{"gene":"DCAF4","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2019,"finding":"DCAF4 functions as a substrate receptor in the CRL4DCAF4 E3 ubiquitin ligase complex (together with CUL4A/4B and DDB1), which specifically ubiquitinates and directs proteasomal degradation of the tumor suppressor ST7 in colitis-associated cancer cells.","method":"In vitro and in vivo ubiquitination assays, co-immunoprecipitation, knockdown experiments with colony formation and tumor growth readouts","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing complex assembly, in vitro and in vivo ubiquitination assays, KD phenotype; replicated across multiple cell lines and in vivo models","pmids":["30945288"],"is_preprint":false},{"year":2020,"finding":"DCAF4 mediates ubiquitination of the autophagy receptor optineurin (OPTN), which in turn facilitates autophagic degradation of DBR-exposed (misfolded) Cu,Zn-superoxide dismutase (SOD1), thereby regulating SOD1 proteostasis relevant to ALS pathogenesis.","method":"Genome-wide siRNA screen, time-resolved FRET assay for SOD1 conformation, ubiquitination assays, autophagy flux experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide siRNA screen plus biochemical ubiquitination assay in a single lab; two orthogonal methods but not independently replicated","pmids":["32014991"],"is_preprint":false},{"year":2020,"finding":"Disruption of the CUL4A-DDB1 interaction by small molecule NSC1892 impairs CRL4DCAF4 E3 ligase assembly, prevents ST7 ubiquitination and degradation, and inhibits colorectal cancer cell growth in vitro and in vivo, confirming that DCAF4 requires intact CUL4-DDB1 scaffolding for its E3 ligase activity.","method":"AlphaScreen assay for protein-protein interaction, biochemical assembly assays, cell proliferation/colony formation assays, in vivo xenograft tumor growth","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro interaction assay plus in vivo tumor model, single lab with multiple orthogonal readouts","pmids":["32140073"],"is_preprint":false},{"year":2020,"finding":"Upstream of CRL4DCAF4 activity, miR-34b-5p directly targets c-MYC mRNA; loss of miR-34b-5p (via inflammation-driven DNA hypermethylation) elevates c-MYC, which in turn activates CUL4A/4B transcription and CRL4DCAF4 E3 ligase activity leading to ST7 ubiquitination in colitis-associated cancer.","method":"miRNA overexpression/target luciferase assays, in vitro oncogenic phenotype assays, in vivo tumor formation, c-MYC rescue experiments","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA-target validation plus c-MYC rescue experiment, single lab, multiple assays","pmids":["31972160"],"is_preprint":false},{"year":2012,"finding":"Computational structural modeling predicted that the WDR21A (DCAF4) protein adopts a Gβ1-like WD-repeat fold and docking analysis suggested it can interact with the glucocorticoid receptor (GR), potentially competing with Gβ1 for GR binding; however, this interaction was not experimentally validated in the study.","method":"Template-based protein structure prediction and computational docking (Zdock); no experimental binding validation performed","journal":"Pharmacogenetics and genomics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — purely computational prediction with no experimental confirmation of the protein-protein interaction","pmids":["22366774"],"is_preprint":false}],"current_model":"DCAF4 (also known as WDR21A) functions as a substrate receptor subunit of the CRL4 Cullin-RING E3 ubiquitin ligase complex, assembling with CUL4A/4B and DDB1 to ubiquitinate and degrade the tumor suppressor ST7; it also ubiquitinates the autophagy receptor optineurin (OPTN), thereby promoting autophagic clearance of misfolded SOD1, with upstream regulation of the complex provided by c-MYC-driven transcription of CUL4A/4B."},"narrative":{"mechanistic_narrative":"DCAF4 (WDR21A) is a substrate receptor subunit of the CRL4 Cullin-RING E3 ubiquitin ligase, assembling with CUL4A/4B and DDB1 to target specific proteins for ubiquitination and degradation [PMID:30945288]. In colitis-associated and colorectal cancer cells, CRL4DCAF4 ubiquitinates the tumor suppressor ST7 and directs it to proteasomal degradation, thereby promoting tumor cell growth; this activity requires intact CUL4-DDB1 scaffolding, since disrupting that interaction abolishes ST7 turnover and inhibits tumor growth [PMID:30945288, PMID:32140073]. The complex's output is set transcriptionally upstream: inflammation-driven loss of miR-34b-5p elevates c-MYC, which activates CUL4A/4B transcription and downstream CRL4DCAF4 activity toward ST7 [PMID:31972160]. Beyond this oncogenic axis, DCAF4 also mediates ubiquitination of the autophagy receptor optineurin (OPTN), promoting autophagic clearance of misfolded SOD1 and linking the ligase to proteostasis relevant to ALS [PMID:32014991].","teleology":[{"year":2012,"claim":"An initial structural hypothesis asked what fold DCAF4/WDR21A adopts and what it might bind, establishing it as a WD-repeat protein potentially engaging the glucocorticoid receptor.","evidence":"Template-based structure prediction and computational docking (Zdock), no experimental binding validation","pmids":["22366774"],"confidence":"Low","gaps":["Purely computational prediction with no experimental confirmation of the GR interaction","Does not establish any enzymatic or ligase function","WD-repeat fold inferred, not solved"]},{"year":2019,"claim":"Defined DCAF4's biochemical identity by showing it serves as a substrate receptor within a CRL4 complex that ubiquitinates and degrades the tumor suppressor ST7, establishing its oncogenic role in colitis-associated cancer.","evidence":"Reciprocal Co-IP, in vitro and in vivo ubiquitination assays, and knockdown with colony formation and tumor growth readouts across multiple cell lines and models","pmids":["30945288"],"confidence":"High","gaps":["Substrate range beyond ST7 not mapped","Structural basis of ST7 recognition by the WD-repeat domain not resolved","Whether ST7 is a direct or indirect substrate of the receptor not fully dissected"]},{"year":2020,"claim":"Extended DCAF4 function beyond cancer by showing it ubiquitinates the autophagy receptor OPTN to drive autophagic clearance of misfolded SOD1, linking the ligase to proteostasis and ALS.","evidence":"Genome-wide siRNA screen, time-resolved FRET for SOD1 conformation, ubiquitination assays, and autophagy flux experiments in a single lab","pmids":["32014991"],"confidence":"Medium","gaps":["Two orthogonal methods but not independently replicated","Whether OPTN ubiquitination uses the same CUL4-DDB1 scaffold not directly tested","Type/topology of ubiquitin chains on OPTN unspecified"]},{"year":2020,"claim":"Validated the scaffolding requirement for DCAF4 ligase activity by showing small-molecule disruption of CUL4A-DDB1 blocks complex assembly, ST7 degradation, and tumor growth.","evidence":"AlphaScreen protein-protein interaction assay, biochemical assembly assays, proliferation/colony formation, and in vivo xenograft growth","pmids":["32140073"],"confidence":"Medium","gaps":["Single lab with one inhibitor compound","Selectivity of NSC1892 for this complex not exhaustively established","Does not address DCAF4-specific (versus general CRL4) dependence"]},{"year":2020,"claim":"Placed CRL4DCAF4 in a regulatory hierarchy by showing that inflammation-driven loss of miR-34b-5p de-represses c-MYC, which transcriptionally activates CUL4A/4B to elevate ligase activity against ST7.","evidence":"miRNA-target luciferase assays, oncogenic phenotype assays, in vivo tumor formation, and c-MYC rescue experiments","pmids":["31972160"],"confidence":"Medium","gaps":["Single lab; mechanism inferred from rescue rather than endogenous chromatin occupancy data","Whether DCAF4 itself is transcriptionally regulated by this axis not shown","Generalizability beyond colitis-associated cancer not tested"]},{"year":null,"claim":"The full substrate repertoire of CRL4DCAF4 and the structural basis by which its WD-repeat domain selects ST7 versus OPTN remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of DCAF4 bound to a substrate","Determinants of substrate choice across cancer versus autophagy contexts unknown","Unbiased substrate identification (e.g. degradomics) not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1]}],"complexes":["CRL4 (CUL4A/4B-DDB1-DCAF4) E3 ubiquitin ligase"],"partners":["CUL4A","CUL4B","DDB1","ST7","OPTN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WV16","full_name":"DDB1- and CUL4-associated factor 4","aliases":["WD repeat-containing protein 21A"],"length_aa":495,"mass_kda":55.7,"function":"May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8WV16/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DCAF4","classification":"Not Classified","n_dependent_lines":31,"n_total_lines":1208,"dependency_fraction":0.02566225165562914},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DCAF4","total_profiled":1310},"omim":[{"mim_id":"616372","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 4; DCAF4","url":"https://www.omim.org/entry/616372"},{"mim_id":"609113","title":"TELOMERE LENGTH, MEAN LEUKOCYTE; LTL","url":"https://www.omim.org/entry/609113"}],"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/DCAF4"},"hgnc":{"alias_symbol":["DKFZp434K114"],"prev_symbol":["WDR21","WDR21A"]},"alphafold":{"accession":"Q8WV16","domains":[{"cath_id":"2.130.10.10","chopping":"158-494","consensus_level":"medium","plddt":86.5884,"start":158,"end":494}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WV16","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WV16-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WV16-F1-predicted_aligned_error_v6.png","plddt_mean":77.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DCAF4","jax_strain_url":"https://www.jax.org/strain/search?query=DCAF4"},"sequence":{"accession":"Q8WV16","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WV16.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WV16/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WV16"}},"corpus_meta":[{"pmid":"8524837","id":"PMC_8524837","title":"Assembly of regularly spaced nucleosome arrays by Drosophila chromatin assembly factor 1 and a 56-kDa histone-binding protein.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8524837","citation_count":71,"is_preprint":false},{"pmid":"25624462","id":"PMC_25624462","title":"DCAF4, a novel gene associated with leucocyte telomere length.","date":"2015","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25624462","citation_count":63,"is_preprint":false},{"pmid":"30945288","id":"PMC_30945288","title":"Inflammation-dependent overexpression of c-Myc enhances CRL4DCAF4 E3 ligase activity and promotes ubiquitination of ST7 in colitis-associated cancer.","date":"2019","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30945288","citation_count":37,"is_preprint":false},{"pmid":"31972160","id":"PMC_31972160","title":"Inflammation and DNA Methylation-Dependent Down-Regulation of miR-34b-5p Mediates c-MYC Expression and CRL4DCAF4 E3 Ligase Activity in Colitis-Associated Cancer.","date":"2020","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31972160","citation_count":21,"is_preprint":false},{"pmid":"28383684","id":"PMC_28383684","title":"Functional variants in DCAF4 associated with lung cancer risk in European populations.","date":"2017","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28383684","citation_count":18,"is_preprint":false},{"pmid":"32140073","id":"PMC_32140073","title":"Small molecule NSC1892 targets the CUL4A/4B-DDB1 interactions and causes impairment of CRL4DCAF4 E3 ligases to inhibit colorectal cancer cell growth.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32140073","citation_count":17,"is_preprint":false},{"pmid":"28336923","id":"PMC_28336923","title":"Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28336923","citation_count":16,"is_preprint":false},{"pmid":"38001857","id":"PMC_38001857","title":"Associations between the New DNA-Methylation-Based Telomere Length Estimator, the Mediterranean Diet and Genetics in a Spanish Population at High Cardiovascular Risk.","date":"2023","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38001857","citation_count":5,"is_preprint":false},{"pmid":"22366774","id":"PMC_22366774","title":"Association between WDR21A polymorphisms and airway responsiveness to inhaled corticosteroids in asthmatic patients.","date":"2012","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/22366774","citation_count":4,"is_preprint":false},{"pmid":"32014991","id":"PMC_32014991","title":"Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu,Zn-superoxide dismutase.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32014991","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7851,"output_tokens":1340,"usd":0.021826,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7990,"output_tokens":2311,"usd":0.048863,"stage2_stop_reason":"end_turn"},"total_usd":0.070689,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"DCAF4 functions as a substrate receptor in the CRL4DCAF4 E3 ubiquitin ligase complex (together with CUL4A/4B and DDB1), which specifically ubiquitinates and directs proteasomal degradation of the tumor suppressor ST7 in colitis-associated cancer cells.\",\n      \"method\": \"In vitro and in vivo ubiquitination assays, co-immunoprecipitation, knockdown experiments with colony formation and tumor growth readouts\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing complex assembly, in vitro and in vivo ubiquitination assays, KD phenotype; replicated across multiple cell lines and in vivo models\",\n      \"pmids\": [\"30945288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DCAF4 mediates ubiquitination of the autophagy receptor optineurin (OPTN), which in turn facilitates autophagic degradation of DBR-exposed (misfolded) Cu,Zn-superoxide dismutase (SOD1), thereby regulating SOD1 proteostasis relevant to ALS pathogenesis.\",\n      \"method\": \"Genome-wide siRNA screen, time-resolved FRET assay for SOD1 conformation, ubiquitination assays, autophagy flux experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide siRNA screen plus biochemical ubiquitination assay in a single lab; two orthogonal methods but not independently replicated\",\n      \"pmids\": [\"32014991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Disruption of the CUL4A-DDB1 interaction by small molecule NSC1892 impairs CRL4DCAF4 E3 ligase assembly, prevents ST7 ubiquitination and degradation, and inhibits colorectal cancer cell growth in vitro and in vivo, confirming that DCAF4 requires intact CUL4-DDB1 scaffolding for its E3 ligase activity.\",\n      \"method\": \"AlphaScreen assay for protein-protein interaction, biochemical assembly assays, cell proliferation/colony formation assays, in vivo xenograft tumor growth\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro interaction assay plus in vivo tumor model, single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"32140073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Upstream of CRL4DCAF4 activity, miR-34b-5p directly targets c-MYC mRNA; loss of miR-34b-5p (via inflammation-driven DNA hypermethylation) elevates c-MYC, which in turn activates CUL4A/4B transcription and CRL4DCAF4 E3 ligase activity leading to ST7 ubiquitination in colitis-associated cancer.\",\n      \"method\": \"miRNA overexpression/target luciferase assays, in vitro oncogenic phenotype assays, in vivo tumor formation, c-MYC rescue experiments\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA-target validation plus c-MYC rescue experiment, single lab, multiple assays\",\n      \"pmids\": [\"31972160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Computational structural modeling predicted that the WDR21A (DCAF4) protein adopts a Gβ1-like WD-repeat fold and docking analysis suggested it can interact with the glucocorticoid receptor (GR), potentially competing with Gβ1 for GR binding; however, this interaction was not experimentally validated in the study.\",\n      \"method\": \"Template-based protein structure prediction and computational docking (Zdock); no experimental binding validation performed\",\n      \"journal\": \"Pharmacogenetics and genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — purely computational prediction with no experimental confirmation of the protein-protein interaction\",\n      \"pmids\": [\"22366774\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DCAF4 (also known as WDR21A) functions as a substrate receptor subunit of the CRL4 Cullin-RING E3 ubiquitin ligase complex, assembling with CUL4A/4B and DDB1 to ubiquitinate and degrade the tumor suppressor ST7; it also ubiquitinates the autophagy receptor optineurin (OPTN), thereby promoting autophagic clearance of misfolded SOD1, with upstream regulation of the complex provided by c-MYC-driven transcription of CUL4A/4B.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DCAF4 (WDR21A) is a substrate receptor subunit of the CRL4 Cullin-RING E3 ubiquitin ligase, assembling with CUL4A/4B and DDB1 to target specific proteins for ubiquitination and degradation [#0]. In colitis-associated and colorectal cancer cells, CRL4DCAF4 ubiquitinates the tumor suppressor ST7 and directs it to proteasomal degradation, thereby promoting tumor cell growth; this activity requires intact CUL4-DDB1 scaffolding, since disrupting that interaction abolishes ST7 turnover and inhibits tumor growth [#0, #2]. The complex's output is set transcriptionally upstream: inflammation-driven loss of miR-34b-5p elevates c-MYC, which activates CUL4A/4B transcription and downstream CRL4DCAF4 activity toward ST7 [#3]. Beyond this oncogenic axis, DCAF4 also mediates ubiquitination of the autophagy receptor optineurin (OPTN), promoting autophagic clearance of misfolded SOD1 and linking the ligase to proteostasis relevant to ALS [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"An initial structural hypothesis asked what fold DCAF4/WDR21A adopts and what it might bind, establishing it as a WD-repeat protein potentially engaging the glucocorticoid receptor.\",\n      \"evidence\": \"Template-based structure prediction and computational docking (Zdock), no experimental binding validation\",\n      \"pmids\": [\"22366774\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational prediction with no experimental confirmation of the GR interaction\", \"Does not establish any enzymatic or ligase function\", \"WD-repeat fold inferred, not solved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined DCAF4's biochemical identity by showing it serves as a substrate receptor within a CRL4 complex that ubiquitinates and degrades the tumor suppressor ST7, establishing its oncogenic role in colitis-associated cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro and in vivo ubiquitination assays, and knockdown with colony formation and tumor growth readouts across multiple cell lines and models\",\n      \"pmids\": [\"30945288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate range beyond ST7 not mapped\", \"Structural basis of ST7 recognition by the WD-repeat domain not resolved\", \"Whether ST7 is a direct or indirect substrate of the receptor not fully dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended DCAF4 function beyond cancer by showing it ubiquitinates the autophagy receptor OPTN to drive autophagic clearance of misfolded SOD1, linking the ligase to proteostasis and ALS.\",\n      \"evidence\": \"Genome-wide siRNA screen, time-resolved FRET for SOD1 conformation, ubiquitination assays, and autophagy flux experiments in a single lab\",\n      \"pmids\": [\"32014991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Two orthogonal methods but not independently replicated\", \"Whether OPTN ubiquitination uses the same CUL4-DDB1 scaffold not directly tested\", \"Type/topology of ubiquitin chains on OPTN unspecified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Validated the scaffolding requirement for DCAF4 ligase activity by showing small-molecule disruption of CUL4A-DDB1 blocks complex assembly, ST7 degradation, and tumor growth.\",\n      \"evidence\": \"AlphaScreen protein-protein interaction assay, biochemical assembly assays, proliferation/colony formation, and in vivo xenograft growth\",\n      \"pmids\": [\"32140073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab with one inhibitor compound\", \"Selectivity of NSC1892 for this complex not exhaustively established\", \"Does not address DCAF4-specific (versus general CRL4) dependence\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed CRL4DCAF4 in a regulatory hierarchy by showing that inflammation-driven loss of miR-34b-5p de-represses c-MYC, which transcriptionally activates CUL4A/4B to elevate ligase activity against ST7.\",\n      \"evidence\": \"miRNA-target luciferase assays, oncogenic phenotype assays, in vivo tumor formation, and c-MYC rescue experiments\",\n      \"pmids\": [\"31972160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; mechanism inferred from rescue rather than endogenous chromatin occupancy data\", \"Whether DCAF4 itself is transcriptionally regulated by this axis not shown\", \"Generalizability beyond colitis-associated cancer not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full substrate repertoire of CRL4DCAF4 and the structural basis by which its WD-repeat domain selects ST7 versus OPTN remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of DCAF4 bound to a substrate\", \"Determinants of substrate choice across cancer versus autophagy contexts unknown\", \"Unbiased substrate identification (e.g. degradomics) not reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"CRL4 (CUL4A/4B-DDB1-DCAF4) E3 ubiquitin ligase\"],\n    \"partners\": [\"CUL4A\", \"CUL4B\", \"DDB1\", \"ST7\", \"OPTN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}