{"gene":"WDR43","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2019,"finding":"WDR43 binds prominently to promoter-associated noncoding/nascent RNAs and occupies thousands of gene promoters and enhancers in embryonic stem cells (ESCs), acting as a chromatin-associated RNA-binding protein. Nascent transcripts and transcription recruit WDR43 to active promoters, where WDR43 facilitates release of the elongation factor P-TEFb and paused Pol II, promoting Pol II elongation and pluripotency-associated gene expression.","method":"CLIP-seq (FbioCLIP), ChIP-seq, auxin-mediated rapid protein degradation, Pol II ChIP-seq upon WDR43 knockdown/degradation, Co-IP with Pol II machinery","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (CLIP-seq, ChIP-seq, auxin degron, Co-IP), genome-wide readouts, functional rescue experiments in single rigorous study","pmids":["31128943"],"is_preprint":false},{"year":2022,"finding":"WDR43 promotes chemoresistance in colorectal cancer by binding to RPL11, thereby enhancing MDM2-mediated ubiquitination of p53 and reducing p53 protein stability. c-MYC transcriptionally upregulates WDR43 expression upon oxaliplatin stimulation.","method":"Co-immunoprecipitation (WDR43–RPL11 interaction), ubiquitination assays, western blot for p53 stability, chromatin immunoprecipitation (c-MYC binding to WDR43 promoter), siRNA knockdown, in vitro and in vivo tumor models","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for protein interaction, ubiquitination assay, ChIP for transcriptional regulation, single lab with multiple orthogonal methods","pmids":["36525936"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, the C-terminus of Wdr43 is both necessary and sufficient for its nucleolar localization and protein interactions in metazoans. Wdr43 functions in ribosome biogenesis, and developmental defects in wdr43 mutants are mediated by a p53-dependent pathway. Proper nucleolar localization of multiple nucleolar proteins including TCOF1 depends on that of WDR43.","method":"Zebrafish genetic mutant (fantome/fan), truncation/rescue constructs for nucleolar localization, p53 morpholino epistasis, immunofluorescence for nucleolar protein localization","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined molecular phenotype, domain mapping by truncation rescue, epistasis with p53, localization of multiple proteins tested","pmids":["24497835"],"is_preprint":false},{"year":2020,"finding":"WDR43 forms a protein complex with NOL11 and Cirhin (the NWC complex) in mitotic cells. This complex, present in nucleoli during interphase, translocates to perichromosomal regions during mitosis and is required for centromeric enrichment of Aurora B, Aurora B-dependent phosphorylation of histone H3 at Thr3, chromosome congression to the metaphase plate, and sister chromatid cohesion.","method":"Co-immunoprecipitation (NWC complex), immunofluorescence of mitotic cells, siRNA knockdown with mitotic phenotype readouts (chromosome alignment, cohesion), Aurora B ChIP/immunofluorescence","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for complex, siRNA knockdown with specific mitotic phenotypes, multiple orthogonal functional readouts in single rigorous study","pmids":["32479628"],"is_preprint":false},{"year":2013,"finding":"Human WDR43, along with CIRH1A and UTP15, forms the t-UTP sub-complex of the SSU processome. These three WD-repeat proteins bind directly to each other in vitro and localize to the fibrillar center regions of nucleoli. Their mobility in living cells is very slow and independent of rDNA transcription. CIRH1A is phosphorylated at Thr131 by a mitotic Xenopus egg extract, and this phosphorylation suppresses its binding to UTP15 and WDR43.","method":"In vitro GST-pulldown binding assays, GFP-fusion live-cell imaging (FRAP), nuclear matrix fractionation, in vitro phosphorylation assay with Xenopus egg extract","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding, live-cell FRAP, phosphorylation assay; single lab with multiple orthogonal methods","pmids":["24219289"],"is_preprint":false},{"year":2014,"finding":"Human WDR43 (t-UTP sub-complex component) is immobilized in the fibrillar centers of nucleoli in living cells, and its mobility is very low, consistent with tight binding to large protein complexes. When rRNA transcription is suppressed, mobility of t-UTP sub-complex components increases but remains slow.","method":"GFP-fusion live-cell imaging (FRAP), rRNA transcription inhibition experiments","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — live-cell FRAP with functional perturbation (transcription inhibition), replicated across multiple WD-repeat proteins in same study","pmids":["24754225"],"is_preprint":false},{"year":2022,"finding":"WDR43 directly interacts with CDK2 (cyclin-dependent kinase 2) and induces expression of cyclin proteins, promoting cell cycle progression. Knockdown of WDR43 causes G1-phase cell cycle arrest in NSCLC cells.","method":"Co-immunoprecipitation (WDR43–CDK2 interaction), siRNA knockdown with cell cycle analysis, western blot for cyclin proteins","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for protein interaction, knockdown with specific cell cycle phenotype, single lab","pmids":["36041702"],"is_preprint":false},{"year":2021,"finding":"WDR43 knockdown inhibits vimentin (VIM) expression in colorectal cancer cells, and overexpression of VIM can partially reverse the proliferation, migration, invasion, and apoptosis phenotypes caused by WDR43 knockdown both in vitro and in vivo, placing VIM downstream of WDR43.","method":"siRNA knockdown, VIM overexpression rescue, subcutaneous xenograft mouse model, apoptosis assays, migration/invasion assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue experiment with downstream target, in vivo validation, multiple functional readouts; single lab","pmids":["34372874"],"is_preprint":false},{"year":2025,"finding":"WDR43-containing snoRNP complexes enrich for specific subsets of snoRNA-target RNA interactions with distinct roles in ribosome and spliceosome biogenesis, as shown by chimeric eCLIP using WDR43 as bait.","method":"Chimeric eCLIP using WDR43 as bait protein in mouse and human cell lines, identification of snoRNA-target RNA interactions","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical profiling of RNA interactions via eCLIP, multiple cell lines; single lab","pmids":["40001124"],"is_preprint":false},{"year":2025,"finding":"Narciclasine binds directly to recombinant WDR43 in vitro, and silencing WDR43 attenuates narciclasine-mediated inhibition of NRF2, indicating WDR43 mediates the effect of narciclasine on NRF2.","method":"In vitro binding assay with recombinant WDR43, siRNA knockdown of WDR43 with NRF2 activity readout (luciferase, target gene expression)","journal":"Free radical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro binding assay and knockdown, mechanism by which WDR43 affects NRF2 not established, single lab single study","pmids":["39783823"],"is_preprint":false}],"current_model":"WDR43 is a WD-repeat protein that functions as a core component of the t-UTP sub-complex of the SSU processome in nucleoli, where it is required for ribosome biogenesis and nucleolar integrity (including proper localization of TCOF1 and other nucleolar proteins); it additionally acts as a chromatin-associated RNA-binding protein in ESCs that is recruited to active gene promoters by nascent RNA and facilitates P-TEFb release and Pol II pause-release to promote transcription elongation; during mitosis, WDR43 forms the NWC complex with NOL11 and Cirhin that translocates to perichromosomal regions and is required for Aurora B centromeric enrichment and faithful chromosome segregation; in cancer contexts, WDR43 promotes cell proliferation and chemoresistance by binding RPL11 to enhance MDM2-mediated p53 ubiquitination/degradation (downstream of c-MYC) and by interacting with CDK2 to drive cell cycle progression."},"narrative":{"mechanistic_narrative":"WDR43 is a WD-repeat protein with a dual role in nucleolar ribosome biogenesis and the regulation of transcription, and it is co-opted in cancer to drive proliferation [PMID:24219289, PMID:31128943, PMID:36525936]. In nucleoli it forms the t-UTP sub-complex of the SSU processome together with CIRH1A and UTP15, three WD-repeat proteins that bind directly to one another and localize to nucleolar fibrillar centers as tightly bound, slowly mobile assemblies whose dynamics are largely independent of rDNA transcription [PMID:24219289, PMID:24754225]. Its C-terminus is necessary and sufficient for nucleolar localization and protein interactions, and proper nucleolar positioning of other nucleolar proteins including TCOF1 depends on WDR43; loss of WDR43 disrupts ribosome biogenesis and produces developmental defects through a p53-dependent pathway [PMID:24497835]. WDR43-containing snoRNP complexes capture distinct snoRNA–target RNA interactions linked to ribosome and spliceosome biogenesis [PMID:40001124]. Beyond the nucleolus, WDR43 acts as a chromatin-associated RNA-binding protein in embryonic stem cells, recruited to active promoters and enhancers by nascent transcripts, where it facilitates P-TEFb release and Pol II pause-release to promote transcription elongation and pluripotency gene expression [PMID:31128943]. During mitosis WDR43 assembles with NOL11 and Cirhin into the NWC complex that relocates from nucleoli to perichromosomal regions and is required for centromeric enrichment of Aurora B, histone H3 Thr3 phosphorylation, chromosome congression, and sister chromatid cohesion [PMID:32479628]. In cancer, WDR43 promotes proliferation, chemoresistance, and cell-cycle progression: it binds RPL11 to enhance MDM2-mediated p53 ubiquitination downstream of c-MYC, and it directly interacts with CDK2 to drive cyclin expression and G1/S progression [PMID:36525936, PMID:36041702].","teleology":[{"year":2013,"claim":"Established the biochemical identity of WDR43 as a direct partner of CIRH1A and UTP15 in the nucleolar t-UTP sub-complex, defining its place in ribosome biogenesis machinery and revealing mitotic phospho-regulation of the complex.","evidence":"In vitro GST-pulldown binding, GFP-fusion FRAP live-cell imaging, nuclear matrix fractionation, and Xenopus egg extract phosphorylation assays in human cells","pmids":["24219289"],"confidence":"Medium","gaps":["Stoichiometry and architecture of the t-UTP sub-complex not resolved","Functional consequence of CIRH1A Thr131 phosphorylation on processome assembly in cells not shown","No structural model of WDR43 within the SSU processome"]},{"year":2014,"claim":"Mapped the WDR43 C-terminus as the determinant of nucleolar localization and showed WDR43 organizes the localization of other nucleolar proteins, linking its loss to ribosome biogenesis failure and p53-dependent developmental defects.","evidence":"Zebrafish fantome mutant, truncation/rescue constructs, p53 morpholino epistasis, and immunofluorescence of nucleolar protein localization","pmids":["24497835"],"confidence":"High","gaps":["Direct molecular interactions mediated by the C-terminus not enumerated","Mechanism linking ribosome biogenesis defects to p53 activation not detailed","Whether TCOF1 mislocalization is cause or consequence of nucleolar disruption unclear"]},{"year":2014,"claim":"Refined the dynamic behavior of WDR43 in nucleoli, showing it is essentially immobilized in fibrillar centers as part of large complexes with only partial dependence on rRNA transcription.","evidence":"GFP-fusion FRAP with rRNA transcription inhibition across multiple t-UTP components","pmids":["24754225"],"confidence":"Medium","gaps":["Identity of the immobilizing binding partners not defined","Relationship between immobile fraction and functional processome activity unknown"]},{"year":2019,"claim":"Revealed an unexpected extranucleolar role: WDR43 is a chromatin-associated RNA-binding protein recruited to active promoters by nascent RNA to promote Pol II pause-release and elongation, connecting it to transcriptional control of pluripotency.","evidence":"CLIP-seq, ChIP-seq, auxin-mediated degron, Pol II ChIP-seq, and Co-IP in embryonic stem cells","pmids":["31128943"],"confidence":"High","gaps":["Molecular mechanism by which WDR43 promotes P-TEFb release not resolved","Whether this role requires or is separable from nucleolar ribosome biogenesis function unclear","Direct binding interface between WDR43 and Pol II/P-TEFb machinery not mapped"]},{"year":2020,"claim":"Identified a mitosis-specific NWC complex (WDR43–NOL11–Cirhin) that relocalizes from nucleoli to perichromosomal regions and is required for Aurora B centromeric enrichment and faithful chromosome segregation, extending WDR43 function into mitotic fidelity.","evidence":"Reciprocal Co-IP, mitotic immunofluorescence, siRNA knockdown with chromosome alignment/cohesion readouts in human cells","pmids":["32479628"],"confidence":"High","gaps":["How the NWC complex promotes Aurora B centromeric loading mechanistically unknown","Trigger for nucleolar-to-perichromosomal translocation not defined","Relationship between NWC and the t-UTP processome subunits unclear"]},{"year":2021,"claim":"Placed vimentin downstream of WDR43 in colorectal cancer, providing an effector link between WDR43 and proliferative/invasive phenotypes.","evidence":"siRNA knockdown with VIM overexpression rescue, xenograft model, apoptosis and migration/invasion assays","pmids":["34372874"],"confidence":"Medium","gaps":["Mechanism by which WDR43 regulates VIM expression not defined","Whether the effect is direct or transcriptional unknown"]},{"year":2022,"claim":"Defined two cancer-relevant mechanisms: WDR43 binds RPL11 to enhance MDM2-mediated p53 degradation downstream of c-MYC driving chemoresistance, and it interacts with CDK2 to induce cyclins and drive cell-cycle progression.","evidence":"Co-IP (RPL11, CDK2), ubiquitination assays, p53 western blot, c-MYC ChIP, siRNA knockdown with cell-cycle analysis, in vitro and in vivo tumor models","pmids":["36525936","36041702"],"confidence":"Medium","gaps":["Whether RPL11 binding is linked to WDR43's nucleolar/ribosome biogenesis role unclear","Direct vs. indirect nature of CDK2 interaction not structurally defined","Reciprocal validation of interactions limited"]},{"year":2025,"claim":"Used WDR43 as bait to profile snoRNP-associated snoRNA–target RNA interactions, distinguishing subsets directed at ribosome versus spliceosome biogenesis.","evidence":"Chimeric eCLIP with WDR43 as bait in mouse and human cell lines","pmids":["40001124"],"confidence":"Medium","gaps":["Functional requirement of WDR43 for the captured snoRNA interactions not tested","Whether WDR43 is a stable snoRNP component or transient interactor unclear"]},{"year":2025,"claim":"Identified WDR43 as a direct binding target of narciclasine mediating its inhibition of NRF2, implicating WDR43 in a redox/drug-response axis.","evidence":"In vitro binding with recombinant WDR43 and siRNA knockdown with NRF2 activity readout","pmids":["39783823"],"confidence":"Low","gaps":["Single in vitro binding assay; mechanism by which WDR43 affects NRF2 not established","Not independently confirmed","Physiological relevance of the WDR43-NRF2 link unclear"]},{"year":null,"claim":"How WDR43's distinct nucleolar (ribosome biogenesis), chromatin (transcription elongation), and mitotic (NWC/Aurora B) roles are coordinated by a single protein, and which interactions are direct versus complex-mediated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating WDR43's WD-repeat surface across its multiple complexes","Determinants partitioning WDR43 between nucleolus, chromatin, and perichromosomal regions unknown","Unclear whether cancer phenotypes derive from ribosome biogenesis, transcription, or mitotic functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[2,4,5,3]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,5,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,4]}],"complexes":["t-UTP sub-complex (SSU processome)","NWC complex (WDR43-NOL11-Cirhin)"],"partners":["CIRH1A","UTP15","NOL11","RPL11","CDK2","P-TEFB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15061","full_name":"WD repeat-containing protein 43","aliases":["U3 small nucleolar RNA-associated protein 5 homolog"],"length_aa":677,"mass_kda":74.9,"function":"Ribosome biogenesis factor that coordinates hyperactive transcription and ribogenesis (PubMed:17699751). 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. Involved in nucleolar processing of pre-18S ribosomal RNA. Required for optimal pre-ribosomal RNA transcription by RNA polymerase I (PubMed:17699751, PubMed:34516797). Essential for stem cell pluripotency and embryonic development. In the nucleoplasm, recruited by promoter-associated/nascent transcripts and transcription to active promoters where it facilitates releases of elongation factor P-TEFb and paused RNA polymerase II to allow transcription elongation and maintain high-level expression of its targets genes (By similarity)","subcellular_location":"Nucleus, nucleolus; Nucleus, nucleolus fibrillar center; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q15061/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR43","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NOL11","stoichiometry":4.0},{"gene":"UTP4","stoichiometry":4.0},{"gene":"WDR75","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR43","total_profiled":1310},"omim":[{"mim_id":"616195","title":"WD REPEAT-CONTAINING PROTEIN 43; WDR43","url":"https://www.omim.org/entry/616195"},{"mim_id":"616194","title":"UTP15 SMALL SUBUNIT PROCESSOME COMPONENT; UTP15","url":"https://www.omim.org/entry/616194"},{"mim_id":"607456","title":"UTP4 SMALL SUBUNIT PROCESSOME COMPONENT; UTP4","url":"https://www.omim.org/entry/607456"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR43"},"hgnc":{"alias_symbol":["KIAA0007","NET12","UTP5"],"prev_symbol":[]},"alphafold":{"accession":"Q15061","domains":[{"cath_id":"2.130.10.10","chopping":"20-71_95-375","consensus_level":"medium","plddt":83.9699,"start":20,"end":375},{"cath_id":"1.25.40","chopping":"462-558","consensus_level":"high","plddt":85.1771,"start":462,"end":558}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15061","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15061-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15061-F1-predicted_aligned_error_v6.png","plddt_mean":69.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR43","jax_strain_url":"https://www.jax.org/strain/search?query=WDR43"},"sequence":{"accession":"Q15061","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15061.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15061/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15061"}},"corpus_meta":[{"pmid":"27117709","id":"PMC_27117709","title":"Identification 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loci","date":"2024-12-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.13.24318996","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18024,"output_tokens":2709,"usd":0.047353,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9995,"output_tokens":4040,"usd":0.075487,"stage2_stop_reason":"end_turn"},"total_usd":0.12284,"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\": 2019,\n      \"finding\": \"WDR43 binds prominently to promoter-associated noncoding/nascent RNAs and occupies thousands of gene promoters and enhancers in embryonic stem cells (ESCs), acting as a chromatin-associated RNA-binding protein. Nascent transcripts and transcription recruit WDR43 to active promoters, where WDR43 facilitates release of the elongation factor P-TEFb and paused Pol II, promoting Pol II elongation and pluripotency-associated gene expression.\",\n      \"method\": \"CLIP-seq (FbioCLIP), ChIP-seq, auxin-mediated rapid protein degradation, Pol II ChIP-seq upon WDR43 knockdown/degradation, Co-IP with Pol II machinery\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (CLIP-seq, ChIP-seq, auxin degron, Co-IP), genome-wide readouts, functional rescue experiments in single rigorous study\",\n      \"pmids\": [\"31128943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WDR43 promotes chemoresistance in colorectal cancer by binding to RPL11, thereby enhancing MDM2-mediated ubiquitination of p53 and reducing p53 protein stability. c-MYC transcriptionally upregulates WDR43 expression upon oxaliplatin stimulation.\",\n      \"method\": \"Co-immunoprecipitation (WDR43–RPL11 interaction), ubiquitination assays, western blot for p53 stability, chromatin immunoprecipitation (c-MYC binding to WDR43 promoter), siRNA knockdown, in vitro and in vivo tumor models\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for protein interaction, ubiquitination assay, ChIP for transcriptional regulation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36525936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, the C-terminus of Wdr43 is both necessary and sufficient for its nucleolar localization and protein interactions in metazoans. Wdr43 functions in ribosome biogenesis, and developmental defects in wdr43 mutants are mediated by a p53-dependent pathway. Proper nucleolar localization of multiple nucleolar proteins including TCOF1 depends on that of WDR43.\",\n      \"method\": \"Zebrafish genetic mutant (fantome/fan), truncation/rescue constructs for nucleolar localization, p53 morpholino epistasis, immunofluorescence for nucleolar protein localization\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined molecular phenotype, domain mapping by truncation rescue, epistasis with p53, localization of multiple proteins tested\",\n      \"pmids\": [\"24497835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WDR43 forms a protein complex with NOL11 and Cirhin (the NWC complex) in mitotic cells. This complex, present in nucleoli during interphase, translocates to perichromosomal regions during mitosis and is required for centromeric enrichment of Aurora B, Aurora B-dependent phosphorylation of histone H3 at Thr3, chromosome congression to the metaphase plate, and sister chromatid cohesion.\",\n      \"method\": \"Co-immunoprecipitation (NWC complex), immunofluorescence of mitotic cells, siRNA knockdown with mitotic phenotype readouts (chromosome alignment, cohesion), Aurora B ChIP/immunofluorescence\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for complex, siRNA knockdown with specific mitotic phenotypes, multiple orthogonal functional readouts in single rigorous study\",\n      \"pmids\": [\"32479628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human WDR43, along with CIRH1A and UTP15, forms the t-UTP sub-complex of the SSU processome. These three WD-repeat proteins bind directly to each other in vitro and localize to the fibrillar center regions of nucleoli. Their mobility in living cells is very slow and independent of rDNA transcription. CIRH1A is phosphorylated at Thr131 by a mitotic Xenopus egg extract, and this phosphorylation suppresses its binding to UTP15 and WDR43.\",\n      \"method\": \"In vitro GST-pulldown binding assays, GFP-fusion live-cell imaging (FRAP), nuclear matrix fractionation, in vitro phosphorylation assay with Xenopus egg extract\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding, live-cell FRAP, phosphorylation assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24219289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human WDR43 (t-UTP sub-complex component) is immobilized in the fibrillar centers of nucleoli in living cells, and its mobility is very low, consistent with tight binding to large protein complexes. When rRNA transcription is suppressed, mobility of t-UTP sub-complex components increases but remains slow.\",\n      \"method\": \"GFP-fusion live-cell imaging (FRAP), rRNA transcription inhibition experiments\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — live-cell FRAP with functional perturbation (transcription inhibition), replicated across multiple WD-repeat proteins in same study\",\n      \"pmids\": [\"24754225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WDR43 directly interacts with CDK2 (cyclin-dependent kinase 2) and induces expression of cyclin proteins, promoting cell cycle progression. Knockdown of WDR43 causes G1-phase cell cycle arrest in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation (WDR43–CDK2 interaction), siRNA knockdown with cell cycle analysis, western blot for cyclin proteins\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for protein interaction, knockdown with specific cell cycle phenotype, single lab\",\n      \"pmids\": [\"36041702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR43 knockdown inhibits vimentin (VIM) expression in colorectal cancer cells, and overexpression of VIM can partially reverse the proliferation, migration, invasion, and apoptosis phenotypes caused by WDR43 knockdown both in vitro and in vivo, placing VIM downstream of WDR43.\",\n      \"method\": \"siRNA knockdown, VIM overexpression rescue, subcutaneous xenograft mouse model, apoptosis assays, migration/invasion assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue experiment with downstream target, in vivo validation, multiple functional readouts; single lab\",\n      \"pmids\": [\"34372874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WDR43-containing snoRNP complexes enrich for specific subsets of snoRNA-target RNA interactions with distinct roles in ribosome and spliceosome biogenesis, as shown by chimeric eCLIP using WDR43 as bait.\",\n      \"method\": \"Chimeric eCLIP using WDR43 as bait protein in mouse and human cell lines, identification of snoRNA-target RNA interactions\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical profiling of RNA interactions via eCLIP, multiple cell lines; single lab\",\n      \"pmids\": [\"40001124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Narciclasine binds directly to recombinant WDR43 in vitro, and silencing WDR43 attenuates narciclasine-mediated inhibition of NRF2, indicating WDR43 mediates the effect of narciclasine on NRF2.\",\n      \"method\": \"In vitro binding assay with recombinant WDR43, siRNA knockdown of WDR43 with NRF2 activity readout (luciferase, target gene expression)\",\n      \"journal\": \"Free radical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro binding assay and knockdown, mechanism by which WDR43 affects NRF2 not established, single lab single study\",\n      \"pmids\": [\"39783823\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR43 is a WD-repeat protein that functions as a core component of the t-UTP sub-complex of the SSU processome in nucleoli, where it is required for ribosome biogenesis and nucleolar integrity (including proper localization of TCOF1 and other nucleolar proteins); it additionally acts as a chromatin-associated RNA-binding protein in ESCs that is recruited to active gene promoters by nascent RNA and facilitates P-TEFb release and Pol II pause-release to promote transcription elongation; during mitosis, WDR43 forms the NWC complex with NOL11 and Cirhin that translocates to perichromosomal regions and is required for Aurora B centromeric enrichment and faithful chromosome segregation; in cancer contexts, WDR43 promotes cell proliferation and chemoresistance by binding RPL11 to enhance MDM2-mediated p53 ubiquitination/degradation (downstream of c-MYC) and by interacting with CDK2 to drive cell cycle progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR43 is a WD-repeat protein with a dual role in nucleolar ribosome biogenesis and the regulation of transcription, and it is co-opted in cancer to drive proliferation [#4, #0, #1]. In nucleoli it forms the t-UTP sub-complex of the SSU processome together with CIRH1A and UTP15, three WD-repeat proteins that bind directly to one another and localize to nucleolar fibrillar centers as tightly bound, slowly mobile assemblies whose dynamics are largely independent of rDNA transcription [#4, #5]. Its C-terminus is necessary and sufficient for nucleolar localization and protein interactions, and proper nucleolar positioning of other nucleolar proteins including TCOF1 depends on WDR43; loss of WDR43 disrupts ribosome biogenesis and produces developmental defects through a p53-dependent pathway [#2]. WDR43-containing snoRNP complexes capture distinct snoRNA–target RNA interactions linked to ribosome and spliceosome biogenesis [#8]. Beyond the nucleolus, WDR43 acts as a chromatin-associated RNA-binding protein in embryonic stem cells, recruited to active promoters and enhancers by nascent transcripts, where it facilitates P-TEFb release and Pol II pause-release to promote transcription elongation and pluripotency gene expression [#0]. During mitosis WDR43 assembles with NOL11 and Cirhin into the NWC complex that relocates from nucleoli to perichromosomal regions and is required for centromeric enrichment of Aurora B, histone H3 Thr3 phosphorylation, chromosome congression, and sister chromatid cohesion [#3]. In cancer, WDR43 promotes proliferation, chemoresistance, and cell-cycle progression: it binds RPL11 to enhance MDM2-mediated p53 ubiquitination downstream of c-MYC, and it directly interacts with CDK2 to drive cyclin expression and G1/S progression [#1, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the biochemical identity of WDR43 as a direct partner of CIRH1A and UTP15 in the nucleolar t-UTP sub-complex, defining its place in ribosome biogenesis machinery and revealing mitotic phospho-regulation of the complex.\",\n      \"evidence\": \"In vitro GST-pulldown binding, GFP-fusion FRAP live-cell imaging, nuclear matrix fractionation, and Xenopus egg extract phosphorylation assays in human cells\",\n      \"pmids\": [\"24219289\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Stoichiometry and architecture of the t-UTP sub-complex not resolved\",\n        \"Functional consequence of CIRH1A Thr131 phosphorylation on processome assembly in cells not shown\",\n        \"No structural model of WDR43 within the SSU processome\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the WDR43 C-terminus as the determinant of nucleolar localization and showed WDR43 organizes the localization of other nucleolar proteins, linking its loss to ribosome biogenesis failure and p53-dependent developmental defects.\",\n      \"evidence\": \"Zebrafish fantome mutant, truncation/rescue constructs, p53 morpholino epistasis, and immunofluorescence of nucleolar protein localization\",\n      \"pmids\": [\"24497835\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Direct molecular interactions mediated by the C-terminus not enumerated\",\n        \"Mechanism linking ribosome biogenesis defects to p53 activation not detailed\",\n        \"Whether TCOF1 mislocalization is cause or consequence of nucleolar disruption unclear\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Refined the dynamic behavior of WDR43 in nucleoli, showing it is essentially immobilized in fibrillar centers as part of large complexes with only partial dependence on rRNA transcription.\",\n      \"evidence\": \"GFP-fusion FRAP with rRNA transcription inhibition across multiple t-UTP components\",\n      \"pmids\": [\"24754225\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Identity of the immobilizing binding partners not defined\",\n        \"Relationship between immobile fraction and functional processome activity unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed an unexpected extranucleolar role: WDR43 is a chromatin-associated RNA-binding protein recruited to active promoters by nascent RNA to promote Pol II pause-release and elongation, connecting it to transcriptional control of pluripotency.\",\n      \"evidence\": \"CLIP-seq, ChIP-seq, auxin-mediated degron, Pol II ChIP-seq, and Co-IP in embryonic stem cells\",\n      \"pmids\": [\"31128943\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular mechanism by which WDR43 promotes P-TEFb release not resolved\",\n        \"Whether this role requires or is separable from nucleolar ribosome biogenesis function unclear\",\n        \"Direct binding interface between WDR43 and Pol II/P-TEFb machinery not mapped\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a mitosis-specific NWC complex (WDR43–NOL11–Cirhin) that relocalizes from nucleoli to perichromosomal regions and is required for Aurora B centromeric enrichment and faithful chromosome segregation, extending WDR43 function into mitotic fidelity.\",\n      \"evidence\": \"Reciprocal Co-IP, mitotic immunofluorescence, siRNA knockdown with chromosome alignment/cohesion readouts in human cells\",\n      \"pmids\": [\"32479628\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"How the NWC complex promotes Aurora B centromeric loading mechanistically unknown\",\n        \"Trigger for nucleolar-to-perichromosomal translocation not defined\",\n        \"Relationship between NWC and the t-UTP processome subunits unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed vimentin downstream of WDR43 in colorectal cancer, providing an effector link between WDR43 and proliferative/invasive phenotypes.\",\n      \"evidence\": \"siRNA knockdown with VIM overexpression rescue, xenograft model, apoptosis and migration/invasion assays\",\n      \"pmids\": [\"34372874\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Mechanism by which WDR43 regulates VIM expression not defined\",\n        \"Whether the effect is direct or transcriptional unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined two cancer-relevant mechanisms: WDR43 binds RPL11 to enhance MDM2-mediated p53 degradation downstream of c-MYC driving chemoresistance, and it interacts with CDK2 to induce cyclins and drive cell-cycle progression.\",\n      \"evidence\": \"Co-IP (RPL11, CDK2), ubiquitination assays, p53 western blot, c-MYC ChIP, siRNA knockdown with cell-cycle analysis, in vitro and in vivo tumor models\",\n      \"pmids\": [\"36525936\", \"36041702\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Whether RPL11 binding is linked to WDR43's nucleolar/ribosome biogenesis role unclear\",\n        \"Direct vs. indirect nature of CDK2 interaction not structurally defined\",\n        \"Reciprocal validation of interactions limited\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Used WDR43 as bait to profile snoRNP-associated snoRNA–target RNA interactions, distinguishing subsets directed at ribosome versus spliceosome biogenesis.\",\n      \"evidence\": \"Chimeric eCLIP with WDR43 as bait in mouse and human cell lines\",\n      \"pmids\": [\"40001124\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Functional requirement of WDR43 for the captured snoRNA interactions not tested\",\n        \"Whether WDR43 is a stable snoRNP component or transient interactor unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified WDR43 as a direct binding target of narciclasine mediating its inhibition of NRF2, implicating WDR43 in a redox/drug-response axis.\",\n      \"evidence\": \"In vitro binding with recombinant WDR43 and siRNA knockdown with NRF2 activity readout\",\n      \"pmids\": [\"39783823\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single in vitro binding assay; mechanism by which WDR43 affects NRF2 not established\",\n        \"Not independently confirmed\",\n        \"Physiological relevance of the WDR43-NRF2 link unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR43's distinct nucleolar (ribosome biogenesis), chromatin (transcription elongation), and mitotic (NWC/Aurora B) roles are coordinated by a single protein, and which interactions are direct versus complex-mediated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No structural model integrating WDR43's WD-repeat surface across its multiple complexes\",\n        \"Determinants partitioning WDR43 between nucleolus, chromatin, and perichromosomal regions unknown\",\n        \"Unclear whether cancer phenotypes derive from ribosome biogenesis, transcription, or mitotic functions\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [2, 4, 5, 3]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 5, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\"t-UTP sub-complex (SSU processome)\", \"NWC complex (WDR43-NOL11-Cirhin)\"],\n    \"partners\": [\"CIRH1A\", \"UTP15\", \"NOL11\", \"RPL11\", \"CDK2\", \"P-TEFb\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}