{"gene":"DCAF8","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2026,"finding":"Cryo-EM structure (2.53 Å) of DCAF8 in complex with DDB1 reveals that DCAF8 engages DDB1 primarily through an N-terminal helix-loop-helix (HLH) motif inserting into a conserved pocket formed by the BPA and BPC domains of DDB1. Disruption of this interface impairs CRL4DCAF8 complex assembly, attenuates CDC25A ubiquitination, and causes cell cycle defects. The conserved double DxR box of DCAF8 is positioned away from the DDB1 interface and is dispensable for adaptor binding.","method":"Cryo-EM structure determination + interface mutagenesis + CDC25A ubiquitination assay + cell cycle analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with mutagenesis and functional ubiquitination assay, multiple orthogonal methods in one study","pmids":["42228576"],"is_preprint":false},{"year":2017,"finding":"CRL4DCAF8 ubiquitin ligase complex targets histone H3 for polyubiquitination at K79 in hepatocytes. Genetic inactivation of DCAF8 abrogates H3 ubiquitination, reactivates fetal liver and cell-cycle genes by interfering with methylated H3K9 occupancy, and leads to cell senescence. Restoring CRL4DCAF8 expression reinstates epigenetic gene silencing.","method":"Genetic inactivation (DCAF8 knockout/knockdown), H3K79 ubiquitination assays, H3K79 point mutant overexpression, inducible CRL4 deletion in mouse liver, ChIP for H3K9 methylation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including genetic inactivation, rescue experiments, and chromatin assays in cells and mouse liver","pmids":["28178526"],"is_preprint":false},{"year":2021,"finding":"DCAF8 acts as an E3 ubiquitin ligase adaptor that mediates proteasomal degradation of DNMT3A. Unstable DNMT3A missense variants identified in a systematic screen are targeted for destruction via DCAF8, as uncovered by a CRISPR screen.","method":"CRISPR screen, protein stability assays of 253 DNMT3A variants, ubiquitin-proteasome pathway analysis","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus systematic protein stability profiling replicated in multiple DNMT3A variant contexts","pmids":["34429321"],"is_preprint":false},{"year":2014,"finding":"The DCAF8 p.R317C mutation, located within the WD repeat region critical for DDB1 binding, reduces the association of DCAF8 with DDB1 and impairs CUL4-based E3 ubiquitin ligase function, causing hereditary motor and sensory neuropathy type 2 (HMSN2) with giant axons and neurofilament accumulation.","method":"Whole-exome sequencing, Sanger sequencing, co-immunoprecipitation of DCAF8 mutant vs. wild-type with DDB1 in HEK293 cells, linkage analysis","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP showing reduced binding of disease mutant to DDB1, supported by genetic linkage, single lab","pmids":["24500646"],"is_preprint":false},{"year":2020,"finding":"CRL4DCAF8 is a bona fide E3 ligase for chromatin remodeler LSH, promoting its polyubiquitination and proteasomal degradation. WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of CRL4DCAF8-LSH complex assembly. During ferroptosis induced by lipid hydroperoxides, DNA hydroxymethylation promotes WDR76 interaction with LSH and an increased DCAF8:WDR76 ratio drives LSH degradation, linking oxidative damage sensing to epigenetic regulation.","method":"CRL4DCAF8 complex reconstitution, degradation assays, co-immunoprecipitation, transcriptomic epistasis, DCAF8/WDR76 manipulation (overexpression/knockdown)","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — complex reconstitution plus degradation assays and competitive inhibition experiments, single lab with multiple orthogonal methods","pmids":["33288900"],"is_preprint":false},{"year":2019,"finding":"DCAF8 physically interacts with muscle-specific E3 ligase MuRF1 and both proteins co-localize in muscle cells. DCAF8 levels increase during muscle atrophy, and downregulation of DCAF8 substantially impedes muscle wasting and myosin heavy chain (MyHC) degradation in C2C12 myotubes. DCAF8 associates with CUL4A-containing ring ubiquitin ligase complex subunits and functions as a substrate receptor within CRL4A to promote MyHC degradation.","method":"Two unbiased protein interaction screens, co-immunoprecipitation, co-localization in muscle cells, siRNA knockdown in C2C12 myotubes with atrophy readout, cullin inhibition assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal pulldowns and functional KD with atrophy phenotype, single lab","pmids":["31391242"],"is_preprint":false},{"year":2020,"finding":"CRL4DCAF8 E3 ligase complex (CUL4A-RBX1-DDB1-DCAF8) ubiquitinates and degrades nuclear receptor corepressor NcoR1. Degradation of NcoR1 prevents its complex formation with SP1 transcription factor, leading to upregulation of HMGB1 and downstream proinflammatory cytokines in LPS-induced sepsis-induced myocardial dysfunction.","method":"Co-immunoprecipitation, ubiquitination assay, in vivo mouse model of SIMD, AlphaScreen small-molecule screen, PSSM0332 inhibition of CUL4A-RBX1 interaction","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay and co-IP plus in vivo model, single lab","pmids":["33061810"],"is_preprint":false},{"year":2020,"finding":"CRL4DCAF8 strongly interacts with MLF2 and promotes its proteasomal degradation via the ubiquitin-proteasome pathway. USP11 deubiquitinase opposes this by associating with MLF2 and increasing its stability. DCAF8 also interacts with MLF1, suggesting CRL4DCAF8 regulates both MLF1 and MLF2 stability.","method":"Co-immunoprecipitation, proteasome inhibitor assays, USP11 overexpression/knockdown, MLF1/MLF2 stability assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and degradation assays, single lab, multiple substrates tested","pmids":["32703400"],"is_preprint":false},{"year":2023,"finding":"ERβ transcriptionally represses DCAF8 expression in NSCLC cells upon cisplatin treatment. Reduced DCAF8 attenuates CRL4DCAF8-mediated proteasomal degradation of ERβ, causing ERβ accumulation and a positive feedback loop that activates Akt via PTEN inhibition, leading to cisplatin resistance.","method":"In vitro and in vivo cisplatin treatment, ERβ knockdown/overexpression, DCAF8 knockdown, PTEN/Akt pathway analysis, cisplatin-ERβ binding assay","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional knockdown experiments with pathway readouts in vitro and in vivo, single lab","pmids":["37913652"],"is_preprint":false},{"year":2012,"finding":"WDR42A (DCAF8) contains a functional nuclear localization signal (114PRRRVQRKR122) and a nuclear export signal (39IEVEASDLSLSL50). Nuclear import is mediated by karyopherin-α1/β1 in conjunction with GTPase Ran, and nuclear export is CRM1-dependent, establishing DCAF8 as a nucleocytoplasmic shuttling protein.","method":"Mutational analysis, dominant-negative experiments, co-immunoprecipitation, GST pull-down, live-cell localization assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — mutagenesis of NLS/NES with co-IP of import machinery and localization readout, single lab","pmids":["22500989"],"is_preprint":false},{"year":2025,"finding":"DCAF8 mediates proteasomal degradation of DOCK11, a guanine nucleotide exchange factor for CDC42, in hematopoietic stem cells (HSCs). Loss of DCAF8 causes DOCK11 accumulation, elevated CDC42 activity, loss of HSC polarity, cellular senescence, and DNA damage with impaired self-renewal. Knockout of Dock11 rescues the senescence, DNA damage, and self-renewal defects of Dcaf8-/- HSCs.","method":"Dcaf8 knockout mouse, Dock11 knockout epistasis, CDC42 activity assay, polarity assays, senescence/DNA damage markers, HSC transplantation functional assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double KO rescue), functional HSC assays, multiple orthogonal readouts in a defined in vivo model","pmids":["40643159"],"is_preprint":false},{"year":2025,"finding":"USP11 deubiquitinase counters CUL4-DCAF8 E3 ligase-mediated degradation of DNMT3A to maintain its protein stability. USP11 also enhances DNMT3A SUMOylation by promoting DNMT3A interaction with SUMO E3 ligases, and maintains DNMT3A DNA methyltransferase activity and its binding to the polycomb complex. Inhibition of E1 enzyme or stable USP11 expression partially rescues mislocalization of unstable DNMT3A mutants.","method":"E1 enzyme inhibition, USP11 stable overexpression, ubiquitination and SUMOylation assays, DNMT3A localization imaging, methyltransferase activity assay, co-immunoprecipitation with polycomb complex","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays on preprint, not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.03.05.641683"],"is_preprint":true},{"year":2026,"finding":"DCAF8 loss in mouse mammary gland elevates ERβ expression, which inhibits ERα/PR signaling, resulting in delayed ductal elongation and abnormal branching morphogenesis. DCAF8 promotes proteasomal degradation of ERβ (consistent with its CRL4 adaptor role), and its absence leads to ERβ accumulation and downstream suppression of PR signaling effectors.","method":"Dcaf8 homozygous knockout mice, transcriptomic sequencing, biochemical experiments (Western blot/co-IP implied), mammary whole-mount analysis","journal":"Journal of mammary gland biology and neoplasia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KO phenotype with transcriptomic and biochemical follow-up, single lab, mechanistic detail limited in abstract","pmids":["41790307"],"is_preprint":false}],"current_model":"DCAF8 is a WD40-repeat substrate recognition adaptor of the CUL4-RBX1-DDB1 Cullin-RING ubiquitin ligase (CRL4DCAF8) that engages DDB1 via an N-terminal helix-loop-helix motif (defined by cryo-EM structure); it targets multiple substrates—including histone H3 (at K79), DNMT3A, LSH, MLF1/2, NcoR1, DOCK11, CDC25A, ERβ, and myosin heavy chain—for polyubiquitination and proteasomal degradation, thereby regulating diverse processes such as epigenetic gene silencing in liver, hematopoietic stem cell polarity and self-renewal, muscle atrophy, cell cycle progression, and DNA methylation homeostasis."},"narrative":{"mechanistic_narrative":"DCAF8 is a WD40-repeat substrate-recognition adaptor of the CUL4-RBX1-DDB1 Cullin-RING ubiquitin ligase (CRL4DCAF8) that targets diverse substrates for polyubiquitination and proteasomal degradation, thereby controlling epigenetic gene silencing, cell cycle progression, stem cell maintenance, and muscle homeostasis [PMID:42228576, PMID:28178526]. It engages DDB1 through an N-terminal helix-loop-helix motif that inserts into a pocket formed by the BPA and BPC domains of DDB1, an interface required for complex assembly and substrate ubiquitination, while the WD repeat region disease mutation p.R317C disrupts DDB1 binding and CRL4 ligase function [PMID:42228576, PMID:24500646]. Through this complex DCAF8 degrades a broad substrate set: histone H3 ubiquitinated at K79 to enforce H3K9-methylation-dependent silencing of fetal liver and cell-cycle genes in hepatocytes [PMID:28178526], the de novo methyltransferase DNMT3A (targeting unstable variants) [PMID:34429321], the chromatin remodeler LSH in a manner antagonized by WDR76 during ferroptosis [PMID:33288900], the corepressor NcoR1 to derepress proinflammatory signaling [PMID:33061810], MLF1/MLF2 [PMID:32703400], CDC25A [PMID:42228576], the CDC42 GEF DOCK11 [PMID:40643159], and the nuclear receptor ERβ [PMID:37913652, PMID:41790307]. CRL4DCAF8-mediated degradation of DOCK11 restrains CDC42 activity to preserve hematopoietic stem cell polarity and self-renewal, with Dock11 deletion rescuing the senescence and DNA-damage defects of Dcaf8-null stem cells [PMID:40643159]. DCAF8 also acts as a substrate receptor within CUL4A complexes to drive myosin heavy chain degradation during muscle atrophy [PMID:31391242], and its degradation activity is opposed by the deubiquitinase USP11 on multiple substrates [PMID:32703400]. Human DCAF8 mutation causes hereditary motor and sensory neuropathy type 2 with giant axons and neurofilament accumulation [PMID:24500646].","teleology":[{"year":2012,"claim":"Established the subcellular trafficking behavior of DCAF8, showing it is not statically localized but shuttles between nucleus and cytoplasm, framing where its adaptor activity can occur.","evidence":"NLS/NES mutational analysis with co-IP of karyopherin import machinery and live-cell localization in cells","pmids":["22500989"],"confidence":"Medium","gaps":["Does not connect shuttling to CRL4 substrate selection","No regulatory trigger for export/import identified"]},{"year":2014,"claim":"Linked DCAF8 to human disease and demonstrated its dependence on DDB1 binding, showing a WD-repeat mutation that weakens DDB1 association impairs CUL4 ligase function.","evidence":"Whole-exome/Sanger sequencing with linkage, plus co-IP of mutant vs wild-type DCAF8 with DDB1 in HEK293 cells","pmids":["24500646"],"confidence":"Medium","gaps":["Substrate whose dysregulation causes neuropathy not identified","Single lab, no rescue in neurons"]},{"year":2017,"claim":"Identified the first physiological CRL4DCAF8 substrate and mechanism, showing it ubiquitinates histone H3 at K79 to maintain H3K9-methylation-dependent epigenetic silencing in liver.","evidence":"DCAF8 genetic inactivation, H3K79Ub assays, point mutant overexpression, inducible CRL4 deletion in mouse liver, and H3K9me ChIP","pmids":["28178526"],"confidence":"High","gaps":["Direct enzymatic ubiquitination of H3 by reconstituted complex not shown","How DCAF8 recognizes H3 unresolved"]},{"year":2019,"claim":"Extended DCAF8 function to muscle, establishing it as a CUL4A substrate receptor partnering MuRF1 to drive myosin heavy chain degradation during atrophy.","evidence":"Unbiased interaction screens, reciprocal co-IP, co-localization, siRNA knockdown in C2C12 myotubes with atrophy readout, and cullin inhibition","pmids":["31391242"],"confidence":"Medium","gaps":["Whether MyHC is a direct DCAF8 substrate vs indirect not resolved","Functional relationship between DCAF8 and MuRF1 ligase activity unclear"]},{"year":2020,"claim":"Defined multiple new substrates and a recurring regulatory theme, showing CRL4DCAF8 degrades LSH (antagonized by WDR76 during ferroptosis), NcoR1, and MLF1/MLF2 (opposed by USP11).","evidence":"Complex reconstitution and degradation assays for LSH; co-IP and ubiquitination assays plus in vivo sepsis model for NcoR1; co-IP and USP11 manipulation for MLF1/2","pmids":["33288900","33061810","32703400"],"confidence":"High","gaps":["Substrate degron motifs not mapped","Each substrate characterized in a single context/lab"]},{"year":2021,"claim":"Showed DCAF8 acts as a quality-control adaptor for protein stability, targeting destabilized DNMT3A missense variants for proteasomal destruction.","evidence":"CRISPR screen and systematic stability profiling of 253 DNMT3A variants with ubiquitin-proteasome analysis","pmids":["34429321"],"confidence":"High","gaps":["Structural basis for recognizing unstable variants not defined","Effect on wild-type DNMT3A turnover less clear"]},{"year":2023,"claim":"Connected DCAF8 to drug resistance, showing its CRL4-mediated degradation of ERβ is repressed during cisplatin treatment, creating an ERβ/Akt feedback loop that confers resistance.","evidence":"In vitro and in vivo cisplatin treatment with ERβ and DCAF8 knockdown/overexpression and PTEN/Akt pathway readouts in NSCLC","pmids":["37913652"],"confidence":"Medium","gaps":["Direct ubiquitination of ERβ by reconstituted complex not shown","Single lab"]},{"year":2025,"claim":"Established a stem-cell maintenance role via genetic epistasis, showing DCAF8 degrades the CDC42 GEF DOCK11 to preserve HSC polarity and self-renewal.","evidence":"Dcaf8 knockout mouse, Dock11 double-knockout epistasis rescue, CDC42 activity and polarity assays, and HSC transplantation","pmids":["40643159"],"confidence":"High","gaps":["Direct DOCK11 ubiquitination not biochemically reconstituted","Upstream regulation of DCAF8-DOCK11 axis unknown"]},{"year":2026,"claim":"Provided the structural basis for CRL4DCAF8 assembly, defining the N-terminal HLH-DDB1 interface and linking it to CDC25A ubiquitination and cell cycle control.","evidence":"2.53 Å cryo-EM structure with interface mutagenesis, CDC25A ubiquitination assay, and cell cycle analysis","pmids":["42228576"],"confidence":"High","gaps":["No structure with bound substrate","How the WD40 domain selects diverse substrates not visualized"]},{"year":null,"claim":"How a single WD40 adaptor achieves recognition of its structurally unrelated substrates, and which degrons it reads, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No substrate-bound CRL4DCAF8 structure","Degron consensus across substrates not defined","Tissue-specific substrate selection mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,6,7,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,4,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,4,7]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,10]}],"complexes":["CRL4DCAF8 (CUL4-RBX1-DDB1-DCAF8)"],"partners":["DDB1","CUL4A","RBX1","MURF1","WDR76","USP11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5TAQ9","full_name":"DDB1- and CUL4-associated factor 8","aliases":["WD repeat-containing protein 42A"],"length_aa":597,"mass_kda":66.9,"function":"May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q5TAQ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DCAF8","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SEC61B","stoichiometry":4.0},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"DDB1","stoichiometry":0.2},{"gene":"EZR","stoichiometry":0.2},{"gene":"MYO9B","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DCAF8","total_profiled":1310},"omim":[{"mim_id":"615820","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 8; DCAF8","url":"https://www.omim.org/entry/615820"},{"mim_id":"610100","title":"GIANT AXONAL NEUROPATHY 2, AUTOSOMAL DOMINANT; GAN2","url":"https://www.omim.org/entry/610100"},{"mim_id":"256850","title":"GIANT AXONAL NEUROPATHY 1, AUTOSOMAL RECESSIVE; GAN1","url":"https://www.omim.org/entry/256850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DCAF8"},"hgnc":{"alias_symbol":["H326","FLJ35857"],"prev_symbol":["WDR42A"]},"alphafold":{"accession":"Q5TAQ9","domains":[{"cath_id":"-","chopping":"150-181","consensus_level":"medium","plddt":87.5706,"start":150,"end":181},{"cath_id":"2.130.10.10","chopping":"184-531","consensus_level":"high","plddt":94.1556,"start":184,"end":531}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TAQ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5TAQ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5TAQ9-F1-predicted_aligned_error_v6.png","plddt_mean":74.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DCAF8","jax_strain_url":"https://www.jax.org/strain/search?query=DCAF8"},"sequence":{"accession":"Q5TAQ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5TAQ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5TAQ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TAQ9"}},"corpus_meta":[{"pmid":"34429321","id":"PMC_34429321","title":"Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.","date":"2021","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34429321","citation_count":68,"is_preprint":false},{"pmid":"28178526","id":"PMC_28178526","title":"CRL4DCAF8 Ubiquitin Ligase Targets Histone H3K79 and Promotes H3K9 Methylation in the Liver.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28178526","citation_count":31,"is_preprint":false},{"pmid":"24500646","id":"PMC_24500646","title":"Ubiquitin ligase defect by DCAF8 mutation causes HMSN2 with giant axons.","date":"2014","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24500646","citation_count":30,"is_preprint":false},{"pmid":"33288900","id":"PMC_33288900","title":"CRL4DCAF8 dependent opposing stability control over the chromatin remodeler LSH orchestrates epigenetic dynamics in ferroptosis.","date":"2020","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/33288900","citation_count":28,"is_preprint":false},{"pmid":"37913652","id":"PMC_37913652","title":"Cisplatin-activated ERβ/DCAF8 positive feedback loop induces chemoresistance in non-small cell lung cancer via PTEN/Akt axis.","date":"2023","source":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/37913652","citation_count":27,"is_preprint":false},{"pmid":"31391242","id":"PMC_31391242","title":"DCAF8, a novel MuRF1 interaction partner, promotes muscle atrophy.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31391242","citation_count":25,"is_preprint":false},{"pmid":"32703400","id":"PMC_32703400","title":"CRL4DCAF8 and USP11 oppositely regulate the stability of myeloid leukemia factors (MLFs).","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32703400","citation_count":13,"is_preprint":false},{"pmid":"33061810","id":"PMC_33061810","title":"The small molecule PSSM0332 disassociates the CRL4ADCAF8 E3 ligase complex to decrease the ubiquitination of NcoR1 and inhibit the inflammatory response in a mouse sepsis-induced myocardial dysfunction model.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33061810","citation_count":8,"is_preprint":false},{"pmid":"22500989","id":"PMC_22500989","title":"Characterization of nuclear import and export signals determining the subcellular localization of WD repeat-containing protein 42A (WDR42A).","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22500989","citation_count":7,"is_preprint":false},{"pmid":"40643159","id":"PMC_40643159","title":"Loss of DCAF8 impairs hematopoietic stem cell function with cellular senescence via the DOCK11-CDC42 axis.","date":"2025","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/40643159","citation_count":2,"is_preprint":false},{"pmid":"41790307","id":"PMC_41790307","title":"Role of DCAF8 in Mammary Ductal Elongation and Branching Morphogenesis.","date":"2026","source":"Journal of mammary gland biology and neoplasia","url":"https://pubmed.ncbi.nlm.nih.gov/41790307","citation_count":0,"is_preprint":false},{"pmid":"42228576","id":"PMC_42228576","title":"DCAF8 binds DDB1 via an N-terminal helix-loop-helix motif to assemble CRL4 and promote cell cycle progression.","date":"2026","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/42228576","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.05.641683","title":"Stability and DNA Methyltransferase Activity of DNMT3A are Maintained by Ubiquitin-Specific Peptidase 11 (USP11) and Sumoylation Countering Degradation","date":"2025-03-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.05.641683","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8216,"output_tokens":3689,"usd":0.039991,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11365,"output_tokens":3507,"usd":0.07225,"stage2_stop_reason":"end_turn"},"total_usd":0.112241,"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\": 2026,\n      \"finding\": \"Cryo-EM structure (2.53 Å) of DCAF8 in complex with DDB1 reveals that DCAF8 engages DDB1 primarily through an N-terminal helix-loop-helix (HLH) motif inserting into a conserved pocket formed by the BPA and BPC domains of DDB1. Disruption of this interface impairs CRL4DCAF8 complex assembly, attenuates CDC25A ubiquitination, and causes cell cycle defects. The conserved double DxR box of DCAF8 is positioned away from the DDB1 interface and is dispensable for adaptor binding.\",\n      \"method\": \"Cryo-EM structure determination + interface mutagenesis + CDC25A ubiquitination assay + cell cycle analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with mutagenesis and functional ubiquitination assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"42228576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRL4DCAF8 ubiquitin ligase complex targets histone H3 for polyubiquitination at K79 in hepatocytes. Genetic inactivation of DCAF8 abrogates H3 ubiquitination, reactivates fetal liver and cell-cycle genes by interfering with methylated H3K9 occupancy, and leads to cell senescence. Restoring CRL4DCAF8 expression reinstates epigenetic gene silencing.\",\n      \"method\": \"Genetic inactivation (DCAF8 knockout/knockdown), H3K79 ubiquitination assays, H3K79 point mutant overexpression, inducible CRL4 deletion in mouse liver, ChIP for H3K9 methylation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including genetic inactivation, rescue experiments, and chromatin assays in cells and mouse liver\",\n      \"pmids\": [\"28178526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DCAF8 acts as an E3 ubiquitin ligase adaptor that mediates proteasomal degradation of DNMT3A. Unstable DNMT3A missense variants identified in a systematic screen are targeted for destruction via DCAF8, as uncovered by a CRISPR screen.\",\n      \"method\": \"CRISPR screen, protein stability assays of 253 DNMT3A variants, ubiquitin-proteasome pathway analysis\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus systematic protein stability profiling replicated in multiple DNMT3A variant contexts\",\n      \"pmids\": [\"34429321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The DCAF8 p.R317C mutation, located within the WD repeat region critical for DDB1 binding, reduces the association of DCAF8 with DDB1 and impairs CUL4-based E3 ubiquitin ligase function, causing hereditary motor and sensory neuropathy type 2 (HMSN2) with giant axons and neurofilament accumulation.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, co-immunoprecipitation of DCAF8 mutant vs. wild-type with DDB1 in HEK293 cells, linkage analysis\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP showing reduced binding of disease mutant to DDB1, supported by genetic linkage, single lab\",\n      \"pmids\": [\"24500646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRL4DCAF8 is a bona fide E3 ligase for chromatin remodeler LSH, promoting its polyubiquitination and proteasomal degradation. WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of CRL4DCAF8-LSH complex assembly. During ferroptosis induced by lipid hydroperoxides, DNA hydroxymethylation promotes WDR76 interaction with LSH and an increased DCAF8:WDR76 ratio drives LSH degradation, linking oxidative damage sensing to epigenetic regulation.\",\n      \"method\": \"CRL4DCAF8 complex reconstitution, degradation assays, co-immunoprecipitation, transcriptomic epistasis, DCAF8/WDR76 manipulation (overexpression/knockdown)\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — complex reconstitution plus degradation assays and competitive inhibition experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33288900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DCAF8 physically interacts with muscle-specific E3 ligase MuRF1 and both proteins co-localize in muscle cells. DCAF8 levels increase during muscle atrophy, and downregulation of DCAF8 substantially impedes muscle wasting and myosin heavy chain (MyHC) degradation in C2C12 myotubes. DCAF8 associates with CUL4A-containing ring ubiquitin ligase complex subunits and functions as a substrate receptor within CRL4A to promote MyHC degradation.\",\n      \"method\": \"Two unbiased protein interaction screens, co-immunoprecipitation, co-localization in muscle cells, siRNA knockdown in C2C12 myotubes with atrophy readout, cullin inhibition assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal pulldowns and functional KD with atrophy phenotype, single lab\",\n      \"pmids\": [\"31391242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRL4DCAF8 E3 ligase complex (CUL4A-RBX1-DDB1-DCAF8) ubiquitinates and degrades nuclear receptor corepressor NcoR1. Degradation of NcoR1 prevents its complex formation with SP1 transcription factor, leading to upregulation of HMGB1 and downstream proinflammatory cytokines in LPS-induced sepsis-induced myocardial dysfunction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, in vivo mouse model of SIMD, AlphaScreen small-molecule screen, PSSM0332 inhibition of CUL4A-RBX1 interaction\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay and co-IP plus in vivo model, single lab\",\n      \"pmids\": [\"33061810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRL4DCAF8 strongly interacts with MLF2 and promotes its proteasomal degradation via the ubiquitin-proteasome pathway. USP11 deubiquitinase opposes this by associating with MLF2 and increasing its stability. DCAF8 also interacts with MLF1, suggesting CRL4DCAF8 regulates both MLF1 and MLF2 stability.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor assays, USP11 overexpression/knockdown, MLF1/MLF2 stability assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and degradation assays, single lab, multiple substrates tested\",\n      \"pmids\": [\"32703400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERβ transcriptionally represses DCAF8 expression in NSCLC cells upon cisplatin treatment. Reduced DCAF8 attenuates CRL4DCAF8-mediated proteasomal degradation of ERβ, causing ERβ accumulation and a positive feedback loop that activates Akt via PTEN inhibition, leading to cisplatin resistance.\",\n      \"method\": \"In vitro and in vivo cisplatin treatment, ERβ knockdown/overexpression, DCAF8 knockdown, PTEN/Akt pathway analysis, cisplatin-ERβ binding assay\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional knockdown experiments with pathway readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"37913652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WDR42A (DCAF8) contains a functional nuclear localization signal (114PRRRVQRKR122) and a nuclear export signal (39IEVEASDLSLSL50). Nuclear import is mediated by karyopherin-α1/β1 in conjunction with GTPase Ran, and nuclear export is CRM1-dependent, establishing DCAF8 as a nucleocytoplasmic shuttling protein.\",\n      \"method\": \"Mutational analysis, dominant-negative experiments, co-immunoprecipitation, GST pull-down, live-cell localization assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — mutagenesis of NLS/NES with co-IP of import machinery and localization readout, single lab\",\n      \"pmids\": [\"22500989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DCAF8 mediates proteasomal degradation of DOCK11, a guanine nucleotide exchange factor for CDC42, in hematopoietic stem cells (HSCs). Loss of DCAF8 causes DOCK11 accumulation, elevated CDC42 activity, loss of HSC polarity, cellular senescence, and DNA damage with impaired self-renewal. Knockout of Dock11 rescues the senescence, DNA damage, and self-renewal defects of Dcaf8-/- HSCs.\",\n      \"method\": \"Dcaf8 knockout mouse, Dock11 knockout epistasis, CDC42 activity assay, polarity assays, senescence/DNA damage markers, HSC transplantation functional assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double KO rescue), functional HSC assays, multiple orthogonal readouts in a defined in vivo model\",\n      \"pmids\": [\"40643159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP11 deubiquitinase counters CUL4-DCAF8 E3 ligase-mediated degradation of DNMT3A to maintain its protein stability. USP11 also enhances DNMT3A SUMOylation by promoting DNMT3A interaction with SUMO E3 ligases, and maintains DNMT3A DNA methyltransferase activity and its binding to the polycomb complex. Inhibition of E1 enzyme or stable USP11 expression partially rescues mislocalization of unstable DNMT3A mutants.\",\n      \"method\": \"E1 enzyme inhibition, USP11 stable overexpression, ubiquitination and SUMOylation assays, DNMT3A localization imaging, methyltransferase activity assay, co-immunoprecipitation with polycomb complex\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays on preprint, not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.03.05.641683\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DCAF8 loss in mouse mammary gland elevates ERβ expression, which inhibits ERα/PR signaling, resulting in delayed ductal elongation and abnormal branching morphogenesis. DCAF8 promotes proteasomal degradation of ERβ (consistent with its CRL4 adaptor role), and its absence leads to ERβ accumulation and downstream suppression of PR signaling effectors.\",\n      \"method\": \"Dcaf8 homozygous knockout mice, transcriptomic sequencing, biochemical experiments (Western blot/co-IP implied), mammary whole-mount analysis\",\n      \"journal\": \"Journal of mammary gland biology and neoplasia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KO phenotype with transcriptomic and biochemical follow-up, single lab, mechanistic detail limited in abstract\",\n      \"pmids\": [\"41790307\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DCAF8 is a WD40-repeat substrate recognition adaptor of the CUL4-RBX1-DDB1 Cullin-RING ubiquitin ligase (CRL4DCAF8) that engages DDB1 via an N-terminal helix-loop-helix motif (defined by cryo-EM structure); it targets multiple substrates—including histone H3 (at K79), DNMT3A, LSH, MLF1/2, NcoR1, DOCK11, CDC25A, ERβ, and myosin heavy chain—for polyubiquitination and proteasomal degradation, thereby regulating diverse processes such as epigenetic gene silencing in liver, hematopoietic stem cell polarity and self-renewal, muscle atrophy, cell cycle progression, and DNA methylation homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DCAF8 is a WD40-repeat substrate-recognition adaptor of the CUL4-RBX1-DDB1 Cullin-RING ubiquitin ligase (CRL4DCAF8) that targets diverse substrates for polyubiquitination and proteasomal degradation, thereby controlling epigenetic gene silencing, cell cycle progression, stem cell maintenance, and muscle homeostasis [#0, #1]. It engages DDB1 through an N-terminal helix-loop-helix motif that inserts into a pocket formed by the BPA and BPC domains of DDB1, an interface required for complex assembly and substrate ubiquitination, while the WD repeat region disease mutation p.R317C disrupts DDB1 binding and CRL4 ligase function [#0, #3]. Through this complex DCAF8 degrades a broad substrate set: histone H3 ubiquitinated at K79 to enforce H3K9-methylation-dependent silencing of fetal liver and cell-cycle genes in hepatocytes [#1], the de novo methyltransferase DNMT3A (targeting unstable variants) [#2], the chromatin remodeler LSH in a manner antagonized by WDR76 during ferroptosis [#4], the corepressor NcoR1 to derepress proinflammatory signaling [#6], MLF1/MLF2 [#7], CDC25A [#0], the CDC42 GEF DOCK11 [#10], and the nuclear receptor ER\\u03b2 [#8, #12]. CRL4DCAF8-mediated degradation of DOCK11 restrains CDC42 activity to preserve hematopoietic stem cell polarity and self-renewal, with Dock11 deletion rescuing the senescence and DNA-damage defects of Dcaf8-null stem cells [#10]. DCAF8 also acts as a substrate receptor within CUL4A complexes to drive myosin heavy chain degradation during muscle atrophy [#5], and its degradation activity is opposed by the deubiquitinase USP11 on multiple substrates [#7]. Human DCAF8 mutation causes hereditary motor and sensory neuropathy type 2 with giant axons and neurofilament accumulation [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the subcellular trafficking behavior of DCAF8, showing it is not statically localized but shuttles between nucleus and cytoplasm, framing where its adaptor activity can occur.\",\n      \"evidence\": \"NLS/NES mutational analysis with co-IP of karyopherin import machinery and live-cell localization in cells\",\n      \"pmids\": [\"22500989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not connect shuttling to CRL4 substrate selection\", \"No regulatory trigger for export/import identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked DCAF8 to human disease and demonstrated its dependence on DDB1 binding, showing a WD-repeat mutation that weakens DDB1 association impairs CUL4 ligase function.\",\n      \"evidence\": \"Whole-exome/Sanger sequencing with linkage, plus co-IP of mutant vs wild-type DCAF8 with DDB1 in HEK293 cells\",\n      \"pmids\": [\"24500646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate whose dysregulation causes neuropathy not identified\", \"Single lab, no rescue in neurons\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the first physiological CRL4DCAF8 substrate and mechanism, showing it ubiquitinates histone H3 at K79 to maintain H3K9-methylation-dependent epigenetic silencing in liver.\",\n      \"evidence\": \"DCAF8 genetic inactivation, H3K79Ub assays, point mutant overexpression, inducible CRL4 deletion in mouse liver, and H3K9me ChIP\",\n      \"pmids\": [\"28178526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic ubiquitination of H3 by reconstituted complex not shown\", \"How DCAF8 recognizes H3 unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended DCAF8 function to muscle, establishing it as a CUL4A substrate receptor partnering MuRF1 to drive myosin heavy chain degradation during atrophy.\",\n      \"evidence\": \"Unbiased interaction screens, reciprocal co-IP, co-localization, siRNA knockdown in C2C12 myotubes with atrophy readout, and cullin inhibition\",\n      \"pmids\": [\"31391242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MyHC is a direct DCAF8 substrate vs indirect not resolved\", \"Functional relationship between DCAF8 and MuRF1 ligase activity unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined multiple new substrates and a recurring regulatory theme, showing CRL4DCAF8 degrades LSH (antagonized by WDR76 during ferroptosis), NcoR1, and MLF1/MLF2 (opposed by USP11).\",\n      \"evidence\": \"Complex reconstitution and degradation assays for LSH; co-IP and ubiquitination assays plus in vivo sepsis model for NcoR1; co-IP and USP11 manipulation for MLF1/2\",\n      \"pmids\": [\"33288900\", \"33061810\", \"32703400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate degron motifs not mapped\", \"Each substrate characterized in a single context/lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed DCAF8 acts as a quality-control adaptor for protein stability, targeting destabilized DNMT3A missense variants for proteasomal destruction.\",\n      \"evidence\": \"CRISPR screen and systematic stability profiling of 253 DNMT3A variants with ubiquitin-proteasome analysis\",\n      \"pmids\": [\"34429321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for recognizing unstable variants not defined\", \"Effect on wild-type DNMT3A turnover less clear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected DCAF8 to drug resistance, showing its CRL4-mediated degradation of ER\\u03b2 is repressed during cisplatin treatment, creating an ER\\u03b2/Akt feedback loop that confers resistance.\",\n      \"evidence\": \"In vitro and in vivo cisplatin treatment with ER\\u03b2 and DCAF8 knockdown/overexpression and PTEN/Akt pathway readouts in NSCLC\",\n      \"pmids\": [\"37913652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination of ER\\u03b2 by reconstituted complex not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a stem-cell maintenance role via genetic epistasis, showing DCAF8 degrades the CDC42 GEF DOCK11 to preserve HSC polarity and self-renewal.\",\n      \"evidence\": \"Dcaf8 knockout mouse, Dock11 double-knockout epistasis rescue, CDC42 activity and polarity assays, and HSC transplantation\",\n      \"pmids\": [\"40643159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DOCK11 ubiquitination not biochemically reconstituted\", \"Upstream regulation of DCAF8-DOCK11 axis unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided the structural basis for CRL4DCAF8 assembly, defining the N-terminal HLH-DDB1 interface and linking it to CDC25A ubiquitination and cell cycle control.\",\n      \"evidence\": \"2.53 \\u00c5 cryo-EM structure with interface mutagenesis, CDC25A ubiquitination assay, and cell cycle analysis\",\n      \"pmids\": [\"42228576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure with bound substrate\", \"How the WD40 domain selects diverse substrates not visualized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single WD40 adaptor achieves recognition of its structurally unrelated substrates, and which degrons it reads, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No substrate-bound CRL4DCAF8 structure\", \"Degron consensus across substrates not defined\", \"Tissue-specific substrate selection mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6, 7, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 4, 7]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"complexes\": [\"CRL4DCAF8 (CUL4-RBX1-DDB1-DCAF8)\"],\n    \"partners\": [\"DDB1\", \"CUL4A\", \"RBX1\", \"MuRF1\", \"WDR76\", \"USP11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}