{"gene":"FBXO42","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2022,"finding":"FBXO42 physically interacts with RBPJ (identified by proteomic approach) and promotes K63-linked polyubiquitination of RBPJ at lysine-175, which enhances RBPJ association with chromatin remodeling complexes and induces global chromatin relaxation, thereby facilitating Notch signaling activation. Genetic depletion or pharmacological inhibition of FBXO42 E3 ligase activity attenuates Notch signaling-related leukemia development in vivo.","method":"Proteomic approach (co-IP/MS), site-directed mutagenesis (K175 ubiquitination site), chromatin fractionation, in vivo leukemia model with FBXO42 depletion","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of ubiquitination site, in vivo functional validation, multiple orthogonal methods in one study","pmids":["36129980"],"is_preprint":false},{"year":2021,"finding":"FBXO42, as the substrate receptor of a CUL1 E3 ubiquitin ligase complex, is required for HB007-induced ubiquitination and degradation of SUMO1. HB007 binds CAPRIN1 and induces CAPRIN1-FBXO42 interaction, which then recruits SUMO1 to the CAPRIN1-CUL1-FBXO42 complex for ubiquitination.","method":"CRISPR-Cas9 knockout screen, pull-down proteomics, biolayer interferometry, competitive immunoblot, co-immunoprecipitation","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen, pull-down proteomics, biolayer interferometry, and co-IP all converge; multiple orthogonal methods","pmids":["34644148"],"is_preprint":false},{"year":2021,"finding":"GASC1 histone demethylase transcriptionally represses FBXO42, and FBXO42 acts as a ubiquitin ligase that promotes K63-linked poly-ubiquitination and degradation of ROCK2, placing FBXO42 downstream of GASC1 in the regulation of Rho-GTPase/ROCK2 signaling in hepatocellular carcinoma.","method":"ChIP/transcriptional repression assay, ubiquitination assay (K63-linkage), FBXO42 knockdown/overexpression, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined pathway position by epistasis and ubiquitination assay, single lab, multiple methods","pmids":["33692332"],"is_preprint":false},{"year":2023,"finding":"CAND1 deficiency enhances assembly of a Cullin1-FBXO42-ACAA2 complex, promoting ubiquitinated degradation of ACAA2 (acetyl-CoA acyltransferase 2). ACAA2 overexpression rescues the effects of CAND1 deficiency, establishing FBXO42 as the substrate receptor that targets ACAA2 for proteasomal degradation within the CRL1 complex.","method":"Co-immunoprecipitation, hepatocyte-specific CAND1 knockout/knockin mouse models, overexpression rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo KO/KI models, and rescue experiments across multiple orthogonal approaches","pmids":["37528093"],"is_preprint":false},{"year":2024,"finding":"FBXO42 activity prevents chromosome alignment defects, mitotic cell cycle arrest, and cell death in sensitive cancer cells. The cell cycle arrest triggered by FBXO42 inactivation can be suppressed by inhibition of Mps1 (a key spindle assembly checkpoint kinase), indicating FBXO42 prevents activation of the spindle assembly checkpoint (SAC). FBXO42's cancer-essential function requires both its F-box and Kelch domains (substrate recognition/SCF complex assembly). Notably, none of the previously proposed FBXO42 targets (ING4, p53, RBPJ) were responsible for the mitotic phenotypes.","method":"Functional genomic lethality screens, FBXO42 inactivation with mitotic phenotype readout, chemical inhibition of Mps1, domain mutants (F-box, Kelch)","journal":"NAR cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis, chemical epistasis with Mps1 inhibitor, functional genomic screens; single lab","pmids":["38774470"],"is_preprint":false},{"year":2019,"finding":"FBXO42 (an E3 ubiquitin ligase) is involved in the TAK1 signaling pathway in NRAS-mutant melanoma, with FBXO42 loss causing increased active P38, contributing to resistance to MEK inhibitor trametinib.","method":"Genome-wide CRISPR-Cas9 knockout screen, follow-up signaling analysis (P38 activation), pharmacological combination experiments","journal":"Pigment cell & melanoma research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CRISPR screen identification with limited mechanistic follow-up; pathway placement inferred from P38 activation, single lab","pmids":["31549767"],"is_preprint":false},{"year":2024,"finding":"FBXO42 emerged as a positive regulator of a subset of p53 mutants, working together with CCDC6 to control USP28-mediated mutant p53 stabilization.","method":"Genome-wide CRISPR screens for p53 stability regulators","journal":"Molecular systems biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CRISPR screen identification, limited mechanistic follow-up described in abstract, single method","pmids":["38580884"],"is_preprint":false},{"year":2021,"finding":"Loss of FBXO42 renders cells sensitive to a cluster of mitotic inhibitors in a chemical-genetic CRISPR screen, and mutation of FBXO42 (along with other E3s sensitive to mitotic inhibitors) leads to increased aberrant mitoses, suggesting a role in cell cycle regulation.","method":"Chemical-genetic CRISPR-Cas9 screens with 41 compounds, mitotic phenotype scoring","journal":"Molecular cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — screen-level identification with phenotypic follow-up, no direct biochemical mechanism established for FBXO42 specifically","pmids":["33539788"],"is_preprint":false},{"year":2025,"finding":"Drosophila Fbxo42, as part of a Skp-A/Cullin-1 SCF complex, ubiquitylates and degrades the RNA-binding protein Ataxin-2. During ER stress, Xbp1 mRNA is sequestered in Ataxin-2 granules; Fbxo42 recruitment to these granules promotes Ataxin-2 degradation, releasing Xbp1 mRNA for translation and triggering cell death in the terminal UPR.","method":"Drosophila genetic screen (loss-of-function mutations), ubiquitylation assay, imaging of Ataxin-2 granules, genetic epistasis (Fbxo42 KO suppresses Xbp1s-induced death)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic screen, biochemical ubiquitylation assay, epistasis, and mechanistic granule imaging, multiple orthogonal methods","pmids":["40804044"],"is_preprint":false},{"year":2026,"finding":"The SCF-FBXO42 complex (with CCDC6 as a co-adaptor) degrades holoenzyme-free PP2A catalytic subunit (PP2Ac). Cryo-EM structure of the FBXO42-CCDC6-PP2Ac assembly reveals a pseudosymmetric architecture where CCDC6 forms a central dimeric template recruiting multiple PP2Ac copies; both the quaternary CCDC6-PP2Ac heterodimer structure and the post-translationally methylated C-terminal tail of PP2Ac are recognized by FBXO42 for ubiquitination. This multivalent scaffold enables assembly of multiple degradation complexes along a single coiled coil.","method":"Cryo-EM structure determination, biochemical reconstitution, co-immunoprecipitation, ubiquitination assays, functional cell viability assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with biochemical reconstitution, mutagenesis-level validation of key contacts, and functional assays in a single rigorous study","pmids":["41986709"],"is_preprint":false},{"year":2026,"finding":"FBXO42 ubiquitinates the PP4 phosphatase complex to govern the assembly of regulatory and catalytic subunits of PP4, with the net effect of restraining PP4 phosphatase activity. FBXO42 depletion unleashes PP4 activity with broad cellular effects.","method":"Co-immunoprecipitation, ubiquitination assays, PP4 activity assays upon FBXO42 depletion, proteomics","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, phosphatase activity readout; single lab, multiple methods; peer-reviewed publication","pmids":["41484364"],"is_preprint":false},{"year":2025,"finding":"FBXO42 binds, ubiquitinates, and negatively regulates the expression of PPP4C (protein phosphatase 4 catalytic subunit) independently of CCDC6. FBXO42 loss is synthetically lethal with mutations in γ-tubulin ring complex proteins MZT1/MZT2B, suggesting sensitivity of cells with centrosome/mitotic spindle dysfunction to FBXO42 loss. Aberrant PPP4C expression is confirmed as a major driver of cell death in FBXO42-essential neuroblastoma cells by rescue experiments.","method":"Mass spectrometry proteomics, CRISPR synthetic lethality screen, ubiquitination assays, gene knockdown rescue experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS proteomics, CRISPR screen, ubiquitination assay, rescue experiments; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.04.22.649889"],"is_preprint":true},{"year":2025,"finding":"FBXO42 interacts with p57Kip2 (a CDK inhibitor), promoting its ubiquitination and proteasomal degradation, which drives hepatocellular carcinoma cell proliferation and migration. YY1 transcription factor upregulates FBXO42 expression via transcriptional regulation.","method":"Co-immunoprecipitation (UbiBrowser prediction confirmed by Co-IP), ubiquitination assay, CCK8/clone formation/EDU proliferation assays, transwell migration assay","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed interaction, ubiquitination assay, multiple functional readouts; single lab","pmids":["40842039"],"is_preprint":false},{"year":2024,"finding":"FBXO42 promotes neuroblastoma cell proliferation in a TP53-dependent manner, functioning as a tumor-promoting E3 ubiquitin ligase in this context.","method":"Proteomic analysis of neuroblastoma cases, functional experiments (cell proliferation with TP53 dependency)","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional experiment establishing TP53 dependence without detailed mechanistic dissection; single lab","pmids":["39134694"],"is_preprint":false}],"current_model":"FBXO42 is an F-box protein that functions as the substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, targeting diverse substrates—including PP2Ac (with CCDC6 as a co-adaptor template), PP4C, RBPJ (via K63-linked polyubiquitination), SUMO1 (via CAPRIN1 bridging), ACAA2, ROCK2, Ataxin-2, and p57Kip2—for ubiquitination and/or degradation, thereby regulating mitotic fidelity, the spindle assembly checkpoint, Notch and TAK1 signaling, the unfolded protein response, phosphatase activity, and cancer cell survival."},"narrative":{"mechanistic_narrative":"FBXO42 is an F-box protein that serves as the substrate-recognition subunit of an SCF/CRL1 (SKP1–CUL1–F-box) E3 ubiquitin ligase, using its F-box and Kelch domains to assemble the complex and capture substrates for ubiquitination [PMID:38774470, PMID:41986709]. Through this activity it controls the abundance and assembly state of multiple regulatory targets, most prominently protein phosphatases: it degrades holoenzyme-free PP2A catalytic subunit (PP2Ac) using CCDC6 as a dimeric co-adaptor that templates recruitment of multiple PP2Ac copies along a coiled coil, recognizing both the CCDC6–PP2Ac quaternary structure and the methylated PP2Ac C-terminal tail [PMID:41986709], and it ubiquitinates the PP4 complex to restrain PP4 phosphatase activity, in part by acting on the catalytic subunit PPP4C [PMID:41484364]. A central cellular role of FBXO42 is the maintenance of mitotic fidelity: its activity prevents chromosome alignment defects and spindle assembly checkpoint activation, and FBXO42 inactivation triggers an Mps1-dependent mitotic arrest and cell death in sensitive cancer cells [PMID:38774470]. FBXO42 also shapes signaling outputs by K63-linked polyubiquitination of RBPJ at lysine-175, which enhances RBPJ–chromatin association and Notch pathway activation to drive leukemia [PMID:36129980], and by directing degradation of additional substrates including ROCK2, ACAA2, p57Kip2, and (in Drosophila) the RNA-binding protein Ataxin-2, the last linking FBXO42 to release of Xbp1 mRNA and terminal UPR-driven cell death [PMID:33692332, PMID:37528093, PMID:40842039, PMID:40804044]. Across these contexts FBXO42 frequently behaves as a tumor-promoting and cancer-essential ligase [PMID:36129980, PMID:40842039].","teleology":[{"year":2019,"claim":"First implicated FBXO42 as an E3 ubiquitin ligase with a signaling role, connecting its loss to altered P38/TAK1 signaling and drug resistance.","evidence":"Genome-wide CRISPR-Cas9 knockout screen with P38 activation readout and trametinib combination experiments in NRAS-mutant melanoma","pmids":["31549767"],"confidence":"Low","gaps":["Pathway placement inferred from P38 activation, no direct substrate identified","No biochemical demonstration of ubiquitination","Single lab, screen-level evidence"]},{"year":2021,"claim":"Established FBXO42 as the substrate receptor of a CUL1 ligase that can be redirected by small molecules and adaptor bridging, demonstrating ligand-induced neosubstrate ubiquitination.","evidence":"CRISPR knockout screen, pull-down proteomics, biolayer interferometry, and Co-IP showing HB007/CAPRIN1-induced FBXO42 recruitment of SUMO1","pmids":["34644148"],"confidence":"High","gaps":["SUMO1 is a drug-induced neosubstrate, not necessarily a physiological target","Endogenous adaptor logic beyond CAPRIN1 not defined"]},{"year":2021,"claim":"Placed FBXO42 in a transcriptional-to-degradation circuit by showing it mediates K63-linked ubiquitination/degradation of ROCK2 downstream of GASC1.","evidence":"ChIP/transcriptional repression assay, K63-linkage ubiquitination assay, knockdown/overexpression, and xenograft model in hepatocellular carcinoma","pmids":["33692332"],"confidence":"Medium","gaps":["Direct vs indirect ubiquitination of ROCK2 not fully resolved","Single lab","Mechanism of K63 chains driving degradation unclear"]},{"year":2021,"claim":"Linked FBXO42 loss to mitotic vulnerability, foreshadowing a cell-cycle role through chemical-genetic sensitivity to mitotic inhibitors.","evidence":"Chemical-genetic CRISPR screen with 41 compounds and mitotic phenotype scoring","pmids":["33539788"],"confidence":"Low","gaps":["No direct biochemical mechanism established for FBXO42","Substrate driving aberrant mitoses not identified"]},{"year":2022,"claim":"Defined a non-degradative ubiquitination function: K63-linked polyubiquitination of RBPJ at K175 that activates Notch signaling and promotes leukemia.","evidence":"Co-IP/MS, K175 site-directed mutagenesis, chromatin fractionation, and in vivo leukemia model with FBXO42 depletion/inhibition","pmids":["36129980"],"confidence":"High","gaps":["Mechanism by which K63 chains enhance chromatin remodeler recruitment not structurally defined","Relationship to FBXO42 degradative substrates unclear"]},{"year":2023,"claim":"Demonstrated CAND1-regulated assembly of a CUL1-FBXO42-ACAA2 complex driving ACAA2 degradation, tying FBXO42 to CRL assembly control and metabolism.","evidence":"Co-IP, hepatocyte-specific CAND1 KO/KI mouse models, and ACAA2 overexpression rescue","pmids":["37528093"],"confidence":"High","gaps":["Physiological signals controlling ACAA2 targeting unclear","How CAND1 status tunes substrate choice not defined"]},{"year":2024,"claim":"Identified the cancer-essential function of FBXO42 as prevention of SAC-driven mitotic arrest, requiring both F-box and Kelch domains and independent of previously proposed substrates.","evidence":"Functional genomic lethality screens, FBXO42 inactivation with mitotic readouts, Mps1 chemical inhibition, and domain mutants","pmids":["38774470"],"confidence":"Medium","gaps":["The mitotically relevant substrate was not identified in this study","Mechanism connecting FBXO42 loss to SAC activation undefined","Single lab"]},{"year":2024,"claim":"Connected FBXO42 to mutant-p53 stabilization, working with CCDC6 to control USP28-mediated stabilization and promote TP53-dependent proliferation.","evidence":"Genome-wide CRISPR screens for p53 stability regulators and proliferation assays in neuroblastoma","pmids":["38580884","39134694"],"confidence":"Low","gaps":["Limited mechanistic follow-up beyond screen identification","Direct vs indirect effect on p53 not established","How CCDC6/USP28 cooperation is wired unclear"]},{"year":2025,"claim":"Extended FBXO42 substrate range to p57Kip2 and demonstrated transcriptional upregulation by YY1, linking FBXO42 to CDK-inhibitor turnover in HCC.","evidence":"Co-IP (UbiBrowser-predicted, validated), ubiquitination assay, and proliferation/migration assays","pmids":["40842039"],"confidence":"Medium","gaps":["Direct ubiquitination linkage type not defined","Single lab","Relationship to other HCC substrates (ROCK2) unclear"]},{"year":2025,"claim":"Identified PPP4C as a CCDC6-independent FBXO42 substrate whose deregulation drives death of FBXO42-essential neuroblastoma cells, with synthetic lethality to γ-TuRC components.","evidence":"MS proteomics, CRISPR synthetic lethality screen, ubiquitination assays, and knockdown rescue (preprint)","pmids":["bio_10.1101_2025.04.22.649889"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Relationship between PPP4C control and mitotic SAC phenotype not fully resolved"]},{"year":2025,"claim":"Defined a conserved FBXO42-Ataxin-2 axis in the terminal UPR, where FBXO42 degrades Ataxin-2 in stress granules to release Xbp1 mRNA and trigger cell death.","evidence":"Drosophila genetic screen, ubiquitylation assay, granule imaging, and epistasis (Fbxo42 KO suppresses Xbp1s-induced death)","pmids":["40804044"],"confidence":"High","gaps":["Conservation of the Ataxin-2 axis in mammalian cells not shown in timeline","Mechanism of FBXO42 recruitment to granules undefined"]},{"year":2026,"claim":"Provided the structural and mechanistic basis for FBXO42-mediated phosphatase control: a CCDC6-templated multivalent scaffold degrading PP2Ac, and ubiquitination of PP4 to restrain its activity.","evidence":"Cryo-EM of FBXO42-CCDC6-PP2Ac with reconstitution and ubiquitination/viability assays; Co-IP, ubiquitination and PP4 activity assays for PP4","pmids":["41986709","41484364"],"confidence":"High","gaps":["How phosphatase control intersects with the mitotic SAC phenotype not integrated","Regulation of CCDC6-dependent vs -independent substrate choice unresolved"]},{"year":null,"claim":"The substrate(s) responsible for FBXO42's core cancer-essential mitotic function and how its many degradative and non-degradative targets are coordinated remain unresolved.","evidence":"No single timeline study reconciles the SAC-prevention phenotype with the identified phosphatase, signaling, and metabolic substrates","pmids":[],"confidence":"Medium","gaps":["Mitotic substrate not definitively assigned","Rules governing CCDC6-dependent vs -independent and K48 vs K63 outcomes undefined","Tissue-specific substrate selection mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,3,8,9,10,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,9,10,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,9,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8]}],"complexes":["SCF (SKP1-CUL1-FBXO42) E3 ubiquitin ligase","CUL1-FBXO42-CCDC6-PP2Ac degradation complex"],"partners":["CUL1","CCDC6","RBPJ","CAPRIN1","ACAA2","PPP4C","ROCK2","P57KIP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6P3S6","full_name":"F-box only protein 42","aliases":["Just one F-box and Kelch domain-containing protein"],"length_aa":717,"mass_kda":77.8,"function":"Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Specifically recognizes p53/TP53, promoting its ubiquitination and degradation","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6P3S6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXO42","classification":"Not Classified","n_dependent_lines":178,"n_total_lines":1208,"dependency_fraction":0.14735099337748345},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXO42","total_profiled":1310},"omim":[{"mim_id":"609109","title":"F-BOX ONLY PROTEIN 42; FBXO42","url":"https://www.omim.org/entry/609109"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXO42"},"hgnc":{"alias_symbol":["KIAA1332","Fbx42"],"prev_symbol":[]},"alphafold":{"accession":"Q6P3S6","domains":[{"cath_id":"1.20.1280","chopping":"53-100","consensus_level":"high","plddt":92.1763,"start":53,"end":100},{"cath_id":"2.120.10.80","chopping":"106-359_547-562_643-716","consensus_level":"high","plddt":83.2009,"start":106,"end":716}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P3S6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P3S6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P3S6-F1-predicted_aligned_error_v6.png","plddt_mean":63.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXO42","jax_strain_url":"https://www.jax.org/strain/search?query=FBXO42"},"sequence":{"accession":"Q6P3S6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P3S6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P3S6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P3S6"}},"corpus_meta":[{"pmid":"33539788","id":"PMC_33539788","title":"A comprehensive phenotypic CRISPR-Cas9 screen of the ubiquitin pathway uncovers roles of ubiquitin ligases in mitosis.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33539788","citation_count":37,"is_preprint":false},{"pmid":"34644148","id":"PMC_34644148","title":"Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors.","date":"2021","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34644148","citation_count":26,"is_preprint":false},{"pmid":"31549767","id":"PMC_31549767","title":"A genome-wide CRISPR screen identifies FBXO42 involvement in resistance toward MEK inhibition in NRAS-mutant melanoma.","date":"2019","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/31549767","citation_count":24,"is_preprint":false},{"pmid":"37528093","id":"PMC_37528093","title":"Cullin-associated and neddylation-dissociated protein 1 (CAND1) 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survival","date":"2025-04-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.22.649889","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11308,"output_tokens":3683,"usd":0.044584,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11315,"output_tokens":4338,"usd":0.082513,"stage2_stop_reason":"end_turn"},"total_usd":0.127097,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXO42 physically interacts with RBPJ (identified by proteomic approach) and promotes K63-linked polyubiquitination of RBPJ at lysine-175, which enhances RBPJ association with chromatin remodeling complexes and induces global chromatin relaxation, thereby facilitating Notch signaling activation. Genetic depletion or pharmacological inhibition of FBXO42 E3 ligase activity attenuates Notch signaling-related leukemia development in vivo.\",\n      \"method\": \"Proteomic approach (co-IP/MS), site-directed mutagenesis (K175 ubiquitination site), chromatin fractionation, in vivo leukemia model with FBXO42 depletion\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of ubiquitination site, in vivo functional validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36129980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXO42, as the substrate receptor of a CUL1 E3 ubiquitin ligase complex, is required for HB007-induced ubiquitination and degradation of SUMO1. HB007 binds CAPRIN1 and induces CAPRIN1-FBXO42 interaction, which then recruits SUMO1 to the CAPRIN1-CUL1-FBXO42 complex for ubiquitination.\",\n      \"method\": \"CRISPR-Cas9 knockout screen, pull-down proteomics, biolayer interferometry, competitive immunoblot, co-immunoprecipitation\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen, pull-down proteomics, biolayer interferometry, and co-IP all converge; multiple orthogonal methods\",\n      \"pmids\": [\"34644148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GASC1 histone demethylase transcriptionally represses FBXO42, and FBXO42 acts as a ubiquitin ligase that promotes K63-linked poly-ubiquitination and degradation of ROCK2, placing FBXO42 downstream of GASC1 in the regulation of Rho-GTPase/ROCK2 signaling in hepatocellular carcinoma.\",\n      \"method\": \"ChIP/transcriptional repression assay, ubiquitination assay (K63-linkage), FBXO42 knockdown/overexpression, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined pathway position by epistasis and ubiquitination assay, single lab, multiple methods\",\n      \"pmids\": [\"33692332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAND1 deficiency enhances assembly of a Cullin1-FBXO42-ACAA2 complex, promoting ubiquitinated degradation of ACAA2 (acetyl-CoA acyltransferase 2). ACAA2 overexpression rescues the effects of CAND1 deficiency, establishing FBXO42 as the substrate receptor that targets ACAA2 for proteasomal degradation within the CRL1 complex.\",\n      \"method\": \"Co-immunoprecipitation, hepatocyte-specific CAND1 knockout/knockin mouse models, overexpression rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo KO/KI models, and rescue experiments across multiple orthogonal approaches\",\n      \"pmids\": [\"37528093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO42 activity prevents chromosome alignment defects, mitotic cell cycle arrest, and cell death in sensitive cancer cells. The cell cycle arrest triggered by FBXO42 inactivation can be suppressed by inhibition of Mps1 (a key spindle assembly checkpoint kinase), indicating FBXO42 prevents activation of the spindle assembly checkpoint (SAC). FBXO42's cancer-essential function requires both its F-box and Kelch domains (substrate recognition/SCF complex assembly). Notably, none of the previously proposed FBXO42 targets (ING4, p53, RBPJ) were responsible for the mitotic phenotypes.\",\n      \"method\": \"Functional genomic lethality screens, FBXO42 inactivation with mitotic phenotype readout, chemical inhibition of Mps1, domain mutants (F-box, Kelch)\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis, chemical epistasis with Mps1 inhibitor, functional genomic screens; single lab\",\n      \"pmids\": [\"38774470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FBXO42 (an E3 ubiquitin ligase) is involved in the TAK1 signaling pathway in NRAS-mutant melanoma, with FBXO42 loss causing increased active P38, contributing to resistance to MEK inhibitor trametinib.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen, follow-up signaling analysis (P38 activation), pharmacological combination experiments\",\n      \"journal\": \"Pigment cell & melanoma research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CRISPR screen identification with limited mechanistic follow-up; pathway placement inferred from P38 activation, single lab\",\n      \"pmids\": [\"31549767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO42 emerged as a positive regulator of a subset of p53 mutants, working together with CCDC6 to control USP28-mediated mutant p53 stabilization.\",\n      \"method\": \"Genome-wide CRISPR screens for p53 stability regulators\",\n      \"journal\": \"Molecular systems biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CRISPR screen identification, limited mechanistic follow-up described in abstract, single method\",\n      \"pmids\": [\"38580884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of FBXO42 renders cells sensitive to a cluster of mitotic inhibitors in a chemical-genetic CRISPR screen, and mutation of FBXO42 (along with other E3s sensitive to mitotic inhibitors) leads to increased aberrant mitoses, suggesting a role in cell cycle regulation.\",\n      \"method\": \"Chemical-genetic CRISPR-Cas9 screens with 41 compounds, mitotic phenotype scoring\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — screen-level identification with phenotypic follow-up, no direct biochemical mechanism established for FBXO42 specifically\",\n      \"pmids\": [\"33539788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Drosophila Fbxo42, as part of a Skp-A/Cullin-1 SCF complex, ubiquitylates and degrades the RNA-binding protein Ataxin-2. During ER stress, Xbp1 mRNA is sequestered in Ataxin-2 granules; Fbxo42 recruitment to these granules promotes Ataxin-2 degradation, releasing Xbp1 mRNA for translation and triggering cell death in the terminal UPR.\",\n      \"method\": \"Drosophila genetic screen (loss-of-function mutations), ubiquitylation assay, imaging of Ataxin-2 granules, genetic epistasis (Fbxo42 KO suppresses Xbp1s-induced death)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic screen, biochemical ubiquitylation assay, epistasis, and mechanistic granule imaging, multiple orthogonal methods\",\n      \"pmids\": [\"40804044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The SCF-FBXO42 complex (with CCDC6 as a co-adaptor) degrades holoenzyme-free PP2A catalytic subunit (PP2Ac). Cryo-EM structure of the FBXO42-CCDC6-PP2Ac assembly reveals a pseudosymmetric architecture where CCDC6 forms a central dimeric template recruiting multiple PP2Ac copies; both the quaternary CCDC6-PP2Ac heterodimer structure and the post-translationally methylated C-terminal tail of PP2Ac are recognized by FBXO42 for ubiquitination. This multivalent scaffold enables assembly of multiple degradation complexes along a single coiled coil.\",\n      \"method\": \"Cryo-EM structure determination, biochemical reconstitution, co-immunoprecipitation, ubiquitination assays, functional cell viability assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with biochemical reconstitution, mutagenesis-level validation of key contacts, and functional assays in a single rigorous study\",\n      \"pmids\": [\"41986709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FBXO42 ubiquitinates the PP4 phosphatase complex to govern the assembly of regulatory and catalytic subunits of PP4, with the net effect of restraining PP4 phosphatase activity. FBXO42 depletion unleashes PP4 activity with broad cellular effects.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, PP4 activity assays upon FBXO42 depletion, proteomics\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, phosphatase activity readout; single lab, multiple methods; peer-reviewed publication\",\n      \"pmids\": [\"41484364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO42 binds, ubiquitinates, and negatively regulates the expression of PPP4C (protein phosphatase 4 catalytic subunit) independently of CCDC6. FBXO42 loss is synthetically lethal with mutations in γ-tubulin ring complex proteins MZT1/MZT2B, suggesting sensitivity of cells with centrosome/mitotic spindle dysfunction to FBXO42 loss. Aberrant PPP4C expression is confirmed as a major driver of cell death in FBXO42-essential neuroblastoma cells by rescue experiments.\",\n      \"method\": \"Mass spectrometry proteomics, CRISPR synthetic lethality screen, ubiquitination assays, gene knockdown rescue experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS proteomics, CRISPR screen, ubiquitination assay, rescue experiments; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.04.22.649889\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO42 interacts with p57Kip2 (a CDK inhibitor), promoting its ubiquitination and proteasomal degradation, which drives hepatocellular carcinoma cell proliferation and migration. YY1 transcription factor upregulates FBXO42 expression via transcriptional regulation.\",\n      \"method\": \"Co-immunoprecipitation (UbiBrowser prediction confirmed by Co-IP), ubiquitination assay, CCK8/clone formation/EDU proliferation assays, transwell migration assay\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed interaction, ubiquitination assay, multiple functional readouts; single lab\",\n      \"pmids\": [\"40842039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO42 promotes neuroblastoma cell proliferation in a TP53-dependent manner, functioning as a tumor-promoting E3 ubiquitin ligase in this context.\",\n      \"method\": \"Proteomic analysis of neuroblastoma cases, functional experiments (cell proliferation with TP53 dependency)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional experiment establishing TP53 dependence without detailed mechanistic dissection; single lab\",\n      \"pmids\": [\"39134694\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO42 is an F-box protein that functions as the substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, targeting diverse substrates—including PP2Ac (with CCDC6 as a co-adaptor template), PP4C, RBPJ (via K63-linked polyubiquitination), SUMO1 (via CAPRIN1 bridging), ACAA2, ROCK2, Ataxin-2, and p57Kip2—for ubiquitination and/or degradation, thereby regulating mitotic fidelity, the spindle assembly checkpoint, Notch and TAK1 signaling, the unfolded protein response, phosphatase activity, and cancer cell survival.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXO42 is an F-box protein that serves as the substrate-recognition subunit of an SCF/CRL1 (SKP1–CUL1–F-box) E3 ubiquitin ligase, using its F-box and Kelch domains to assemble the complex and capture substrates for ubiquitination [#4, #9]. Through this activity it controls the abundance and assembly state of multiple regulatory targets, most prominently protein phosphatases: it degrades holoenzyme-free PP2A catalytic subunit (PP2Ac) using CCDC6 as a dimeric co-adaptor that templates recruitment of multiple PP2Ac copies along a coiled coil, recognizing both the CCDC6–PP2Ac quaternary structure and the methylated PP2Ac C-terminal tail [#9], and it ubiquitinates the PP4 complex to restrain PP4 phosphatase activity, in part by acting on the catalytic subunit PPP4C [#10]. A central cellular role of FBXO42 is the maintenance of mitotic fidelity: its activity prevents chromosome alignment defects and spindle assembly checkpoint activation, and FBXO42 inactivation triggers an Mps1-dependent mitotic arrest and cell death in sensitive cancer cells [#4]. FBXO42 also shapes signaling outputs by K63-linked polyubiquitination of RBPJ at lysine-175, which enhances RBPJ–chromatin association and Notch pathway activation to drive leukemia [#0], and by directing degradation of additional substrates including ROCK2, ACAA2, p57Kip2, and (in Drosophila) the RNA-binding protein Ataxin-2, the last linking FBXO42 to release of Xbp1 mRNA and terminal UPR-driven cell death [#2, #3, #12, #8]. Across these contexts FBXO42 frequently behaves as a tumor-promoting and cancer-essential ligase [#0, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"First implicated FBXO42 as an E3 ubiquitin ligase with a signaling role, connecting its loss to altered P38/TAK1 signaling and drug resistance.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 knockout screen with P38 activation readout and trametinib combination experiments in NRAS-mutant melanoma\",\n      \"pmids\": [\"31549767\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement inferred from P38 activation, no direct substrate identified\", \"No biochemical demonstration of ubiquitination\", \"Single lab, screen-level evidence\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established FBXO42 as the substrate receptor of a CUL1 ligase that can be redirected by small molecules and adaptor bridging, demonstrating ligand-induced neosubstrate ubiquitination.\",\n      \"evidence\": \"CRISPR knockout screen, pull-down proteomics, biolayer interferometry, and Co-IP showing HB007/CAPRIN1-induced FBXO42 recruitment of SUMO1\",\n      \"pmids\": [\"34644148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO1 is a drug-induced neosubstrate, not necessarily a physiological target\", \"Endogenous adaptor logic beyond CAPRIN1 not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed FBXO42 in a transcriptional-to-degradation circuit by showing it mediates K63-linked ubiquitination/degradation of ROCK2 downstream of GASC1.\",\n      \"evidence\": \"ChIP/transcriptional repression assay, K63-linkage ubiquitination assay, knockdown/overexpression, and xenograft model in hepatocellular carcinoma\",\n      \"pmids\": [\"33692332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect ubiquitination of ROCK2 not fully resolved\", \"Single lab\", \"Mechanism of K63 chains driving degradation unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked FBXO42 loss to mitotic vulnerability, foreshadowing a cell-cycle role through chemical-genetic sensitivity to mitotic inhibitors.\",\n      \"evidence\": \"Chemical-genetic CRISPR screen with 41 compounds and mitotic phenotype scoring\",\n      \"pmids\": [\"33539788\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical mechanism established for FBXO42\", \"Substrate driving aberrant mitoses not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a non-degradative ubiquitination function: K63-linked polyubiquitination of RBPJ at K175 that activates Notch signaling and promotes leukemia.\",\n      \"evidence\": \"Co-IP/MS, K175 site-directed mutagenesis, chromatin fractionation, and in vivo leukemia model with FBXO42 depletion/inhibition\",\n      \"pmids\": [\"36129980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which K63 chains enhance chromatin remodeler recruitment not structurally defined\", \"Relationship to FBXO42 degradative substrates unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated CAND1-regulated assembly of a CUL1-FBXO42-ACAA2 complex driving ACAA2 degradation, tying FBXO42 to CRL assembly control and metabolism.\",\n      \"evidence\": \"Co-IP, hepatocyte-specific CAND1 KO/KI mouse models, and ACAA2 overexpression rescue\",\n      \"pmids\": [\"37528093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals controlling ACAA2 targeting unclear\", \"How CAND1 status tunes substrate choice not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the cancer-essential function of FBXO42 as prevention of SAC-driven mitotic arrest, requiring both F-box and Kelch domains and independent of previously proposed substrates.\",\n      \"evidence\": \"Functional genomic lethality screens, FBXO42 inactivation with mitotic readouts, Mps1 chemical inhibition, and domain mutants\",\n      \"pmids\": [\"38774470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The mitotically relevant substrate was not identified in this study\", \"Mechanism connecting FBXO42 loss to SAC activation undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected FBXO42 to mutant-p53 stabilization, working with CCDC6 to control USP28-mediated stabilization and promote TP53-dependent proliferation.\",\n      \"evidence\": \"Genome-wide CRISPR screens for p53 stability regulators and proliferation assays in neuroblastoma\",\n      \"pmids\": [\"38580884\", \"39134694\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic follow-up beyond screen identification\", \"Direct vs indirect effect on p53 not established\", \"How CCDC6/USP28 cooperation is wired unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended FBXO42 substrate range to p57Kip2 and demonstrated transcriptional upregulation by YY1, linking FBXO42 to CDK-inhibitor turnover in HCC.\",\n      \"evidence\": \"Co-IP (UbiBrowser-predicted, validated), ubiquitination assay, and proliferation/migration assays\",\n      \"pmids\": [\"40842039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination linkage type not defined\", \"Single lab\", \"Relationship to other HCC substrates (ROCK2) unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified PPP4C as a CCDC6-independent FBXO42 substrate whose deregulation drives death of FBXO42-essential neuroblastoma cells, with synthetic lethality to γ-TuRC components.\",\n      \"evidence\": \"MS proteomics, CRISPR synthetic lethality screen, ubiquitination assays, and knockdown rescue (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.22.649889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Relationship between PPP4C control and mitotic SAC phenotype not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a conserved FBXO42-Ataxin-2 axis in the terminal UPR, where FBXO42 degrades Ataxin-2 in stress granules to release Xbp1 mRNA and trigger cell death.\",\n      \"evidence\": \"Drosophila genetic screen, ubiquitylation assay, granule imaging, and epistasis (Fbxo42 KO suppresses Xbp1s-induced death)\",\n      \"pmids\": [\"40804044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of the Ataxin-2 axis in mammalian cells not shown in timeline\", \"Mechanism of FBXO42 recruitment to granules undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided the structural and mechanistic basis for FBXO42-mediated phosphatase control: a CCDC6-templated multivalent scaffold degrading PP2Ac, and ubiquitination of PP4 to restrain its activity.\",\n      \"evidence\": \"Cryo-EM of FBXO42-CCDC6-PP2Ac with reconstitution and ubiquitination/viability assays; Co-IP, ubiquitination and PP4 activity assays for PP4\",\n      \"pmids\": [\"41986709\", \"41484364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphatase control intersects with the mitotic SAC phenotype not integrated\", \"Regulation of CCDC6-dependent vs -independent substrate choice unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The substrate(s) responsible for FBXO42's core cancer-essential mitotic function and how its many degradative and non-degradative targets are coordinated remain unresolved.\",\n      \"evidence\": \"No single timeline study reconciles the SAC-prevention phenotype with the identified phosphatase, signaling, and metabolic substrates\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitotic substrate not definitively assigned\", \"Rules governing CCDC6-dependent vs -independent and K48 vs K63 outcomes undefined\", \"Tissue-specific substrate selection mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 3, 8, 9, 10, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 9, 10, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 9, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"SCF (SKP1-CUL1-FBXO42) E3 ubiquitin ligase\",\n      \"CUL1-FBXO42-CCDC6-PP2Ac degradation complex\"\n    ],\n    \"partners\": [\n      \"CUL1\",\n      \"CCDC6\",\n      \"RBPJ\",\n      \"CAPRIN1\",\n      \"ACAA2\",\n      \"PPP4C\",\n      \"ROCK2\",\n      \"p57Kip2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}