{"gene":"WDR46","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2013,"finding":"WDR46 is a highly insoluble nucleolar scaffold protein whose N- and C-terminal intrinsically disordered regions are required for its own nucleolar localization and for association with binding partners nucleolin, DDX21, NOP2, and EBP2. Knockdown of WDR46 caused mislocalization of nucleolin and DDX21 (involved in 18S rRNA processing) from the granular component to the edges of nucleoli, while NOP2 and EBP2 (involved in 28S rRNA processing) were unaffected. WDR46 ensures proper recruitment of nucleolin and DDX21 to nucleoli in daughter cells after cell division.","method":"siRNA knockdown, fluorescence microscopy, domain deletion analysis, co-immunoprecipitation/binding partner identification","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype and domain analysis, single lab, two orthogonal methods (knockdown + domain deletion)","pmids":["23848194"],"is_preprint":false},{"year":2014,"finding":"GFP-WDR46 localizes predominantly to the dense fibrillar component and granular component regions of nucleoli. FRAP analysis showed that approximately half of GFP-WDR46 has very low mobility in living cells, consistent with tight association with macro-protein complexes, functioning as a scaffold or core component. When rRNA transcription is suppressed, mobility of the immobile fraction is partially accelerated.","method":"GFP fusion protein live-cell imaging, FRAP analysis in HeLa cells, rRNA transcription suppression","journal":"Biochemistry and cell biology = Biochimie et biologie cellulaire","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell localization with FRAP functional analysis, single lab, two orthogonal methods","pmids":["24754225"],"is_preprint":false},{"year":2008,"finding":"Yeast ortholog Utp7 (WDR46 ortholog) is present at kinetochores in addition to the nucleolus, and associates with and regulates localization of Sli15 (INCENP) and Cdc14 phosphatase. Before anaphase onset, Utp7 prevents premature nucleolar release of Cdc14 and premature concentration of Sli15 on the spindle. Utp7 also regulates Sli15 localization and phosphorylation status independently of its effect on Cdc14, placing it at the intersection of ribosome biogenesis, chromosome segregation, and cell cycle control.","method":"Genetic epistasis, co-immunoprecipitation, localization studies in S. cerevisiae, phosphorylation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, epistasis, localization with functional consequence, multiple orthogonal methods in single rigorous study","pmids":["18794331"],"is_preprint":false},{"year":2011,"finding":"C. elegans WDR-46 (ortholog of WDR46/UTP7) is required for rRNA processing and is expressed in nucleoli. Mutation or silencing of WDR-46 activates the CnC transcription factor SKN-1 and increases expression of its detoxification target genes. The C. elegans p53 homologue CEP-1 is partially required for activation of gst-4 when wdr-46 is silenced, suggesting disruption of nucleolar function activates SKN-1 via a p53-dependent mechanism independent of protein translation.","method":"RNAi knockdown, mutant allele analysis, genetic epistasis (SKN-1, CEP-1 pathway), reporter gene assays in C. elegans","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple pathway components, single lab, ortholog system","pmids":["22240150"],"is_preprint":false},{"year":2025,"finding":"HBV core protein (HBC) enhances WDR46 protein stability by blocking the interaction between WDR46 and the E3 ubiquitin ligase TRIM25, thereby reducing WDR46 ubiquitination and preventing its degradation. HBC also enhances the interaction between WDR46 and transcription factor c-Myc, facilitating c-Myc recruitment to the NUSAP1 promoter and increasing NUSAP1 transcription. WDR46 is required for HBC-induced HCC cell growth and migration in vitro and in vivo.","method":"Co-immunoprecipitation, western blotting, chromatin immunoprecipitation, ubiquitination assays, in vitro and in vivo oncology functional assays","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, ubiquitination assay, multiple orthogonal methods in single lab study","pmids":["40366140"],"is_preprint":false}],"current_model":"WDR46 is a highly insoluble nucleolar scaffold protein (human/mammalian) and SSU processome component that, via its intrinsically disordered N- and C-terminal regions, anchors nucleolin and DDX21 in the granular compartment to support 18S rRNA processing; its yeast ortholog Utp7 additionally associates with kinetochore proteins Sli15/INCENP and Cdc14 phosphatase to coordinate chromosome segregation with ribosome biogenesis; in C. elegans, loss of the ortholog WDR-46 triggers nucleolar stress signaling through SKN-1/Nrf and p53/CEP-1; and in HCC, HBC stabilizes WDR46 by blocking TRIM25-mediated ubiquitination, allowing WDR46 to recruit c-Myc to the NUSAP1 promoter and promote tumor cell growth and migration."},"narrative":{"mechanistic_narrative":"WDR46 is a highly insoluble nucleolar scaffold protein that supports ribosome biogenesis by organizing factors required for small-subunit rRNA processing [PMID:23848194, PMID:24754225]. Through its intrinsically disordered N- and C-terminal regions, it anchors itself within the dense fibrillar and granular compartments of the nucleolus and binds nucleolin, DDX21, NOP2, and EBP2; loss of WDR46 selectively mislocalizes the 18S rRNA processing factors nucleolin and DDX21 to the nucleolar periphery while leaving the 28S processing factors NOP2 and EBP2 intact, establishing WDR46 as a recruitment hub that re-establishes the granular component in daughter cells after division [PMID:23848194]. FRAP measurements show a large, very-low-mobility WDR46 fraction tied to macro-protein complexes that is partly released when rRNA transcription is suppressed, consistent with a core structural role [PMID:24754225]. The yeast ortholog Utp7 extends this function to the cell cycle, localizing to kinetochores and regulating Sli15 (INCENP) and Cdc14 phosphatase to restrain their premature release/concentration before anaphase, linking ribosome biogenesis to chromosome segregation [PMID:18794331], and in C. elegans loss of the ortholog activates SKN-1/Nrf detoxification gene expression via the p53 homolog CEP-1, defining a nucleolar-stress signaling output [PMID:22240150]. In hepatocellular carcinoma, the HBV core protein stabilizes WDR46 by blocking TRIM25-mediated ubiquitination and promotes WDR46-dependent recruitment of c-Myc to the NUSAP1 promoter, driving tumor cell growth and migration [PMID:40366140].","teleology":[{"year":2008,"claim":"Whether a nucleolar WDR-repeat protein could couple ribosome biogenesis to mitotic control was unknown; characterization of the yeast ortholog Utp7 placed it at kinetochores regulating Sli15/INCENP and Cdc14, establishing a node connecting rRNA biogenesis with chromosome segregation.","evidence":"Reciprocal co-IP, genetic epistasis, localization and phosphorylation assays in S. cerevisiae","pmids":["18794331"],"confidence":"High","gaps":["Kinetochore role demonstrated only in yeast, not shown for human WDR46","Mechanism by which Utp7 restrains Cdc14/Sli15 not resolved at molecular level"]},{"year":2011,"claim":"It was unclear what cellular signaling follows disruption of nucleolar function; loss of the C. elegans ortholog was shown to activate the SKN-1/Nrf detoxification program partly through the p53 homolog CEP-1, defining a nucleolar-stress signaling output.","evidence":"RNAi, mutant allele analysis, genetic epistasis and reporter assays in C. elegans","pmids":["22240150"],"confidence":"Medium","gaps":["Molecular link between nucleolar disruption and SKN-1 activation undefined","Conservation of this stress axis in mammals untested"]},{"year":2013,"claim":"The molecular function of human WDR46 was unknown; knockdown and domain analysis showed it is an insoluble nucleolar scaffold whose disordered termini recruit nucleolin and DDX21 to selectively support 18S rRNA processing.","evidence":"siRNA knockdown, fluorescence microscopy, domain deletion, co-IP of binding partners in human cells","pmids":["23848194"],"confidence":"Medium","gaps":["Direct vs indirect binding to each partner not distinguished","Effect on mature 18S rRNA yield not quantified"]},{"year":2014,"claim":"The dynamic behavior of WDR46 in the nucleolus was unknown; live-cell imaging with FRAP demonstrated a large immobile fraction tied to macro-protein complexes that is partly mobilized when rRNA transcription stops, supporting a core scaffold role.","evidence":"GFP-fusion live-cell imaging and FRAP in HeLa cells with transcription suppression","pmids":["24754225"],"confidence":"Medium","gaps":["Identity of the complexes constraining mobility not defined","Single cell line"]},{"year":2025,"claim":"Whether WDR46 contributes to disease was unaddressed; in HCC the HBV core protein stabilizes WDR46 by blocking TRIM25-mediated ubiquitination and routes it to co-activate c-Myc at the NUSAP1 promoter, driving tumor growth and migration.","evidence":"Co-IP, ChIP, ubiquitination assays, in vitro and in vivo oncology assays","pmids":["40366140"],"confidence":"Medium","gaps":["Direct WDR46–c-Myc binding interface not mapped","Whether transcriptional role is separable from nucleolar scaffold function unclear"]},{"year":null,"claim":"How WDR46's nucleolar scaffold function mechanistically integrates with its cell-cycle (kinetochore) and transcriptional (c-Myc) activities in human cells remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of WDR46 within the SSU processome","Human kinetochore association not tested","Substrate/target specificity of its disordered recruitment regions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]}],"complexes":["SSU processome"],"partners":["NCL","DDX21","NOP2","EBP2","TRIM25","MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15213","full_name":"WD repeat-containing protein 46","aliases":["WD repeat-containing protein BING4"],"length_aa":610,"mass_kda":68.1,"function":"Scaffold component of the nucleolar structure. Required for localization of DDX21 and NCL to the granular compartment of the nucleolus (PubMed:23848194). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797)","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/O15213/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR46","classification":"Common Essential","n_dependent_lines":1108,"n_total_lines":1208,"dependency_fraction":0.9172185430463576},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000227057","cell_line_id":"CID001086","localizations":[{"compartment":"nucleolus_gc","grade":3}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001086","total_profiled":1310},"omim":[{"mim_id":"611440","title":"WD REPEAT-CONTAINING PROTEIN 46; WDR46","url":"https://www.omim.org/entry/611440"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR46"},"hgnc":{"alias_symbol":["BING4","UTP7"],"prev_symbol":["C6orf11"]},"alphafold":{"accession":"O15213","domains":[{"cath_id":"2.130.10.10","chopping":"169-500","consensus_level":"medium","plddt":93.1487,"start":169,"end":500}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15213","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15213-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15213-F1-predicted_aligned_error_v6.png","plddt_mean":81.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR46","jax_strain_url":"https://www.jax.org/strain/search?query=WDR46"},"sequence":{"accession":"O15213","fasta_url":"https://rest.uniprot.org/uniprotkb/O15213.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15213/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15213"}},"corpus_meta":[{"pmid":"11859131","id":"PMC_11859131","title":"Identification of BING-4 cancer antigen translated from an alternative open reading frame of a gene in the extended MHC class II region using lymphocytes from a patient with a durable complete regression following immunotherapy.","date":"2002","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11859131","citation_count":50,"is_preprint":false},{"pmid":"9545376","id":"PMC_9545376","title":"TAPASIN, DAXX, RGL2, HKE2 and four new genes (BING 1, 3 to 5) form a dense cluster at the centromeric end of the MHC.","date":"1998","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9545376","citation_count":48,"is_preprint":false},{"pmid":"10452889","id":"PMC_10452889","title":"Gene organisation, sequence variation and isochore structure at the centromeric boundary of the human MHC.","date":"1999","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10452889","citation_count":47,"is_preprint":false},{"pmid":"10970097","id":"PMC_10970097","title":"Physical mapping and evolution of the centromeric class I gene-containing region of the rat MHC.","date":"2000","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/10970097","citation_count":33,"is_preprint":false},{"pmid":"23848194","id":"PMC_23848194","title":"Nucleolar scaffold protein, WDR46, determines the granular compartmental localization of nucleolin and DDX21.","date":"2013","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/23848194","citation_count":18,"is_preprint":false},{"pmid":"24754225","id":"PMC_24754225","title":"Dynamics of WD-repeat containing proteins in SSU processome components.","date":"2014","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/24754225","citation_count":17,"is_preprint":false},{"pmid":"22240150","id":"PMC_22240150","title":"Depletion of a nucleolar protein activates xenobiotic detoxification genes in Caenorhabditis elegans via Nrf /SKN-1 and p53/CEP-1.","date":"2011","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22240150","citation_count":14,"is_preprint":false},{"pmid":"22754713","id":"PMC_22754713","title":"WDR46 is a Genetic Risk Factor for Aspirin-Exacerbated Respiratory Disease in a Korean Population.","date":"2012","source":"Allergy, asthma & immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/22754713","citation_count":9,"is_preprint":false},{"pmid":"18794331","id":"PMC_18794331","title":"Regulation of Sli15/INCENP, kinetochore, and Cdc14 phosphatase functions by the ribosome biogenesis protein Utp7.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18794331","citation_count":8,"is_preprint":false},{"pmid":"40366140","id":"PMC_40366140","title":"HBV core protein enhances WDR46 stabilization to upregulate NUSAP1 and promote HCC progression.","date":"2025","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/40366140","citation_count":4,"is_preprint":false},{"pmid":"40877397","id":"PMC_40877397","title":"Integrated analysis of m6A regulator mediated RNA methylation and key immune related genes in ischemic stroke.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40877397","citation_count":1,"is_preprint":false},{"pmid":"39809148","id":"PMC_39809148","title":"Roles of NOC3L and DDX17 in acquired immunodeficiency complicated with viral myocarditis and osteoporosis.","date":"2024","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39809148","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8288,"output_tokens":1646,"usd":0.024777,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8421,"output_tokens":2290,"usd":0.049677,"stage2_stop_reason":"end_turn"},"total_usd":0.074454,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"WDR46 is a highly insoluble nucleolar scaffold protein whose N- and C-terminal intrinsically disordered regions are required for its own nucleolar localization and for association with binding partners nucleolin, DDX21, NOP2, and EBP2. Knockdown of WDR46 caused mislocalization of nucleolin and DDX21 (involved in 18S rRNA processing) from the granular component to the edges of nucleoli, while NOP2 and EBP2 (involved in 28S rRNA processing) were unaffected. WDR46 ensures proper recruitment of nucleolin and DDX21 to nucleoli in daughter cells after cell division.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy, domain deletion analysis, co-immunoprecipitation/binding partner identification\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype and domain analysis, single lab, two orthogonal methods (knockdown + domain deletion)\",\n      \"pmids\": [\"23848194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GFP-WDR46 localizes predominantly to the dense fibrillar component and granular component regions of nucleoli. FRAP analysis showed that approximately half of GFP-WDR46 has very low mobility in living cells, consistent with tight association with macro-protein complexes, functioning as a scaffold or core component. When rRNA transcription is suppressed, mobility of the immobile fraction is partially accelerated.\",\n      \"method\": \"GFP fusion protein live-cell imaging, FRAP analysis in HeLa cells, rRNA transcription suppression\",\n      \"journal\": \"Biochemistry and cell biology = Biochimie et biologie cellulaire\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell localization with FRAP functional analysis, single lab, two orthogonal methods\",\n      \"pmids\": [\"24754225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yeast ortholog Utp7 (WDR46 ortholog) is present at kinetochores in addition to the nucleolus, and associates with and regulates localization of Sli15 (INCENP) and Cdc14 phosphatase. Before anaphase onset, Utp7 prevents premature nucleolar release of Cdc14 and premature concentration of Sli15 on the spindle. Utp7 also regulates Sli15 localization and phosphorylation status independently of its effect on Cdc14, placing it at the intersection of ribosome biogenesis, chromosome segregation, and cell cycle control.\",\n      \"method\": \"Genetic epistasis, co-immunoprecipitation, localization studies in S. cerevisiae, phosphorylation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, epistasis, localization with functional consequence, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"18794331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C. elegans WDR-46 (ortholog of WDR46/UTP7) is required for rRNA processing and is expressed in nucleoli. Mutation or silencing of WDR-46 activates the CnC transcription factor SKN-1 and increases expression of its detoxification target genes. The C. elegans p53 homologue CEP-1 is partially required for activation of gst-4 when wdr-46 is silenced, suggesting disruption of nucleolar function activates SKN-1 via a p53-dependent mechanism independent of protein translation.\",\n      \"method\": \"RNAi knockdown, mutant allele analysis, genetic epistasis (SKN-1, CEP-1 pathway), reporter gene assays in C. elegans\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple pathway components, single lab, ortholog system\",\n      \"pmids\": [\"22240150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HBV core protein (HBC) enhances WDR46 protein stability by blocking the interaction between WDR46 and the E3 ubiquitin ligase TRIM25, thereby reducing WDR46 ubiquitination and preventing its degradation. HBC also enhances the interaction between WDR46 and transcription factor c-Myc, facilitating c-Myc recruitment to the NUSAP1 promoter and increasing NUSAP1 transcription. WDR46 is required for HBC-induced HCC cell growth and migration in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, chromatin immunoprecipitation, ubiquitination assays, in vitro and in vivo oncology functional assays\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, ubiquitination assay, multiple orthogonal methods in single lab study\",\n      \"pmids\": [\"40366140\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR46 is a highly insoluble nucleolar scaffold protein (human/mammalian) and SSU processome component that, via its intrinsically disordered N- and C-terminal regions, anchors nucleolin and DDX21 in the granular compartment to support 18S rRNA processing; its yeast ortholog Utp7 additionally associates with kinetochore proteins Sli15/INCENP and Cdc14 phosphatase to coordinate chromosome segregation with ribosome biogenesis; in C. elegans, loss of the ortholog WDR-46 triggers nucleolar stress signaling through SKN-1/Nrf and p53/CEP-1; and in HCC, HBC stabilizes WDR46 by blocking TRIM25-mediated ubiquitination, allowing WDR46 to recruit c-Myc to the NUSAP1 promoter and promote tumor cell growth and migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR46 is a highly insoluble nucleolar scaffold protein that supports ribosome biogenesis by organizing factors required for small-subunit rRNA processing [#0, #1]. Through its intrinsically disordered N- and C-terminal regions, it anchors itself within the dense fibrillar and granular compartments of the nucleolus and binds nucleolin, DDX21, NOP2, and EBP2; loss of WDR46 selectively mislocalizes the 18S rRNA processing factors nucleolin and DDX21 to the nucleolar periphery while leaving the 28S processing factors NOP2 and EBP2 intact, establishing WDR46 as a recruitment hub that re-establishes the granular component in daughter cells after division [#0]. FRAP measurements show a large, very-low-mobility WDR46 fraction tied to macro-protein complexes that is partly released when rRNA transcription is suppressed, consistent with a core structural role [#1]. The yeast ortholog Utp7 extends this function to the cell cycle, localizing to kinetochores and regulating Sli15 (INCENP) and Cdc14 phosphatase to restrain their premature release/concentration before anaphase, linking ribosome biogenesis to chromosome segregation [#2], and in C. elegans loss of the ortholog activates SKN-1/Nrf detoxification gene expression via the p53 homolog CEP-1, defining a nucleolar-stress signaling output [#3]. In hepatocellular carcinoma, the HBV core protein stabilizes WDR46 by blocking TRIM25-mediated ubiquitination and promotes WDR46-dependent recruitment of c-Myc to the NUSAP1 promoter, driving tumor cell growth and migration [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Whether a nucleolar WDR-repeat protein could couple ribosome biogenesis to mitotic control was unknown; characterization of the yeast ortholog Utp7 placed it at kinetochores regulating Sli15/INCENP and Cdc14, establishing a node connecting rRNA biogenesis with chromosome segregation.\",\n      \"evidence\": \"Reciprocal co-IP, genetic epistasis, localization and phosphorylation assays in S. cerevisiae\",\n      \"pmids\": [\"18794331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetochore role demonstrated only in yeast, not shown for human WDR46\", \"Mechanism by which Utp7 restrains Cdc14/Sli15 not resolved at molecular level\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"It was unclear what cellular signaling follows disruption of nucleolar function; loss of the C. elegans ortholog was shown to activate the SKN-1/Nrf detoxification program partly through the p53 homolog CEP-1, defining a nucleolar-stress signaling output.\",\n      \"evidence\": \"RNAi, mutant allele analysis, genetic epistasis and reporter assays in C. elegans\",\n      \"pmids\": [\"22240150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between nucleolar disruption and SKN-1 activation undefined\", \"Conservation of this stress axis in mammals untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The molecular function of human WDR46 was unknown; knockdown and domain analysis showed it is an insoluble nucleolar scaffold whose disordered termini recruit nucleolin and DDX21 to selectively support 18S rRNA processing.\",\n      \"evidence\": \"siRNA knockdown, fluorescence microscopy, domain deletion, co-IP of binding partners in human cells\",\n      \"pmids\": [\"23848194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect binding to each partner not distinguished\", \"Effect on mature 18S rRNA yield not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The dynamic behavior of WDR46 in the nucleolus was unknown; live-cell imaging with FRAP demonstrated a large immobile fraction tied to macro-protein complexes that is partly mobilized when rRNA transcription stops, supporting a core scaffold role.\",\n      \"evidence\": \"GFP-fusion live-cell imaging and FRAP in HeLa cells with transcription suppression\",\n      \"pmids\": [\"24754225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the complexes constraining mobility not defined\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether WDR46 contributes to disease was unaddressed; in HCC the HBV core protein stabilizes WDR46 by blocking TRIM25-mediated ubiquitination and routes it to co-activate c-Myc at the NUSAP1 promoter, driving tumor growth and migration.\",\n      \"evidence\": \"Co-IP, ChIP, ubiquitination assays, in vitro and in vivo oncology assays\",\n      \"pmids\": [\"40366140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct WDR46\\u2013c-Myc binding interface not mapped\", \"Whether transcriptional role is separable from nucleolar scaffold function unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR46's nucleolar scaffold function mechanistically integrates with its cell-cycle (kinetochore) and transcriptional (c-Myc) activities in human cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of WDR46 within the SSU processome\", \"Human kinetochore association not tested\", \"Substrate/target specificity of its disordered recruitment regions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"SSU processome\"],\n    \"partners\": [\"NCL\", \"DDX21\", \"NOP2\", \"EBP2\", \"TRIM25\", \"MYC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}