{"gene":"WDR75","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"Nan1/Utp17 (yeast ortholog of WDR75) is a component of the small subunit (SSU) processome, a ~40-protein complex with U3 snoRNA required for ribosome biogenesis; depletion of SSU processome proteins causes G1 cell cycle arrest in yeast, demonstrating the complex is required for cell cycle progression.","method":"Genetic depletion of SSU processome proteins in S. cerevisiae and S. pombe, flow cytometry and marker staining for cell cycle phase, synchronized cell experiments","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype (G1 arrest) in two yeast species, multiple orthogonal readouts; single lab","pmids":["15356263"],"is_preprint":false},{"year":2021,"finding":"Human WDR75 is a nucleolar protein required for pre-rRNA transcription; its depletion reduces levels of RPA194 (a key RNA Polymerase I subunit), activates the RPL5/RPL11-dependent p53 stabilization checkpoint, and causes impaired proliferation and cellular senescence. Under nucleolar stress, WDR75 relocalizes to nucleolar caps.","method":"siRNA knockdown in U2OS cells, subcellular fractionation, immunofluorescence of GFP-tagged WDR75 under chemically induced nucleolar stress, western blotting for RPA194 and p53, functional proliferation and senescence assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunofluorescence, western blot, functional assays), validated in several cell models, single lab","pmids":["34611297"],"is_preprint":false},{"year":2022,"finding":"Nan1/Utp17 (yeast ortholog of WDR75) localizes near the 5'ETS and ITS1 regions of the nascent 35S pre-rRNA and U3 snoRNA within the early small subunit processome, as determined by proximity of its C-terminal domains to these flexible RNA elements.","method":"MNase tethered to Nan1/Utp17 and other assembly factors; structural probing of pre-ribosomal particles in yeast","journal":"Non-coding RNA","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct structural probing assay with tethered MNase, but single study and single lab; provides architectural placement within the SSU processome","pmids":["35076539"],"is_preprint":false},{"year":2025,"finding":"WDR75 binds to an evolutionarily conserved motif in the external transcribed spacer (ETS) region of rRNA to help form the small subunit (SSU) processome; ~25% of WDR75 sites show significant purifying selection, especially at beta-sheet-forming residues, consistent with functional constraints at the rRNA-binding interface.","method":"Comparative molecular evolution analysis of 70 mammalian WDR75 sequences, structural prediction, phylogenetic analysis and site-specific selection tests","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/evolutionary analysis only; no direct biochemical experiment on binding","pmids":["39932919"],"is_preprint":false},{"year":2026,"finding":"Patient-derived cells and a CRISPR/Cas9-modified cell line carrying compound-heterozygous WDR75 variants show altered pre-rRNA processing (impaired A0 cleavage) and increased p21 expression, indicating partial activation of the p53 pathway (nucleolar stress response).","method":"Functional studies in patient-derived cells and CRISPR/Cas9-engineered cell line; pre-rRNA processing assay, p21 western blotting","journal":"Journal of human immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assays (pre-rRNA processing, p21 induction) in patient-derived and CRISPR-edited cells; single study, authors note association rather than proven causality","pmids":["42099922"],"is_preprint":false},{"year":2022,"finding":"Wdr75 was identified as a positive regulator of mouse embryonic stem cell (mESC) self-renewal in a genome-wide CRISPR-Cas9 screen; sgRNA depletion of Wdr75 reduced ESC self-renewal.","method":"Genome-wide CRISPR-Cas9 knockout screen in mouse ESC R1 cells, high-throughput sequencing of sgRNA ratios, functional confirmation","journal":"Stem cells and development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — screen-based identification with limited mechanistic follow-up for Wdr75 specifically; single lab","pmids":["35019759"],"is_preprint":false}],"current_model":"WDR75 (Nan1/Utp17 in yeast) is a nucleolar component of the SSU processome that binds the external transcribed spacer of pre-rRNA to support small ribosomal subunit assembly; it is required for pre-rRNA transcription by maintaining RNA Polymerase I subunit RPA194 levels, and its loss activates the RPL5/RPL11–p53 checkpoint, leading to cell cycle arrest, senescence, and impaired proliferation."},"narrative":{"mechanistic_narrative":"WDR75 is a nucleolar component of the small subunit (SSU) processome that supports biogenesis of the small ribosomal subunit, a role conserved from its yeast ortholog Nan1/Utp17 [PMID:15356263, PMID:34611297]. Within the early SSU processome it is positioned near the 5'ETS, ITS1, and U3 snoRNA elements of the nascent 35S pre-rRNA, and it binds an evolutionarily conserved motif in the external transcribed spacer of rRNA to help assemble the particle [PMID:35076539, PMID:39932919]. In human cells WDR75 is required for pre-rRNA transcription: its depletion lowers levels of the RNA Polymerase I subunit RPA194 and impairs pre-rRNA processing, including A0/A0-type cleavage [PMID:34611297, PMID:42099922]. Loss of WDR75 function triggers the nucleolar stress response, activating the RPL5/RPL11-dependent p53 checkpoint with downstream p21 induction, driving impaired proliferation and cellular senescence; under nucleolar stress WDR75 itself relocalizes to nucleolar caps [PMID:34611297, PMID:42099922]. Compound-heterozygous WDR75 variants in patient-derived cells produce these same processing and p53-pathway defects, linking WDR75 dysfunction to human disease [PMID:42099922].","teleology":[{"year":2004,"claim":"Established that the WDR75 ortholog is a constituent of the ribosome-biogenesis machinery whose loss blocks the cell cycle, defining its core cellular role.","evidence":"Genetic depletion of SSU processome proteins in S. cerevisiae and S. pombe with cell cycle readouts","pmids":["15356263"],"confidence":"Medium","gaps":["Yeast ortholog only — human function not directly tested here","Molecular function of Nan1/Utp17 within the complex not resolved"]},{"year":2021,"claim":"Connected human WDR75 to pre-rRNA transcription and the nucleolar stress checkpoint, showing how its loss converts a biogenesis defect into a p53-mediated proliferative arrest.","evidence":"siRNA knockdown in U2OS, fractionation, immunofluorescence of GFP-WDR75 under nucleolar stress, western blots for RPA194 and p53, proliferation/senescence assays","pmids":["34611297"],"confidence":"High","gaps":["Mechanism by which WDR75 maintains RPA194 levels not defined","Single lab; cap relocalization function unknown"]},{"year":2022,"claim":"Placed the ortholog architecturally near specific pre-rRNA spacer and U3 snoRNA elements, indicating direct engagement with the nascent transcript during early assembly.","evidence":"Tethered-MNase structural probing of yeast pre-ribosomal particles","pmids":["35076539"],"confidence":"Medium","gaps":["Yeast system; human contacts inferred","Functional consequence of these contacts not tested"]},{"year":2022,"claim":"Identified Wdr75 as a positive regulator of stem-cell self-renewal, extending its biogenesis role to a developmental/proliferative phenotype.","evidence":"Genome-wide CRISPR-Cas9 knockout screen in mouse ESCs with sgRNA depletion readout","pmids":["35019759"],"confidence":"Low","gaps":["Screen-based hit with limited Wdr75-specific mechanistic follow-up","Link to ribosome biogenesis in this context not established"]},{"year":2025,"claim":"Argued that the rRNA-binding interface of WDR75 is under purifying selection, supporting a functionally constrained direct contact with the ETS motif.","evidence":"Comparative evolutionary and structural-prediction analysis of 70 mammalian WDR75 sequences","pmids":["39932919"],"confidence":"Low","gaps":["Computational only — no direct biochemical binding assay","Beta-sheet residue contacts not experimentally validated"]},{"year":2026,"claim":"Tied WDR75 variants to human disease by showing patient and CRISPR-engineered cells recapitulate the pre-rRNA processing defect and p53-pathway activation.","evidence":"Pre-rRNA processing assays and p21 western blotting in patient-derived and CRISPR/Cas9-edited cells carrying compound-heterozygous variants","pmids":["42099922"],"confidence":"Medium","gaps":["Authors note association rather than proven causality","Specific disease entity and full clinical mechanism not established here"]},{"year":null,"claim":"How WDR75 mechanistically sustains RNA Pol I subunit RPA194 levels and couples SSU processome assembly to the p53 checkpoint remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct biochemical demonstration of human WDR75–rRNA binding","Mechanism linking WDR75 loss to RPA194 reduction unknown","Structure of human SSU processome with WDR75 not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1]}],"complexes":["SSU processome"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWA0","full_name":"WD repeat-containing protein 75","aliases":["U3 small nucleolar RNA-associated protein 17 homolog"],"length_aa":830,"mass_kda":94.5,"function":"Ribosome biogenesis factor. 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","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q8IWA0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR75","classification":"Common Essential","n_dependent_lines":1202,"n_total_lines":1208,"dependency_fraction":0.9950331125827815},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000115368","cell_line_id":"CID001102","localizations":[{"compartment":"nucleolus_gc","grade":3}],"interactors":[{"gene":"HEATR1","stoichiometry":10.0},{"gene":"NOL11","stoichiometry":4.0},{"gene":"UTP15","stoichiometry":4.0},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"WDR43","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001102","total_profiled":1310},"omim":[{"mim_id":"620341","title":"WD REPEAT-CONTAINING PROTEIN 75; WDR75","url":"https://www.omim.org/entry/620341"}],"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/WDR75"},"hgnc":{"alias_symbol":["FLJ12519","NET16","UTP17"],"prev_symbol":[]},"alphafold":{"accession":"Q8IWA0","domains":[{"cath_id":"2.130.10.10","chopping":"158-299","consensus_level":"medium","plddt":88.3654,"start":158,"end":299},{"cath_id":"2.40.128","chopping":"336-424","consensus_level":"medium","plddt":86.1174,"start":336,"end":424}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWA0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWA0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWA0-F1-predicted_aligned_error_v6.png","plddt_mean":80.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR75","jax_strain_url":"https://www.jax.org/strain/search?query=WDR75"},"sequence":{"accession":"Q8IWA0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWA0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWA0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWA0"}},"corpus_meta":[{"pmid":"15356263","id":"PMC_15356263","title":"The small subunit processome is required for cell cycle progression at G1.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15356263","citation_count":53,"is_preprint":false},{"pmid":"20648054","id":"PMC_20648054","title":"Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency.","date":"2010","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/20648054","citation_count":31,"is_preprint":false},{"pmid":"34611297","id":"PMC_34611297","title":"RNA-interference screen for p53 regulators unveils a role of WDR75 in ribosome biogenesis.","date":"2021","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/34611297","citation_count":29,"is_preprint":false},{"pmid":"39900896","id":"PMC_39900896","title":"Cardiac repair using regenerating neonatal heart tissue-derived extracellular vesicles.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39900896","citation_count":24,"is_preprint":false},{"pmid":"37828440","id":"PMC_37828440","title":"Sequence-based GWAS meta-analyses for beef production traits.","date":"2023","source":"Genetics, selection, evolution : GSE","url":"https://pubmed.ncbi.nlm.nih.gov/37828440","citation_count":22,"is_preprint":false},{"pmid":"12818351","id":"PMC_12818351","title":"Reversal of P-glycoprotein expressed in Escherichia coli leaky mutant by ascorbic acid.","date":"2003","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12818351","citation_count":15,"is_preprint":false},{"pmid":"35444449","id":"PMC_35444449","title":"Identification of Immune-Related Key Genes as Potential Diagnostic Biomarkers of Sepsis in Children.","date":"2022","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/35444449","citation_count":10,"is_preprint":false},{"pmid":"31408972","id":"PMC_31408972","title":"Screening of Duck Tembusu Virus NS3 Interacting Host Proteins and Identification of Its Specific Interplay Domains.","date":"2019","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/31408972","citation_count":9,"is_preprint":false},{"pmid":"35019759","id":"PMC_35019759","title":"Genome-Wide CRISPR Screen Identifies Puf60 as a Novel Stemness Gene of Mouse Embryonic Stem Cells.","date":"2022","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/35019759","citation_count":8,"is_preprint":false},{"pmid":"39932919","id":"PMC_39932919","title":"WDR75: An essential protein for ribosome assembly undergoing purifying selection.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/39932919","citation_count":2,"is_preprint":false},{"pmid":"35076539","id":"PMC_35076539","title":"Structural Probing with MNase Tethered to Ribosome Assembly Factors Resolves Flexible RNA Regions within the Nascent Pre-Ribosomal RNA.","date":"2022","source":"Non-coding RNA","url":"https://pubmed.ncbi.nlm.nih.gov/35076539","citation_count":2,"is_preprint":false},{"pmid":"40950454","id":"PMC_40950454","title":"Transcriptome and microRNAome profiling of human skeletal muscle in pancreatic cancer cachexia.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40950454","citation_count":1,"is_preprint":false},{"pmid":"42099922","id":"PMC_42099922","title":"Ribosomal RNA processing impairments in a B cell immunodeficient patient with WDR75 variants.","date":"2026","source":"Journal of human immunity","url":"https://pubmed.ncbi.nlm.nih.gov/42099922","citation_count":0,"is_preprint":false},{"pmid":"37414911","id":"PMC_37414911","title":"Genome-wide DNA methylation analysis in schizophrenia with tardive dyskinesia: a preliminary study.","date":"2023","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37414911","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8935,"output_tokens":1545,"usd":0.02499,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8283,"output_tokens":2138,"usd":0.047433,"stage2_stop_reason":"end_turn"},"total_usd":0.072423,"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\": 2004,\n      \"finding\": \"Nan1/Utp17 (yeast ortholog of WDR75) is a component of the small subunit (SSU) processome, a ~40-protein complex with U3 snoRNA required for ribosome biogenesis; depletion of SSU processome proteins causes G1 cell cycle arrest in yeast, demonstrating the complex is required for cell cycle progression.\",\n      \"method\": \"Genetic depletion of SSU processome proteins in S. cerevisiae and S. pombe, flow cytometry and marker staining for cell cycle phase, synchronized cell experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype (G1 arrest) in two yeast species, multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"15356263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human WDR75 is a nucleolar protein required for pre-rRNA transcription; its depletion reduces levels of RPA194 (a key RNA Polymerase I subunit), activates the RPL5/RPL11-dependent p53 stabilization checkpoint, and causes impaired proliferation and cellular senescence. Under nucleolar stress, WDR75 relocalizes to nucleolar caps.\",\n      \"method\": \"siRNA knockdown in U2OS cells, subcellular fractionation, immunofluorescence of GFP-tagged WDR75 under chemically induced nucleolar stress, western blotting for RPA194 and p53, functional proliferation and senescence assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunofluorescence, western blot, functional assays), validated in several cell models, single lab\",\n      \"pmids\": [\"34611297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nan1/Utp17 (yeast ortholog of WDR75) localizes near the 5'ETS and ITS1 regions of the nascent 35S pre-rRNA and U3 snoRNA within the early small subunit processome, as determined by proximity of its C-terminal domains to these flexible RNA elements.\",\n      \"method\": \"MNase tethered to Nan1/Utp17 and other assembly factors; structural probing of pre-ribosomal particles in yeast\",\n      \"journal\": \"Non-coding RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct structural probing assay with tethered MNase, but single study and single lab; provides architectural placement within the SSU processome\",\n      \"pmids\": [\"35076539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WDR75 binds to an evolutionarily conserved motif in the external transcribed spacer (ETS) region of rRNA to help form the small subunit (SSU) processome; ~25% of WDR75 sites show significant purifying selection, especially at beta-sheet-forming residues, consistent with functional constraints at the rRNA-binding interface.\",\n      \"method\": \"Comparative molecular evolution analysis of 70 mammalian WDR75 sequences, structural prediction, phylogenetic analysis and site-specific selection tests\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/evolutionary analysis only; no direct biochemical experiment on binding\",\n      \"pmids\": [\"39932919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Patient-derived cells and a CRISPR/Cas9-modified cell line carrying compound-heterozygous WDR75 variants show altered pre-rRNA processing (impaired A0 cleavage) and increased p21 expression, indicating partial activation of the p53 pathway (nucleolar stress response).\",\n      \"method\": \"Functional studies in patient-derived cells and CRISPR/Cas9-engineered cell line; pre-rRNA processing assay, p21 western blotting\",\n      \"journal\": \"Journal of human immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assays (pre-rRNA processing, p21 induction) in patient-derived and CRISPR-edited cells; single study, authors note association rather than proven causality\",\n      \"pmids\": [\"42099922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Wdr75 was identified as a positive regulator of mouse embryonic stem cell (mESC) self-renewal in a genome-wide CRISPR-Cas9 screen; sgRNA depletion of Wdr75 reduced ESC self-renewal.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen in mouse ESC R1 cells, high-throughput sequencing of sgRNA ratios, functional confirmation\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — screen-based identification with limited mechanistic follow-up for Wdr75 specifically; single lab\",\n      \"pmids\": [\"35019759\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR75 (Nan1/Utp17 in yeast) is a nucleolar component of the SSU processome that binds the external transcribed spacer of pre-rRNA to support small ribosomal subunit assembly; it is required for pre-rRNA transcription by maintaining RNA Polymerase I subunit RPA194 levels, and its loss activates the RPL5/RPL11–p53 checkpoint, leading to cell cycle arrest, senescence, and impaired proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR75 is a nucleolar component of the small subunit (SSU) processome that supports biogenesis of the small ribosomal subunit, a role conserved from its yeast ortholog Nan1/Utp17 [#0, #1]. Within the early SSU processome it is positioned near the 5'ETS, ITS1, and U3 snoRNA elements of the nascent 35S pre-rRNA, and it binds an evolutionarily conserved motif in the external transcribed spacer of rRNA to help assemble the particle [#2, #3]. In human cells WDR75 is required for pre-rRNA transcription: its depletion lowers levels of the RNA Polymerase I subunit RPA194 and impairs pre-rRNA processing, including A0/A0-type cleavage [#1, #4]. Loss of WDR75 function triggers the nucleolar stress response, activating the RPL5/RPL11-dependent p53 checkpoint with downstream p21 induction, driving impaired proliferation and cellular senescence; under nucleolar stress WDR75 itself relocalizes to nucleolar caps [#1, #4]. Compound-heterozygous WDR75 variants in patient-derived cells produce these same processing and p53-pathway defects, linking WDR75 dysfunction to human disease [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that the WDR75 ortholog is a constituent of the ribosome-biogenesis machinery whose loss blocks the cell cycle, defining its core cellular role.\",\n      \"evidence\": \"Genetic depletion of SSU processome proteins in S. cerevisiae and S. pombe with cell cycle readouts\",\n      \"pmids\": [\"15356263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Yeast ortholog only — human function not directly tested here\", \"Molecular function of Nan1/Utp17 within the complex not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected human WDR75 to pre-rRNA transcription and the nucleolar stress checkpoint, showing how its loss converts a biogenesis defect into a p53-mediated proliferative arrest.\",\n      \"evidence\": \"siRNA knockdown in U2OS, fractionation, immunofluorescence of GFP-WDR75 under nucleolar stress, western blots for RPA194 and p53, proliferation/senescence assays\",\n      \"pmids\": [\"34611297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which WDR75 maintains RPA194 levels not defined\", \"Single lab; cap relocalization function unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed the ortholog architecturally near specific pre-rRNA spacer and U3 snoRNA elements, indicating direct engagement with the nascent transcript during early assembly.\",\n      \"evidence\": \"Tethered-MNase structural probing of yeast pre-ribosomal particles\",\n      \"pmids\": [\"35076539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Yeast system; human contacts inferred\", \"Functional consequence of these contacts not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified Wdr75 as a positive regulator of stem-cell self-renewal, extending its biogenesis role to a developmental/proliferative phenotype.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 knockout screen in mouse ESCs with sgRNA depletion readout\",\n      \"pmids\": [\"35019759\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Screen-based hit with limited Wdr75-specific mechanistic follow-up\", \"Link to ribosome biogenesis in this context not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Argued that the rRNA-binding interface of WDR75 is under purifying selection, supporting a functionally constrained direct contact with the ETS motif.\",\n      \"evidence\": \"Comparative evolutionary and structural-prediction analysis of 70 mammalian WDR75 sequences\",\n      \"pmids\": [\"39932919\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational only — no direct biochemical binding assay\", \"Beta-sheet residue contacts not experimentally validated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Tied WDR75 variants to human disease by showing patient and CRISPR-engineered cells recapitulate the pre-rRNA processing defect and p53-pathway activation.\",\n      \"evidence\": \"Pre-rRNA processing assays and p21 western blotting in patient-derived and CRISPR/Cas9-edited cells carrying compound-heterozygous variants\",\n      \"pmids\": [\"42099922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Authors note association rather than proven causality\", \"Specific disease entity and full clinical mechanism not established here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR75 mechanistically sustains RNA Pol I subunit RPA194 levels and couples SSU processome assembly to the p53 checkpoint remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical demonstration of human WDR75–rRNA binding\", \"Mechanism linking WDR75 loss to RPA194 reduction unknown\", \"Structure of human SSU processome with WDR75 not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"SSU processome\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}