresses motor neuron excitability, reframing CCNF pathology beyond neuron-intrinsic effects.","evidence":"CRISPR knock-in CcnfS621G mice, iPSC-derived astrocyte/motor-neuron co-culture, mitochondrial and electrophysiology assays","pmids":["42069601"],"confidence":"High","gaps":["Knock-in mice lack overt motor decline at 18 months","Astrocyte-secreted mediator suppressing neuron firing not identified"]},{"year":null,"claim":"The molecular bridge linking Cyclin F's ligase and VCP-enhancing activities to the cell-type-specific neurodegenerative cascade remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting substrate dysregulation, VCP hyperactivity, and astrocyte dysfunction","The full physiological substrate repertoire of SCF(Cyclin F) is incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,9]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,8,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,11]}],"complexes":["SCF(Cyclin F)"],"partners":["VCP","SQSTM1","E2F1","E2F2","E2F3","RRM2","FBXL8","FZR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P41002","full_name":"Cyclin-F","aliases":["F-box only protein 1"],"length_aa":786,"mass_kda":87.6,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:20596027, PubMed:22632967, PubMed:26818844, PubMed:27080313, PubMed:27653696, PubMed:28852778). The SCF(CCNF) E3 ubiquitin-protein ligase complex is an integral component of the ubiquitin proteasome system (UPS) and links proteasome degradation to the cell cycle (PubMed:20596027, PubMed:26818844, PubMed:27653696, PubMed:8706131). Mediates the substrate recognition and the proteasomal degradation of various target proteins involved in the regulation of cell cycle progression and in the maintenance of genome stability (PubMed:20596027, PubMed:22632967, PubMed:26818844, PubMed:27653696). Mediates the ubiquitination and proteasomal degradation of CP110 during G2 phase, thereby acting as an inhibitor of centrosome reduplication (PubMed:20596027). In G2, mediates the ubiquitination and subsequent degradation of ribonucleotide reductase RRM2, thereby maintaining a balanced pool of dNTPs and genome integrity (PubMed:22632967). In G2, mediates the ubiquitination and proteasomal degradation of CDC6, thereby suppressing DNA re-replication and preventing genome instability (PubMed:26818844). Involved in the ubiquitination and degradation of the substrate adapter CDH1 of the anaphase-promoting complex (APC/C), thereby acting as an antagonist of APC/C in regulating G1 progression and S phase entry (PubMed:27653696). May play a role in the G2 cell cycle checkpoint control after DNA damage, possibly by promoting the ubiquitination of MYBL2/BMYB (PubMed:25557911)","subcellular_location":"Nucleus; Cytoplasm, perinuclear region; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/P41002/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNF","classification":"Not Classified","n_dependent_lines":104,"n_total_lines":1208,"dependency_fraction":0.08609271523178808},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCNF","total_profiled":1310},"omim":[{"mim_id":"619141","title":"FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 5; FTDALS5","url":"https://www.omim.org/entry/619141"},{"mim_id":"607112","title":"F-BOX ONLY PROTEIN 2; FBXO2","url":"https://www.omim.org/entry/607112"},{"mim_id":"605657","title":"LYSINE DEMETHYLASE 2A; KDM2A","url":"https://www.omim.org/entry/605657"},{"mim_id":"605656","title":"F-BOX AND LEUCINE-RICH REPEAT PROTEIN 7; FBXL7","url":"https://www.omim.org/entry/605656"},{"mim_id":"605655","title":"F-BOX AND LEUCINE-RICH REPEAT PROTEIN 5; FBXL5","url":"https://www.omim.org/entry/605655"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":14.1}],"url":"https://www.proteinatlas.org/search/CCNF"},"hgnc":{"alias_symbol":["FBX1","FBXO1"],"prev_symbol":[]},"alphafold":{"accession":"P41002","domains":[{"cath_id":"-","chopping":"79-225","consensus_level":"high","plddt":90.1878,"start":79,"end":225},{"cath_id":"-","chopping":"237-283","consensus_level":"medium","plddt":86.5538,"start":237,"end":283},{"cath_id":"1.10.472.10","chopping":"291-408","consensus_level":"medium","plddt":94.0562,"start":291,"end":408},{"cath_id":"1.10.472.10","chopping":"409-544","consensus_level":"medium","plddt":94.0223,"start":409,"end":544}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P41002","model_url":"https://alphafold.ebi.ac.uk/files/AF-P41002-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P41002-F1-predicted_aligned_error_v6.png","plddt_mean":71.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCNF","jax_strain_url":"https://www.jax.org/strain/search?query=CCNF"},"sequence":{"accession":"P41002","fasta_url":"https://rest.uniprot.org/uniprotkb/P41002.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P41002/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P41002"}},"corpus_meta":[{"pmid":"27080313","id":"PMC_27080313","title":"CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27080313","citation_count":179,"is_preprint":false},{"pmid":"28852778","id":"PMC_28852778","title":"Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy.","date":"2017","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/28852778","citation_count":44,"is_preprint":false},{"pmid":"28444311","id":"PMC_28444311","title":"Expression of ALS/FTD-linked mutant CCNF in zebrafish leads to increased cell death in the spinal cord and an aberrant motor phenotype.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28444311","citation_count":40,"is_preprint":false},{"pmid":"31577344","id":"PMC_31577344","title":"Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity.","date":"2019","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31577344","citation_count":28,"is_preprint":false},{"pmid":"28184007","id":"PMC_28184007","title":"Cyclin F/FBXO1 Interacts with HIV-1 Viral Infectivity Factor (Vif) and Restricts Progeny Virion Infectivity by Ubiquitination and Proteasomal Degradation of Vif Protein through SCFcyclin F E3 Ligase Machinery.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28184007","citation_count":25,"is_preprint":false},{"pmid":"29102476","id":"PMC_29102476","title":"Investigating CCNF mutations in a Taiwanese cohort with amyotrophic lateral sclerosis.","date":"2017","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/29102476","citation_count":17,"is_preprint":false},{"pmid":"34201347","id":"PMC_34201347","title":"A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast 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Apoptosis Pathway: A Workflow to Screen Pathogenic Gene Mutations.","date":"2021","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33986643","citation_count":14,"is_preprint":false},{"pmid":"7896286","id":"PMC_7896286","title":"A novel cyclin gene (CCNF) in the region of the polycystic kidney disease gene (PKD1).","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7896286","citation_count":14,"is_preprint":false},{"pmid":"36607545","id":"PMC_36607545","title":"MEKs/ERKs-mediated FBXO1/E2Fs interaction interference modulates G1/S cell cycle transition and cancer cell proliferation.","date":"2023","source":"Archives of pharmacal research","url":"https://pubmed.ncbi.nlm.nih.gov/36607545","citation_count":9,"is_preprint":false},{"pmid":"31445393","id":"PMC_31445393","title":"Generation and characterization of a human induced pluripotent stem cell line UOWi005-A from dermal fibroblasts derived from a CCNFS621G familial amyotrophic 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Patients.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39766833","citation_count":0,"is_preprint":false},{"pmid":"42069601","id":"PMC_42069601","title":"ALS-FTD-linked CCNFS621G drives increased hippocampal astrocyte ramification and mitochondrial dysfunction and impairs motor neuron excitability.","date":"2026","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/42069601","citation_count":0,"is_preprint":false},{"pmid":"41069067","id":"PMC_41069067","title":"Expanding the genetic spectrum of corticobasal syndrome: novel CCNF p.M394L variant from a South Asian cohort.","date":"2025","source":"Neurocase","url":"https://pubmed.ncbi.nlm.nih.gov/41069067","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13673,"output_tokens":3417,"usd":0.046137,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10957,"output_tokens":3382,"usd":0.069667,"stage2_stop_reason":"end_turn"},"total_usd":0.115804,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Cyclin F is a component of an SCF(Cyclin F) E3 ubiquitin-protein ligase complex; expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and an SCF(Cyclin F) substrate, implicating protein homeostasis disruption in neurodegeneration.\",\n      \"method\": \"Transfection of mutant CCNF in neuronal cells, ubiquitination assays, identification of ubiquitinated substrates\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional assay in neuronal cells, substrate identification, replicated across multiple subsequent studies\",\n      \"pmids\": [\"27080313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ALS/FTD-causing mutant cyclin F (S621G) causes increased Lys48-specific ubiquitylation in neuronal cells, and proteomic analysis identified p62/SQSTM1 and autophagy-related proteins as elevated Lys48-ubiquitylated substrates; mutant cyclin F impairs autophagosome-lysosome fusion and cyclin F physically interacts with p62.\",\n      \"method\": \"Transfection in Neuro-2A and SH-SY5Y cells, Lys48-specific ubiquitylation assays, immunoprecipitation of Lys48-ubiquitylated proteins, proteomics, autophagy marker analysis (p62, LC3, Lamp2)\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, Co-IP, autophagy markers), single lab\",\n      \"pmids\": [\"28852778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cyclin F (FBXO1) physically interacts with HIV-1 Vif protein and mediates its ubiquitination and proteasomal degradation through the SCF(Cyclin F) E3 ligase machinery, thereby restoring APOBEC3G expression and reducing progeny virion infectivity; a cyclin F-specific C-terminal motif in Vif is required for this interaction.\",\n      \"method\": \"Co-immunoprecipitation, gene overexpression and knockdown, ubiquitination assays, mutational analysis of Vif degron motif, APOBEC3G expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutational analysis of binding motif, and functional ubiquitination assay in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28184007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ALS-linked CCNF mutations disrupt cellular pathways including caspase-3-mediated apoptosis; mutant CCNF expression in zebrafish caused increased activated caspase-3, increased spinal cord cell death, shortened primary motor axons, and aberrant axonal branching.\",\n      \"method\": \"Proteomic analysis of in vitro models, transient overexpression of human CCNF in zebrafish embryos, immunostaining for cleaved caspase-3, motor axon morphology assessment, photomotor response assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo zebrafish model with multiple readouts and in vitro proteomics, single lab\",\n      \"pmids\": [\"28444311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Two novel ALS-associated CCNF missense mutations (p.S222P and p.S532R) result in dysfunction of the cyclin F-mediated ubiquitin-proteasome pathway in vitro.\",\n      \"method\": \"In vitro functional studies of ubiquitin-proteasome pathway activity with mutant CCNF constructs\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited methodological detail in abstract\",\n      \"pmids\": [\"29102476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cyclin F binds to VCP (valosin-containing protein) via its N-terminal region and colocalizes with VCP in the nucleus; VCP is not ubiquitylated by SCF(Cyclin F) but instead its ATPase activity is enhanced by Cyclin F in vitro; ALS-associated CCNF mutations increase Cyclin F binding to VCP, enhance VCP ATPase activity, cause cytoplasmic mislocalization of Cyclin F, and promote cytoplasmic TDP-43 aggregation.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, in vitro ATPase assay, subcellular fractionation/localization, transfection experiments, TDP-43 aggregation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ATPase assay combined with Co-IP, deletion mapping, and localization studies; multiple orthogonal methods in single study\",\n      \"pmids\": [\"31577344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cyclin F is targeted for proteasomal degradation by FBXL8 and FZR1 E3 ligases (both pull down CCNF; double knockdown causes CCNF accumulation); CCNF itself pulls down RRM2 and CCNF overexpression reduces RRM2 protein levels, indicating RRM2 is a substrate of SCF(Cyclin F).\",\n      \"method\": \"Pulldown assays, double knockdown experiments, overexpression studies, protein level analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown and knockdown with functional protein level readouts, single lab, two orthogonal methods\",\n      \"pmids\": [\"34201347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Multiple ALS-linked CCNF mutations (K97R, S195R, S509P, R574Q, S621G) activate apoptosis pathways in HEK293 cells and iPSC-derived cells, as revealed by label-free quantitative proteomics and validated by immunoblot.\",\n      \"method\": \"Label-free quantitative proteomics of HEK293 cells and patient-derived iPSCs, immunoblot validation\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus immunoblot validation, two cell models, single lab\",\n      \"pmids\": [\"33986643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALS-linked CCNF S621G mutation causes ubiquitin-proteasome system dysfunction in iPSC-derived motor neurons; both wild-type and S621G CCNF overexpression alter free ubiquitin levels; double mutants designed to abolish E3 ligase complex formation improved UPS function and increased free monomeric ubiquitin, demonstrating that SCF(Cyclin F) ligase activity is required for normal ubiquitin homeostasis.\",\n      \"method\": \"iPSC-derived motor neuron model, proteasome activity assays, ubiquitin level measurement, overexpression of E3 ligase-dead double mutants in NSC-34 cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSC-derived neurons plus mechanistic mutagenesis rescue experiments, single lab\",\n      \"pmids\": [\"37220877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO1 (Cyclin F) binds E2F1, E2F2, and E2F3a through R/I and R/V degron motifs in their dimerization domains and mediates K48-linked ubiquitination and proteasomal degradation of these transcription factors; MEK/ERK signaling-mediated phosphorylation of threonine residues near these motifs regulates the FBXO1-E2F interaction and E2F protein stability, thereby controlling G1/S cell cycle transition.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, half-life measurement, binding domain/degron mutagenesis (RI/AA, RV/AA), specific kinase inhibitor analysis, FBXO1 knockdown, cell cycle analysis\",\n      \"journal\": \"Archives of pharmacal research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination assay, mutagenesis, half-life, cell cycle readout), single lab but rigorous mechanistic dissection\",\n      \"pmids\": [\"36607545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of ccnf in zebrafish (CRISPR/TALEN knockout) causes abnormal motor neuron development and axonal outgrowth defects, and ccnf-deficient zebrafish are specifically sensitized to endoplasmic reticulum stress, identifying a role for CCNF in motor neuron development and ER stress response.\",\n      \"method\": \"CRISPR/Cas9 and TALEN-mediated genome editing in zebrafish, motor neuron morphology analysis, stress response assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function model with defined cellular phenotype and stress-pathway readout, single lab\",\n      \"pmids\": [\"38474336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Endogenous knock-in CcnfS621G mice (generated by CRISPR/Cas9) show no motor decline or neuronal loss at 18 months but display increased hippocampal astrocyte ramification; CCNFS621G iPSC-derived astrocytes exhibit impaired mitochondrial membrane potential and altered network morphology; CCNFS621G astrocytes suppress repetitive motor neuron firing, reduce voltage-gated sodium currents, and increase the proportion of neurons unable to fire action potentials when co-cultured with motor neurons, demonstrating a non-cell-autonomous astrocyte-driven mechanism.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse model, immunohistochemistry, proteomics, iPSC-derived astrocyte and motor neuron co-culture, mitochondrial membrane potential assay, electrophysiology (action potential and voltage-gated sodium current recording)\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — endogenous knock-in model plus iPSC-derived cells, multiple orthogonal methods including electrophysiology and proteomics, single lab\",\n      \"pmids\": [\"42069601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CCNF encodes a new member of the cyclin family (Cyclin F) located on chromosome 16p13.3; it is related to A- and B-type cyclins by sequence; its function was not determined at this time.\",\n      \"method\": \"cDNA sequencing, exon-intron boundary determination, Northern blot analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — characterization of transcript structure only, no functional mechanism established\",\n      \"pmids\": [\"7896286\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Cyclin F (CCNF/FBXO1) is the substrate-recognition subunit of the SCF(Cyclin F) E3 ubiquitin ligase complex, which mediates K48-linked ubiquitination and proteasomal degradation of substrates including E2F1/2/3a (regulated by MEK/ERK-mediated phosphorylation of degron motifs) and viral Vif protein; it also enhances VCP ATPase activity through direct N-terminal binding and colocalizes with VCP in the nucleus; ALS/FTD-associated mutations cause cytoplasmic mislocalization of Cyclin F, elevated VCP ATPase activity, disrupted Lys48 ubiquitylation homeostasis (including impaired autophagosome-lysosome fusion), UPS dysfunction, caspase-3-mediated apoptosis, and—via a non-cell-autonomous astrocyte mechanism—suppression of motor neuron excitability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Cyclin F (CCNF/FBXO1) is the substrate-recognition subunit of an SCF(Cyclin F) E3 ubiquitin ligase that controls protein homeostasis through K48-linked ubiquitination and proteasomal turnover of its substrates [#0, #9]. It binds the E2F1/E2F2/E2F3a transcription factors via R/I and R/V degron motifs in their dimerization domains and targets them for K48-linked degradation, with MEK/ERK-mediated phosphorylation near these degrons regulating the interaction and thereby gating the G1/S cell cycle transition [#9]; it also recognizes RRM2 as a substrate [#6] and, in an antiviral role, binds and degrades HIV-1 Vif through a Vif C-terminal motif to restore APOBEC3G and suppress virion infectivity [#2]. Beyond its ligase activity, Cyclin F directly binds VCP through its N-terminal region and colocalizes with VCP in the nucleus, enhancing VCP ATPase activity without ubiquitylating it [#5]. Cyclin F is itself a degradation target of the FBXL8 and FZR1 ligases [#6]. ALS/FTD-associated CCNF mutations (notably S621G) disrupt this homeostatic machinery: they drive cytoplasmic mislocalization of Cyclin F, increase VCP ATPase activity, promote cytoplasmic TDP-43 aggregation, and perturb Lys48-ubiquitylation and free-ubiquitin balance in a manner requiring intact SCF ligase activity [#0, #5, #8]. Mutant Cyclin F impairs autophagosome-lysosome fusion and physically interacts with p62/SQSTM1 [#1], activates caspase-3-mediated apoptosis [#3, #7], and—through a non-cell-autonomous astrocyte mechanism—suppresses motor neuron excitability and sodium currents [#11], establishing CCNF as a causative gene in ALS/FTD pathogenesis.\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established CCNF as a distinct cyclin-family gene, defining the molecule whose function would later be dissected.\",\n      \"evidence\": \"cDNA sequencing and Northern blot mapping CCNF to chromosome 16p13.3\",\n      \"pmids\": [\"7896286\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional mechanism established\", \"No substrates or complex membership defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CCNF to neurodegeneration by showing mutant Cyclin F disrupts ubiquitination homeostasis, addressing how an SCF subunit could drive disease.\",\n      \"evidence\": \"Transfection of mutant CCNF in neuronal cells with ubiquitination and substrate-accumulation assays\",\n      \"pmids\": [\"27080313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which degradation steps are directly impaired\", \"Causal substrate spectrum not fully defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the consequences of mutant Cyclin F on autophagy and on a viral substrate, broadening the substrate landscape of SCF(Cyclin F).\",\n      \"evidence\": \"Lys48-ubiquitylation proteomics, Co-IP with p62 and autophagy-marker analysis (Neuro-2A/SH-SY5Y); Co-IP, degron mutagenesis, and ubiquitination assays for HIV-1 Vif; zebrafish caspase-3 and motor-axon readouts\",\n      \"pmids\": [\"28852778\", \"28184007\", \"28444311\", \"29102476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between autophagy block and ligase activity not isolated\", \"Vif degradation not validated beyond a single lab\", \"Apoptosis readouts correlative in some models\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a ligase-independent function of Cyclin F as a VCP ATPase enhancer and tied mutation-driven mislocalization to TDP-43 aggregation.\",\n      \"evidence\": \"Co-IP, deletion mapping, in vitro ATPase assay, subcellular fractionation, and TDP-43 aggregation assays\",\n      \"pmids\": [\"31577344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of VCP enhancement in vivo unclear\", \"How elevated VCP activity causes TDP-43 mislocalization not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed Cyclin F within its own regulatory turnover circuit and added RRM2 as a substrate, clarifying upstream control of Cyclin F levels.\",\n      \"evidence\": \"Pulldown and double-knockdown of FBXL8/FZR1, plus RRM2 pulldown and overexpression protein-level analysis\",\n      \"pmids\": [\"34201347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination of Cyclin F by FBXL8/FZR1 not shown\", \"RRM2 ubiquitination not directly demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized mutation-driven apoptosis activation across multiple ALS variants and patient-derived cells.\",\n      \"evidence\": \"Label-free quantitative proteomics in HEK293 and iPSC-derived cells with immunoblot validation\",\n      \"pmids\": [\"33986643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from UPS disruption to apoptosis not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that SCF(Cyclin F) ligase activity is required for ubiquitin homeostasis and mapped the E2F degron mechanism, linking Cyclin F to both proteostasis and cell-cycle control.\",\n      \"evidence\": \"iPSC-derived motor neurons with ligase-dead rescue mutants and proteasome/free-ubiquitin assays; Co-IP, degron mutagenesis, half-life, kinase-inhibitor and cell-cycle analyses for E2F1/2/3a\",\n      \"pmids\": [\"37220877\", \"36607545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of E2F regulation in neurons not established\", \"How MEK/ERK signaling intersects disease mutations unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established an endogenous developmental requirement for CCNF in motor neurons and a specific sensitivity to ER stress via loss-of-function.\",\n      \"evidence\": \"CRISPR/TALEN ccnf knockout in zebrafish with motor neuron morphology and stress-response assays\",\n      \"pmids\": [\"38474336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between Cyclin F and ER stress pathway unresolved\", \"Relationship of loss-of-function to gain-of-function mutant phenotypes unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a non-cell-autonomous astrocyte mechanism by which the S621G mutation suppresses motor neuron excitability, reframing CCNF pathology beyond neuron-intrinsic effects.\",\n      \"evidence\": \"CRISPR knock-in CcnfS621G mice, iPSC-derived astrocyte/motor-neuron co-culture, mitochondrial and electrophysiology assays\",\n      \"pmids\": [\"42069601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Knock-in mice lack overt motor decline at 18 months\", \"Astrocyte-secreted mediator suppressing neuron firing not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular bridge linking Cyclin F's ligase and VCP-enhancing activities to the cell-type-specific neurodegenerative cascade remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model connecting substrate dysregulation, VCP hyperactivity, and astrocyte dysfunction\", \"The full physiological substrate repertoire of SCF(Cyclin F) is incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 9]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 8, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 11]}\n    ],\n    \"complexes\": [\"SCF(Cyclin F)\"],\n    \"partners\": [\"VCP\", \"SQSTM1\", \"E2F1\", \"E2F2\", \"E2F3\", \"RRM2\", \"FBXL8\", \"FZR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}