{"gene":"WDR76","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2015,"finding":"Yeast Cmr1 (ortholog of human WDR76) localizes to a novel intranuclear quality control compartment (INQ) in response to genotoxic stress, co-localizing with Mrc1/Claspin, Pph3, and the CCT chaperonin complex along with 25 other proteins; this compartment sequesters misfolded, ubiquitylated, and sumoylated proteins.","method":"Fluorescence microscopy, proteomic analysis, genetic interaction screens in S. cerevisiae","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (proteomics, imaging, genetic screens), replicated finding with human WDR76 orthologue validation","pmids":["25817432"],"is_preprint":false},{"year":2015,"finding":"Human WDR76 relocalized to nuclear foci and physically associated with the CCT chaperonin complex in response to proteasome inhibition and DNA damage, indicating an evolutionarily conserved function of the Cmr1/WDR76 axis in genotoxic stress response.","method":"Co-immunoprecipitation, fluorescence microscopy in human cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction and localization shown in human cells, but single lab study","pmids":["25817432"],"is_preprint":false},{"year":2019,"finding":"WDR76 functions as an E3 linker protein mediating polyubiquitination-dependent proteasomal degradation of RAS (HRAS, KRAS), thereby suppressing RAS signaling and tumorigenesis in hepatocellular carcinoma.","method":"Proteomic analysis of HCC tissue, co-immunoprecipitation, ubiquitination assays, WDR76 knockout mice, liver-specific WDR76 transgenic mice, cell proliferation/invasion assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including in vivo mouse models, biochemical ubiquitination assays, and proteomic identification","pmids":["30655611"],"is_preprint":false},{"year":2019,"finding":"WDR76-mediated RAS degradation suppresses cancer stem cell (CSC) activation and tumorigenesis in colorectal cancer; Wdr76-/- mice crossed with ApcMin/+ mice developed more and larger tumors with elevated RAS and β-catenin levels, and WDR76 modulated CRC spheroid formation.","method":"Wdr76-/- mouse genetics, ApcMin/+ crosses, histology, immunohistochemistry, immunoblotting, CRC spheroid culture with WDR76 overexpression/knockdown","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse genetics and cell-based functional assays, single lab","pmids":["31362761"],"is_preprint":false},{"year":2019,"finding":"WDR76 controls adipocyte differentiation and HFD-induced obesity via HRas destabilization; Wdr76-/- mice are resistant to HFD-induced obesity with elevated HRas, while liver-specific WDR76 transgenic mice show increased obesity with reduced HRas.","method":"Wdr76-/- mice, liver-specific Wdr76 transgenic mice, HFD model, western blotting, 3T3-L1 adipocyte differentiation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models with mechanistic protein-level readout, single lab","pmids":["31873167"],"is_preprint":false},{"year":2016,"finding":"WDR76 associates with histones H2A, H2B, and H4, and with DNA damage response proteins PARP1 and XRCC5, and with heterochromatin proteins CBX1, CBX3, and CBX5; WDR76 is rapidly recruited to sites of laser-induced DNA damage.","method":"Quantitative affinity purification-mass spectrometry (AP-MS), co-immunoprecipitation, quantitative live-cell imaging of laser-induced DNA damage","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP validated AP-MS interactions, live-cell imaging for recruitment, single lab","pmids":["27248496"],"is_preprint":false},{"year":2019,"finding":"WDR76 interacts with the CCT complex via its WD40 repeat domain, and interacts with DNA-PK-KU, PARP1, GAN, SIRT1, and histones outside of the WD40 domain; AP-MS coupled to size-exclusion chromatography resolved distinct WDR76-based protein complexes.","method":"Affinity purification coupled to mass spectrometry (AP-MS), size-exclusion chromatography, reciprocal Co-IP validation","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS with biochemical fractionation and reciprocal validation for select interactions (GAN, SIRT1), single lab","pmids":["31353912"],"is_preprint":false},{"year":2024,"finding":"WDR76 forms a complex with SPIN1, a histone reader that recognizes H3K4me3; the WDR76:SPIN1 complex copurifies with core histones bearing the H3K4me3 mark, and structural modeling places SPIN1 recognizing H3K4me3 while interacting with WDR76; the complex is implicated in the DNA damage response.","method":"Serial capture affinity purification (SCAP), cross-linking mass spectrometry, Bayesian integrative structural modeling (IMP), microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — structural model with cross-linking MS and SCAP, single lab, structural model is computational with experimental constraints","pmids":["39116123"],"is_preprint":false},{"year":2012,"finding":"S. cerevisiae Cmr1/YDL156W binds DNA in vitro and exhibits preferential affinity for UV-damaged DNA substrates; chromatin fractionation showed Cmr1 enrichment in the chromatin fraction upon UV irradiation.","method":"DNA-cellulose column purification, in vitro DNA binding assays with UV-damaged DNA substrates, chromatin fractionation, mass spectrometry","journal":"Journal of microbiology (Seoul, Korea)","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical binding assay with UV-damaged DNA, single lab, yeast ortholog","pmids":["22367945"],"is_preprint":false},{"year":2016,"finding":"S. cerevisiae Cmr1 is recruited to coding regions of actively transcribed genes genome-wide in a transcription-dependent manner; its occupancy correlates with RNA Pol II occupancy and is stimulated by Pol II CTD kinase Kin28 and histone deacetylases Rpd3 and Hos2; Cmr1 facilitates Pol II occupancy at coding sequences but is dispensable for co-transcriptional histone occupancy and modification.","method":"ChIP-seq, genome-wide occupancy analysis, genetic deletion of Kin28, Rpd3, Hos2, Pol II ChIP in cmr1Δ cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with genetic epistasis, single lab, yeast ortholog","pmids":["26848854"],"is_preprint":false},{"year":2022,"finding":"The natural compound kurarinone induces G0/G1 cell cycle arrest in colorectal cancer cells by promoting WDR76-dependent proteasomal degradation of K-RAS, leading to downregulation of cyclin D1/D3 and CDK4/6.","method":"Western blotting, cell viability assays, flow cytometry cell cycle analysis, proteasome inhibitor rescue experiments","journal":"European journal of pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological intervention with western blot readout, no direct ubiquitination assay, single lab","pmids":["35381263"],"is_preprint":false},{"year":2025,"finding":"WDR76 couples with CUL1 E3 ligase (not CUL4) to promote degradation of both wild-type and mutant KRAS; UBE2C cooperates with APC/C-CDH1 to degrade WDR76 via a KEN-box motif, leading to KRAS accumulation and MAPK pathway activation in pancreatic cancer.","method":"Co-immunoprecipitation, ubiquitination assays, AAV-mediated WDR76 knockdown in mouse pancreas, KrasG12D-driven mouse models, western blotting","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models with AAV rescue experiment and biochemical E3 ligase characterization, single lab","pmids":["40889735"],"is_preprint":false},{"year":2023,"finding":"WDR76-mediated degradation of HRAS underlies 5-fluorouracil sensitivity in colon cancer; WDR76 overexpression sensitized resistant cells to 5-FU, while knockdown enhanced resistance that was reversed by HRAS inhibitor Kobe006.","method":"Western blotting, qRT-PCR, cell viability assay, colony formation assay, flow cytometry, xenograft mouse model","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays with inhibitor rescue but no direct ubiquitination assay, single lab","pmids":["37081180"],"is_preprint":false}],"current_model":"WDR76 is a WD40-repeat protein that functions as an E3 linker protein coupling with CUL1 to mediate polyubiquitination-dependent proteasomal degradation of RAS GTPases (HRAS, KRAS), thereby suppressing RAS/MAPK signaling, tumorigenesis, and adipogenesis; it is itself degraded by APC/C-CDH1 via UBE2C; it localizes to nuclear foci and is rapidly recruited to DNA damage sites where it associates with the CCT chaperonin complex, histones (via a SPIN1-H3K4me3 bridge), and DNA damage/heterochromatin proteins, participating in an intranuclear quality control compartment (INQ) that sequesters modified proteins during genotoxic stress."},"narrative":{"mechanistic_narrative":"WDR76 is a WD40-repeat protein with dual roles in genotoxic stress response and in the destabilization of RAS GTPases, linking nuclear quality control to suppression of RAS/MAPK signaling [PMID:25817432, PMID:30655611]. As an E3 linker protein, WDR76 couples with the CUL1 E3 ligase to drive polyubiquitination-dependent proteasomal degradation of both wild-type and mutant HRAS and KRAS, thereby restraining RAS signaling and tumorigenesis across hepatocellular, colorectal, and pancreatic cancers [PMID:30655611, PMID:40889735]. This activity has physiological consequences beyond cancer: loss of WDR76 elevates HRas and confers resistance to high-fat-diet-induced obesity, while WDR76-driven RAS degradation also limits cancer stem cell activation [PMID:31362761, PMID:31873167]. WDR76 itself is degraded by APC/C-CDH1 acting with the E2 enzyme UBE2C through a KEN-box motif, and its loss permits KRAS accumulation and MAPK pathway activation [PMID:40889735]. In parallel, WDR76 and its yeast ortholog Cmr1 are rapidly recruited to sites of DNA damage and concentrate within an intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins, in association with the CCT chaperonin complex [PMID:25817432, PMID:27248496]. WDR76 engages chromatin through multiple interactions: it binds core histones, the DNA damage proteins PARP1 and DNA-PK/KU, and heterochromatin proteins CBX1/3/5, and bridges to H3K4me3-marked nucleosomes via the histone reader SPIN1 [PMID:27248496, PMID:31353912, PMID:39116123].","teleology":[{"year":2012,"claim":"Establishing whether the ortholog had intrinsic chromatin activity, in vitro work showed Cmr1 binds DNA with preference for UV-damaged substrates and accumulates on chromatin after UV, framing it as a damage-responsive chromatin-associated protein.","evidence":"In vitro DNA-binding assays with UV-damaged substrates and chromatin fractionation in S. cerevisiae","pmids":["22367945"],"confidence":"Medium","gaps":["Does not identify the functional consequence of damaged-DNA binding","Yeast ortholog only; human WDR76 DNA-binding not tested"]},{"year":2015,"claim":"Connecting WDR76 to a cellular stress structure, Cmr1/WDR76 was shown to localize to a novel intranuclear quality control compartment (INQ) under genotoxic stress and to associate with the CCT chaperonin, defining a conserved role in protein quality control.","evidence":"Fluorescence microscopy, proteomics and genetic screens in yeast with reciprocal Co-IP and imaging in human cells","pmids":["25817432"],"confidence":"High","gaps":["Mechanism by which WDR76 promotes sequestration of misfolded proteins unresolved","Whether INQ recruitment depends on the WD40 domain not defined"]},{"year":2016,"claim":"To map WDR76's chromatin context, proteomic and imaging work identified its associations with core histones, PARP1/XRCC5 and heterochromatin CBX proteins and confirmed rapid recruitment to laser-induced damage, situating it within the DNA damage response.","evidence":"Quantitative AP-MS, reciprocal Co-IP, and live-cell laser micro-irradiation imaging in human cells","pmids":["27248496"],"confidence":"Medium","gaps":["Direct versus indirect nature of histone and CBX interactions not all resolved","Functional role in repair pathway choice undefined"]},{"year":2016,"claim":"Addressing whether chromatin association reflected transcription, genome-wide profiling showed Cmr1 occupies actively transcribed coding regions in a transcription-dependent manner and facilitates Pol II occupancy, broadening its chromatin function beyond damage.","evidence":"ChIP-seq and genetic epistasis (Kin28, Rpd3, Hos2) in S. cerevisiae","pmids":["26848854"],"confidence":"Medium","gaps":["Mechanism linking Cmr1 to Pol II occupancy unknown","Conservation of transcriptional role in human WDR76 untested"]},{"year":2019,"claim":"Defining a distinct molecular function, WDR76 was shown to act as an E3 linker driving polyubiquitination and proteasomal degradation of HRAS/KRAS, suppressing RAS signaling and tumorigenesis in vivo.","evidence":"HCC proteomics, Co-IP, ubiquitination assays, WDR76 knockout and liver-specific transgenic mouse models","pmids":["30655611"],"confidence":"High","gaps":["Identity of the partner E3 ligase not yet defined in this study","Relationship between RAS degradation and the nuclear INQ role unclear"]},{"year":2019,"claim":"Extending the RAS-degradation axis to physiology, mouse genetics showed WDR76 loss elevates RAS/HRas to accelerate intestinal tumorigenesis and cancer stem cell activation and to alter adipocyte differentiation and diet-induced obesity.","evidence":"Wdr76-/- mice, ApcMin/+ crosses, HFD models, 3T3-L1 differentiation and spheroid assays","pmids":["31362761","31873167"],"confidence":"Medium","gaps":["Tissue-specific determinants of which RAS isoform is targeted unresolved","Direct ubiquitination not re-demonstrated in adipocyte context"]},{"year":2019,"claim":"Dissecting WDR76's interaction architecture, AP-MS with size-exclusion chromatography resolved distinct complexes, mapping CCT binding to the WD40 domain and DNA-PK/KU, PARP1, GAN, SIRT1 and histone contacts outside it.","evidence":"AP-MS coupled to size-exclusion chromatography with reciprocal Co-IP validation","pmids":["31353912"],"confidence":"Medium","gaps":["Functional output of GAN and SIRT1 interactions undefined","Whether complexes are mutually exclusive in vivo unknown"]},{"year":2024,"claim":"Resolving how WDR76 reads chromatin marks, integrative structural modeling showed WDR76 forms a complex with the H3K4me3 reader SPIN1 that copurifies with H3K4me3-marked histones, providing a bridge to active chromatin in the damage response.","evidence":"Serial capture affinity purification, cross-linking MS and Bayesian integrative structural modeling with microscopy","pmids":["39116123"],"confidence":"Medium","gaps":["Structural model is computational with experimental constraints, not an experimental structure","Functional contribution of the SPIN1 bridge to repair untested"]},{"year":2025,"claim":"Identifying the E3 partner and the regulation of WDR76 itself, work showed WDR76 couples with CUL1 (not CUL4) to degrade wild-type and mutant KRAS, while APC/C-CDH1 with UBE2C degrades WDR76 via a KEN-box, completing a regulatory loop controlling MAPK activation.","evidence":"Co-IP, ubiquitination assays, AAV knockdown and KrasG12D-driven pancreatic mouse models","pmids":["40889735"],"confidence":"Medium","gaps":["Signals that engage APC/C-CDH1 toward WDR76 unknown","Single lab; CUL1 coupling mechanism not structurally defined"]},{"year":null,"claim":"How WDR76's nuclear quality-control/chromatin functions mechanistically connect to its cytoplasmic role as a CUL1-coupled RAS-degradation factor remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking INQ/DNA-damage recruitment to RAS ubiquitination","Determinants of WDR76 subcellular partitioning unknown","Whether human WDR76 retains the yeast transcription-elongation role untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,11]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[8]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[5,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[5,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,11]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,11]}],"complexes":["INQ (intranuclear quality control compartment)","WDR76-SPIN1 complex","CCT chaperonin (associated)"],"partners":["CUL1","KRAS","HRAS","SPIN1","PARP1","CBX5","SIRT1","UBE2C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H967","full_name":"WD repeat-containing protein 76","aliases":[],"length_aa":626,"mass_kda":69.8,"function":"Specifically binds 5-hydroxymethylcytosine (5hmC), suggesting that it acts as a specific reader of 5hmC","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9H967/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR76","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR76","total_profiled":1310},"omim":[{"mim_id":"620302","title":"WD REPEAT-CONTAINING PROTEIN 76; WDR76","url":"https://www.omim.org/entry/620302"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":18.0},{"tissue":"lymphoid tissue","ntpm":20.0}],"url":"https://www.proteinatlas.org/search/WDR76"},"hgnc":{"alias_symbol":["FLJ12973","Cmr1"],"prev_symbol":[]},"alphafold":{"accession":"Q9H967","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H967","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H967-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H967-F1-predicted_aligned_error_v6.png","plddt_mean":75.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR76","jax_strain_url":"https://www.jax.org/strain/search?query=WDR76"},"sequence":{"accession":"Q9H967","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H967.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H967/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H967"}},"corpus_meta":[{"pmid":"17237364","id":"PMC_17237364","title":"Melanin biosynthesis in the maize pathogen Cochliobolus heterostrophus depends on two mitogen-activated protein kinases, Chk1 and Mps1, and the transcription factor Cmr1.","date":"2007","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/17237364","citation_count":109,"is_preprint":false},{"pmid":"25817432","id":"PMC_25817432","title":"Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25817432","citation_count":80,"is_preprint":false},{"pmid":"30655611","id":"PMC_30655611","title":"WDR76 is a RAS binding protein that functions as a tumor suppressor via RAS degradation.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30655611","citation_count":41,"is_preprint":false},{"pmid":"31362761","id":"PMC_31362761","title":"WDR76 degrades RAS and suppresses cancer stem cell activation in colorectal cancer.","date":"2019","source":"Cell communication and signaling : 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this compartment sequesters misfolded, ubiquitylated, and sumoylated proteins.\",\n      \"method\": \"Fluorescence microscopy, proteomic analysis, genetic interaction screens in S. cerevisiae\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (proteomics, imaging, genetic screens), replicated finding with human WDR76 orthologue validation\",\n      \"pmids\": [\"25817432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human WDR76 relocalized to nuclear foci and physically associated with the CCT chaperonin complex in response to proteasome inhibition and DNA damage, indicating an evolutionarily conserved function of the Cmr1/WDR76 axis in genotoxic stress response.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy in human cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction and localization shown in human cells, but single lab study\",\n      \"pmids\": [\"25817432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WDR76 functions as an E3 linker protein mediating polyubiquitination-dependent proteasomal degradation of RAS (HRAS, KRAS), thereby suppressing RAS signaling and tumorigenesis in hepatocellular carcinoma.\",\n      \"method\": \"Proteomic analysis of HCC tissue, co-immunoprecipitation, ubiquitination assays, WDR76 knockout mice, liver-specific WDR76 transgenic mice, cell proliferation/invasion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including in vivo mouse models, biochemical ubiquitination assays, and proteomic identification\",\n      \"pmids\": [\"30655611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WDR76-mediated RAS degradation suppresses cancer stem cell (CSC) activation and tumorigenesis in colorectal cancer; Wdr76-/- mice crossed with ApcMin/+ mice developed more and larger tumors with elevated RAS and β-catenin levels, and WDR76 modulated CRC spheroid formation.\",\n      \"method\": \"Wdr76-/- mouse genetics, ApcMin/+ crosses, histology, immunohistochemistry, immunoblotting, CRC spheroid culture with WDR76 overexpression/knockdown\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse genetics and cell-based functional assays, single lab\",\n      \"pmids\": [\"31362761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WDR76 controls adipocyte differentiation and HFD-induced obesity via HRas destabilization; Wdr76-/- mice are resistant to HFD-induced obesity with elevated HRas, while liver-specific WDR76 transgenic mice show increased obesity with reduced HRas.\",\n      \"method\": \"Wdr76-/- mice, liver-specific Wdr76 transgenic mice, HFD model, western blotting, 3T3-L1 adipocyte differentiation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models with mechanistic protein-level readout, single lab\",\n      \"pmids\": [\"31873167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WDR76 associates with histones H2A, H2B, and H4, and with DNA damage response proteins PARP1 and XRCC5, and with heterochromatin proteins CBX1, CBX3, and CBX5; WDR76 is rapidly recruited to sites of laser-induced DNA damage.\",\n      \"method\": \"Quantitative affinity purification-mass spectrometry (AP-MS), co-immunoprecipitation, quantitative live-cell imaging of laser-induced DNA damage\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP validated AP-MS interactions, live-cell imaging for recruitment, single lab\",\n      \"pmids\": [\"27248496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WDR76 interacts with the CCT complex via its WD40 repeat domain, and interacts with DNA-PK-KU, PARP1, GAN, SIRT1, and histones outside of the WD40 domain; AP-MS coupled to size-exclusion chromatography resolved distinct WDR76-based protein complexes.\",\n      \"method\": \"Affinity purification coupled to mass spectrometry (AP-MS), size-exclusion chromatography, reciprocal Co-IP validation\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS with biochemical fractionation and reciprocal validation for select interactions (GAN, SIRT1), single lab\",\n      \"pmids\": [\"31353912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WDR76 forms a complex with SPIN1, a histone reader that recognizes H3K4me3; the WDR76:SPIN1 complex copurifies with core histones bearing the H3K4me3 mark, and structural modeling places SPIN1 recognizing H3K4me3 while interacting with WDR76; the complex is implicated in the DNA damage response.\",\n      \"method\": \"Serial capture affinity purification (SCAP), cross-linking mass spectrometry, Bayesian integrative structural modeling (IMP), microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structural model with cross-linking MS and SCAP, single lab, structural model is computational with experimental constraints\",\n      \"pmids\": [\"39116123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S. cerevisiae Cmr1/YDL156W binds DNA in vitro and exhibits preferential affinity for UV-damaged DNA substrates; chromatin fractionation showed Cmr1 enrichment in the chromatin fraction upon UV irradiation.\",\n      \"method\": \"DNA-cellulose column purification, in vitro DNA binding assays with UV-damaged DNA substrates, chromatin fractionation, mass spectrometry\",\n      \"journal\": \"Journal of microbiology (Seoul, Korea)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical binding assay with UV-damaged DNA, single lab, yeast ortholog\",\n      \"pmids\": [\"22367945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S. cerevisiae Cmr1 is recruited to coding regions of actively transcribed genes genome-wide in a transcription-dependent manner; its occupancy correlates with RNA Pol II occupancy and is stimulated by Pol II CTD kinase Kin28 and histone deacetylases Rpd3 and Hos2; Cmr1 facilitates Pol II occupancy at coding sequences but is dispensable for co-transcriptional histone occupancy and modification.\",\n      \"method\": \"ChIP-seq, genome-wide occupancy analysis, genetic deletion of Kin28, Rpd3, Hos2, Pol II ChIP in cmr1Δ cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with genetic epistasis, single lab, yeast ortholog\",\n      \"pmids\": [\"26848854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The natural compound kurarinone induces G0/G1 cell cycle arrest in colorectal cancer cells by promoting WDR76-dependent proteasomal degradation of K-RAS, leading to downregulation of cyclin D1/D3 and CDK4/6.\",\n      \"method\": \"Western blotting, cell viability assays, flow cytometry cell cycle analysis, proteasome inhibitor rescue experiments\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological intervention with western blot readout, no direct ubiquitination assay, single lab\",\n      \"pmids\": [\"35381263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WDR76 couples with CUL1 E3 ligase (not CUL4) to promote degradation of both wild-type and mutant KRAS; UBE2C cooperates with APC/C-CDH1 to degrade WDR76 via a KEN-box motif, leading to KRAS accumulation and MAPK pathway activation in pancreatic cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, AAV-mediated WDR76 knockdown in mouse pancreas, KrasG12D-driven mouse models, western blotting\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models with AAV rescue experiment and biochemical E3 ligase characterization, single lab\",\n      \"pmids\": [\"40889735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WDR76-mediated degradation of HRAS underlies 5-fluorouracil sensitivity in colon cancer; WDR76 overexpression sensitized resistant cells to 5-FU, while knockdown enhanced resistance that was reversed by HRAS inhibitor Kobe006.\",\n      \"method\": \"Western blotting, qRT-PCR, cell viability assay, colony formation assay, flow cytometry, xenograft mouse model\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays with inhibitor rescue but no direct ubiquitination assay, single lab\",\n      \"pmids\": [\"37081180\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR76 is a WD40-repeat protein that functions as an E3 linker protein coupling with CUL1 to mediate polyubiquitination-dependent proteasomal degradation of RAS GTPases (HRAS, KRAS), thereby suppressing RAS/MAPK signaling, tumorigenesis, and adipogenesis; it is itself degraded by APC/C-CDH1 via UBE2C; it localizes to nuclear foci and is rapidly recruited to DNA damage sites where it associates with the CCT chaperonin complex, histones (via a SPIN1-H3K4me3 bridge), and DNA damage/heterochromatin proteins, participating in an intranuclear quality control compartment (INQ) that sequesters modified proteins during genotoxic stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR76 is a WD40-repeat protein with dual roles in genotoxic stress response and in the destabilization of RAS GTPases, linking nuclear quality control to suppression of RAS/MAPK signaling [#0, #2]. As an E3 linker protein, WDR76 couples with the CUL1 E3 ligase to drive polyubiquitination-dependent proteasomal degradation of both wild-type and mutant HRAS and KRAS, thereby restraining RAS signaling and tumorigenesis across hepatocellular, colorectal, and pancreatic cancers [#2, #11]. This activity has physiological consequences beyond cancer: loss of WDR76 elevates HRas and confers resistance to high-fat-diet-induced obesity, while WDR76-driven RAS degradation also limits cancer stem cell activation [#3, #4]. WDR76 itself is degraded by APC/C-CDH1 acting with the E2 enzyme UBE2C through a KEN-box motif, and its loss permits KRAS accumulation and MAPK pathway activation [#11]. In parallel, WDR76 and its yeast ortholog Cmr1 are rapidly recruited to sites of DNA damage and concentrate within an intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins, in association with the CCT chaperonin complex [#0, #1, #5]. WDR76 engages chromatin through multiple interactions: it binds core histones, the DNA damage proteins PARP1 and DNA-PK/KU, and heterochromatin proteins CBX1/3/5, and bridges to H3K4me3-marked nucleosomes via the histone reader SPIN1 [#5, #6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing whether the ortholog had intrinsic chromatin activity, in vitro work showed Cmr1 binds DNA with preference for UV-damaged substrates and accumulates on chromatin after UV, framing it as a damage-responsive chromatin-associated protein.\",\n      \"evidence\": \"In vitro DNA-binding assays with UV-damaged substrates and chromatin fractionation in S. cerevisiae\",\n      \"pmids\": [\"22367945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the functional consequence of damaged-DNA binding\", \"Yeast ortholog only; human WDR76 DNA-binding not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connecting WDR76 to a cellular stress structure, Cmr1/WDR76 was shown to localize to a novel intranuclear quality control compartment (INQ) under genotoxic stress and to associate with the CCT chaperonin, defining a conserved role in protein quality control.\",\n      \"evidence\": \"Fluorescence microscopy, proteomics and genetic screens in yeast with reciprocal Co-IP and imaging in human cells\",\n      \"pmids\": [\"25817432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which WDR76 promotes sequestration of misfolded proteins unresolved\", \"Whether INQ recruitment depends on the WD40 domain not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"To map WDR76's chromatin context, proteomic and imaging work identified its associations with core histones, PARP1/XRCC5 and heterochromatin CBX proteins and confirmed rapid recruitment to laser-induced damage, situating it within the DNA damage response.\",\n      \"evidence\": \"Quantitative AP-MS, reciprocal Co-IP, and live-cell laser micro-irradiation imaging in human cells\",\n      \"pmids\": [\"27248496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect nature of histone and CBX interactions not all resolved\", \"Functional role in repair pathway choice undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Addressing whether chromatin association reflected transcription, genome-wide profiling showed Cmr1 occupies actively transcribed coding regions in a transcription-dependent manner and facilitates Pol II occupancy, broadening its chromatin function beyond damage.\",\n      \"evidence\": \"ChIP-seq and genetic epistasis (Kin28, Rpd3, Hos2) in S. cerevisiae\",\n      \"pmids\": [\"26848854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking Cmr1 to Pol II occupancy unknown\", \"Conservation of transcriptional role in human WDR76 untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining a distinct molecular function, WDR76 was shown to act as an E3 linker driving polyubiquitination and proteasomal degradation of HRAS/KRAS, suppressing RAS signaling and tumorigenesis in vivo.\",\n      \"evidence\": \"HCC proteomics, Co-IP, ubiquitination assays, WDR76 knockout and liver-specific transgenic mouse models\",\n      \"pmids\": [\"30655611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the partner E3 ligase not yet defined in this study\", \"Relationship between RAS degradation and the nuclear INQ role unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extending the RAS-degradation axis to physiology, mouse genetics showed WDR76 loss elevates RAS/HRas to accelerate intestinal tumorigenesis and cancer stem cell activation and to alter adipocyte differentiation and diet-induced obesity.\",\n      \"evidence\": \"Wdr76-/- mice, ApcMin/+ crosses, HFD models, 3T3-L1 differentiation and spheroid assays\",\n      \"pmids\": [\"31362761\", \"31873167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific determinants of which RAS isoform is targeted unresolved\", \"Direct ubiquitination not re-demonstrated in adipocyte context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissecting WDR76's interaction architecture, AP-MS with size-exclusion chromatography resolved distinct complexes, mapping CCT binding to the WD40 domain and DNA-PK/KU, PARP1, GAN, SIRT1 and histone contacts outside it.\",\n      \"evidence\": \"AP-MS coupled to size-exclusion chromatography with reciprocal Co-IP validation\",\n      \"pmids\": [\"31353912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of GAN and SIRT1 interactions undefined\", \"Whether complexes are mutually exclusive in vivo unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolving how WDR76 reads chromatin marks, integrative structural modeling showed WDR76 forms a complex with the H3K4me3 reader SPIN1 that copurifies with H3K4me3-marked histones, providing a bridge to active chromatin in the damage response.\",\n      \"evidence\": \"Serial capture affinity purification, cross-linking MS and Bayesian integrative structural modeling with microscopy\",\n      \"pmids\": [\"39116123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model is computational with experimental constraints, not an experimental structure\", \"Functional contribution of the SPIN1 bridge to repair untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying the E3 partner and the regulation of WDR76 itself, work showed WDR76 couples with CUL1 (not CUL4) to degrade wild-type and mutant KRAS, while APC/C-CDH1 with UBE2C degrades WDR76 via a KEN-box, completing a regulatory loop controlling MAPK activation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, AAV knockdown and KrasG12D-driven pancreatic mouse models\",\n      \"pmids\": [\"40889735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals that engage APC/C-CDH1 toward WDR76 unknown\", \"Single lab; CUL1 coupling mechanism not structurally defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR76's nuclear quality-control/chromatin functions mechanistically connect to its cytoplasmic role as a CUL1-coupled RAS-degradation factor remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking INQ/DNA-damage recruitment to RAS ubiquitination\", \"Determinants of WDR76 subcellular partitioning unknown\", \"Whether human WDR76 retains the yeast transcription-elongation role untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"complexes\": [\n      \"INQ (intranuclear quality control compartment)\",\n      \"WDR76-SPIN1 complex\",\n      \"CCT chaperonin (associated)\"\n    ],\n    \"partners\": [\n      \"CUL1\",\n      \"KRAS\",\n      \"HRAS\",\n      \"SPIN1\",\n      \"PARP1\",\n      \"CBX5\",\n      \"SIRT1\",\n      \"UBE2C\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}