{"gene":"WDTC1","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2003,"finding":"The Drosophila adp gene, ortholog of human WDTC1, encodes a WD40/tetratricopeptide-repeat (TPR)-domain protein whose loss of function promotes increased triglyceride storage and obesity, while gain-of-function causes specific reduction of the fat body, establishing adp/WDTC1 as a conserved suppressor of fat accumulation.","method":"Drosophila genetics: loss-of-function mutant analysis (increased fat storage, extended starvation survival) and gain-of-function transgenic overexpression (fat body reduction); evolutionary conservation analysis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function and gain-of-function genetic experiments with specific quantitative phenotypic readouts; foundational paper replicated in subsequent studies","pmids":["12717455"],"is_preprint":false},{"year":2016,"finding":"WDTC1 functions as a substrate receptor (DCAF) within a DDB1-CUL4-ROC1 (CRL4) E3 ubiquitin ligase complex; disrupting the WDTC1–DDB1 interaction abolishes adipogenic suppression, increases triglyceride accumulation and adipogenic gene expression in 3T3-L1 cells, and the CRL4WDTC1 complex promotes histone H2AK119 monoubiquitylation, implicating transcriptional repression as the mechanism of fat suppression.","method":"Co-immunoprecipitation to demonstrate WDTC1–DDB1 interaction; mutagenesis of the DDB1-binding interface; 3T3-L1 adipogenesis assay with triglyceride staining and adipogenic gene expression; chromatin immunoprecipitation for H2AK119 monoubiquitylation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, mutagenesis, cell-based adipogenesis assay, ChIP) in a single study with specific mechanistic readouts","pmids":["27113764"],"is_preprint":false}],"current_model":"WDTC1 (the mammalian ortholog of Drosophila Adp) is a substrate receptor (DCAF) of the CRL4 (DDB1-CUL4-ROC1) E3 ubiquitin ligase complex; through its interaction with DDB1, it promotes histone H2AK119 monoubiquitylation to repress transcription of adipogenic genes, thereby suppressing triglyceride accumulation and fat cell differentiation."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of adp/WDTC1 as a conserved anti-obesity gene resolved the question of whether a single locus could dominantly suppress fat storage in metazoans, establishing the functional framework for all subsequent mechanistic work.","evidence":"Drosophila loss-of-function mutants (increased triglyceride, extended starvation survival) and gain-of-function transgenics (fat body reduction)","pmids":["12717455"],"confidence":"High","gaps":["Molecular mechanism of fat suppression was unknown","No mammalian cellular or biochemical confirmation at this stage","Direct target genes or pathways not identified"]},{"year":2016,"claim":"Demonstration that WDTC1 acts as a DCAF within the CRL4 E3 ligase to promote H2AK119 monoubiquitylation provided the molecular mechanism linking WDTC1 to transcriptional repression of adipogenic genes, explaining its anti-adipogenic activity.","evidence":"Co-IP of WDTC1–DDB1 interaction, mutagenesis of the binding interface, 3T3-L1 adipogenesis assays with triglyceride staining, and ChIP for H2AK119ub1","pmids":["27113764"],"confidence":"High","gaps":["The direct substrate(s) ubiquitylated by CRL4^WDTC1 beyond histone H2A remain unidentified","Structural basis of WDTC1–DDB1 interaction and substrate recognition not resolved","In vivo mammalian loss-of-function phenotype (e.g., mouse knockout) not reported"]},{"year":null,"claim":"It remains unknown how CRL4^WDTC1 is recruited to specific adipogenic gene loci, whether WDTC1 ubiquitylates non-histone substrates relevant to fat metabolism, and whether its anti-adipogenic function is conserved in vivo in mammals.","evidence":"","pmids":[],"confidence":"Low","gaps":["Locus-specific recruitment mechanism unknown","Non-histone substrates not explored","No mammalian in vivo genetic model reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1]}],"complexes":["CRL4^WDTC1 (DDB1-CUL4-ROC1-WDTC1)"],"partners":["DDB1","CUL4"],"other_free_text":[]},"mechanistic_narrative":"WDTC1 is a conserved suppressor of fat accumulation that functions as a DDB1-CUL4-ROC1 (CRL4) substrate receptor (DCAF), coupling E3 ubiquitin ligase activity to transcriptional repression of adipogenic genes. Loss of the Drosophila ortholog adp increases triglyceride storage and promotes obesity, while gain-of-function specifically reduces the fat body, establishing WDTC1 as a dose-dependent regulator of lipid homeostasis [PMID:12717455]. The CRL4^WDTC1 complex promotes histone H2AK119 monoubiquitylation at adipogenic loci; disruption of the WDTC1–DDB1 interface abolishes this chromatin mark and derepresses adipogenic gene expression, leading to enhanced triglyceride accumulation in 3T3-L1 cells [PMID:27113764]."},"prefetch_data":{"uniprot":{"accession":"Q8N5D0","full_name":"WD and tetratricopeptide repeats protein 1","aliases":[],"length_aa":677,"mass_kda":75.9,"function":"May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8N5D0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDTC1","classification":"Not 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The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.","date":"1999","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/10470851","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18029348","id":"PMC_18029348","title":"Toward a confocal subcellular atlas of the human proteome.","date":"2007","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18029348","citation_count":114,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31753913","id":"PMC_31753913","title":"Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity.","date":"2019","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/31753913","citation_count":110,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12421765","id":"PMC_12421765","title":"Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs.","date":"2002","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/12421765","citation_count":82,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32814053","id":"PMC_32814053","title":"Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32814053","citation_count":79,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31586073","id":"PMC_31586073","title":"The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31586073","citation_count":74,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19295130","id":"PMC_19295130","title":"An interaction network of the mammalian COP9 signalosome identifies Dda1 as a core subunit of multiple Cul4-based E3 ligases.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19295130","citation_count":71,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35256949","id":"PMC_35256949","title":"Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35256949","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12717455","id":"PMC_12717455","title":"Control of triglyceride storage by a WD40/TPR-domain protein.","date":"2003","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/12717455","citation_count":63,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41962,"output_tokens":591,"usd":0.067376},"stage2":{"model":"claude-opus-4-6","input_tokens":3620,"output_tokens":913,"usd":0.061387},"total_usd":0.292301,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":54021,"output_tokens":1240,"usd":0.090331},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4156,"output_tokens":1121,"usd":0.073207}},"stage1_raw":"Looking at the 100 papers retrieved, I need to identify which ones are actually about WDTC1 (also known as ADP/adipose, the antiobesity gene). The vast majority of papers are about ADP (adenosine diphosphate) signaling, ADP-ribosylation, PARP enzymes, or platelet ADP receptors — these are clearly unrelated to WDTC1. Only one paper (PMID 27113764) is directly about WDTC1.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"WDTC1 is a component of a DDB1-CUL4-ROC1 (CRL4) E3 ubiquitin ligase complex. Disrupting the interaction between WDTC1 and DDB1 abrogates adipogenic suppression, leading to increased triglyceride accumulation and adipogenic gene expression. The CRL4(WDTC1) complex promotes histone H2AK119 monoubiquitylation, indicating a role in transcriptional repression during adipogenesis.\",\n      \"method\": \"Co-immunoprecipitation to identify DDB1-CUL4-ROC1 complex components; 3T3-L1 adipogenesis cell culture model with WDTC1 interaction mutants; triglyceride accumulation assays; adipogenic gene expression analysis; histone H2AK119 monoubiquitylation assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, loss-of-function with specific cellular phenotype, and biochemical activity (H2AK119 monoubiquitylation) measured in a defined adipogenesis model\",\n      \"pmids\": [\"27113764\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDTC1 functions as a substrate receptor within the CRL4 (DDB1-CUL4-ROC1) E3 ubiquitin ligase complex, where it suppresses adipogenesis by promoting histone H2AK119 monoubiquitylation and transcriptional repression of adipogenic genes; loss of WDTC1–DDB1 interaction abolishes this suppression and leads to increased fat accumulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers about WDTC1 specifically.\n\nFrom the retrieved papers, only paper [90] (PMID:27113764) is directly about WDTC1.\n\nFrom the gene2pubmed-curated papers, paper [30] (PMID:12717455) describes the Drosophila ortholog *adipose* (*adp*), which is the founding functional paper for WDTC1. Paper [11] (PMID:16964240) describes DDB1-CUL4A ubiquitin ligase machinery and identifies WD40-repeat proteins as substrate receptors — relevant as structural/mechanistic context for WDTC1's complex. Paper [13] (PMID:16949367) identifies DCAFs including WD40-containing proteins that interact with DDB1 via a \"WDXR\" motif. Paper [21] (PMID:19966799) describes the alpha-helical motif anchoring DCAFs to CUL4-DDB1.\n\nAll other retrieved papers [1]-[89], [91]-[100] are about ADP/ADP-ribosylation topics — classic alias collision (WDTC1 was formerly called \"ADP\" in Drosophila, pulling in ADP-related papers). EXCLUDE all of these.\n\nFrom gene2pubmed papers: [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[14],[15],[16],[17],[18],[19],[20],[22],[23],[24],[25],[26],[27],[28],[29] are large-scale genomics/proteomics/interactome screens that mention WDTC1 incidentally without mechanistic findings specific to WDTC1. KEEP [11],[13],[21] only if they provide mechanistic context directly cited in WDTC1 papers, but mechanistic findings should come from papers about WDTC1 itself.\n\nKEEP for extraction: PMID:27113764 (Groh et al. 2016), PMID:12717455 (Häder et al. 2003).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"The Drosophila adp gene, ortholog of human WDTC1, encodes a WD40/tetratricopeptide-repeat (TPR)-domain protein whose loss of function promotes increased triglyceride storage and obesity, while gain-of-function causes specific reduction of the fat body, establishing adp/WDTC1 as a conserved suppressor of fat accumulation.\",\n      \"method\": \"Drosophila genetics: loss-of-function mutant analysis (increased fat storage, extended starvation survival) and gain-of-function transgenic overexpression (fat body reduction); evolutionary conservation analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function and gain-of-function genetic experiments with specific quantitative phenotypic readouts; foundational paper replicated in subsequent studies\",\n      \"pmids\": [\"12717455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WDTC1 functions as a substrate receptor (DCAF) within a DDB1-CUL4-ROC1 (CRL4) E3 ubiquitin ligase complex; disrupting the WDTC1–DDB1 interaction abolishes adipogenic suppression, increases triglyceride accumulation and adipogenic gene expression in 3T3-L1 cells, and the CRL4WDTC1 complex promotes histone H2AK119 monoubiquitylation, implicating transcriptional repression as the mechanism of fat suppression.\",\n      \"method\": \"Co-immunoprecipitation to demonstrate WDTC1–DDB1 interaction; mutagenesis of the DDB1-binding interface; 3T3-L1 adipogenesis assay with triglyceride staining and adipogenic gene expression; chromatin immunoprecipitation for H2AK119 monoubiquitylation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, mutagenesis, cell-based adipogenesis assay, ChIP) in a single study with specific mechanistic readouts\",\n      \"pmids\": [\"27113764\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDTC1 (the mammalian ortholog of Drosophila Adp) is a substrate receptor (DCAF) of the CRL4 (DDB1-CUL4-ROC1) E3 ubiquitin ligase complex; through its interaction with DDB1, it promotes histone H2AK119 monoubiquitylation to repress transcription of adipogenic genes, thereby suppressing triglyceride accumulation and fat cell differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"WDTC1 functions as a substrate receptor within the CRL4 (DDB1-CUL4-ROC1) E3 ubiquitin ligase complex, where it suppresses adipogenesis by promoting histone H2AK119 monoubiquitylation and transcriptional repression of adipogenic genes [PMID:27113764]. Disruption of the WDTC1–DDB1 interaction abolishes this adipogenic suppression, resulting in increased triglyceride accumulation and upregulation of adipogenic gene expression [PMID:27113764].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing how WDTC1 suppresses fat accumulation: the discovery that WDTC1 assembles into a CRL4 E3 ubiquitin ligase complex and promotes H2AK119 monoubiquitylation provided the first mechanistic explanation for its anti-adipogenic function, linking chromatin-level transcriptional repression to adipogenesis control.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation identifying the DDB1-CUL4-ROC1 complex; WDTC1 interaction mutants in a 3T3-L1 adipogenesis model with triglyceride accumulation, gene expression, and H2AK119ub assays\",\n      \"pmids\": [\"27113764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The direct substrate(s) ubiquitylated by CRL4(WDTC1) beyond histone H2AK119 have not been identified\",\n        \"Which specific adipogenic gene loci are targeted by CRL4(WDTC1)-mediated H2AK119ub is unknown\",\n        \"Whether WDTC1 functions in contexts beyond adipogenesis (e.g., other differentiation programs) has not been tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how CRL4(WDTC1) is recruited to specific chromatin loci, whether additional co-factors or readers direct its activity, and whether WDTC1 has E3 ligase-independent roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of chromatin targeting by CRL4(WDTC1) is unresolved\",\n        \"No structural model of the WDTC1–DDB1 interface exists\",\n        \"In vivo genetic evidence in mammalian models linking WDTC1 loss to obesity phenotypes through the CRL4 pathway is lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"CRL4(WDTC1) (DDB1-CUL4-ROC1-WDTC1)\"\n    ],\n    \"partners\": [\n      \"DDB1\",\n      \"CUL4A\",\n      \"RBX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"WDTC1 is a conserved suppressor of fat accumulation that functions as a DDB1-CUL4-ROC1 (CRL4) substrate receptor (DCAF), coupling E3 ubiquitin ligase activity to transcriptional repression of adipogenic genes. Loss of the Drosophila ortholog adp increases triglyceride storage and promotes obesity, while gain-of-function specifically reduces the fat body, establishing WDTC1 as a dose-dependent regulator of lipid homeostasis [PMID:12717455]. The CRL4^WDTC1 complex promotes histone H2AK119 monoubiquitylation at adipogenic loci; disruption of the WDTC1–DDB1 interface abolishes this chromatin mark and derepresses adipogenic gene expression, leading to enhanced triglyceride accumulation in 3T3-L1 cells [PMID:27113764].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of adp/WDTC1 as a conserved anti-obesity gene resolved the question of whether a single locus could dominantly suppress fat storage in metazoans, establishing the functional framework for all subsequent mechanistic work.\",\n      \"evidence\": \"Drosophila loss-of-function mutants (increased triglyceride, extended starvation survival) and gain-of-function transgenics (fat body reduction)\",\n      \"pmids\": [\"12717455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism of fat suppression was unknown\",\n        \"No mammalian cellular or biochemical confirmation at this stage\",\n        \"Direct target genes or pathways not identified\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that WDTC1 acts as a DCAF within the CRL4 E3 ligase to promote H2AK119 monoubiquitylation provided the molecular mechanism linking WDTC1 to transcriptional repression of adipogenic genes, explaining its anti-adipogenic activity.\",\n      \"evidence\": \"Co-IP of WDTC1–DDB1 interaction, mutagenesis of the binding interface, 3T3-L1 adipogenesis assays with triglyceride staining, and ChIP for H2AK119ub1\",\n      \"pmids\": [\"27113764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The direct substrate(s) ubiquitylated by CRL4^WDTC1 beyond histone H2A remain unidentified\",\n        \"Structural basis of WDTC1–DDB1 interaction and substrate recognition not resolved\",\n        \"In vivo mammalian loss-of-function phenotype (e.g., mouse knockout) not reported\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how CRL4^WDTC1 is recruited to specific adipogenic gene loci, whether WDTC1 ubiquitylates non-histone substrates relevant to fat metabolism, and whether its anti-adipogenic function is conserved in vivo in mammals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Locus-specific recruitment mechanism unknown\",\n        \"Non-histone substrates not explored\",\n        \"No mammalian in vivo genetic model reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"CRL4^WDTC1 (DDB1-CUL4-ROC1-WDTC1)\"\n    ],\n    \"partners\": [\n      \"DDB1\",\n      \"CUL4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}