{"gene":"UTP4","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2002,"finding":"UTP4/Cirhin contains WD repeats and the R565W missense mutation in its C-terminus causes North American Indian childhood cirrhosis (NAIC); the protein is preferentially expressed in embryonic liver.","method":"Genetic mapping, sequencing of patient samples, bioinformatic domain analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct identification of disease-causing mutation with genetic mapping and sequencing, replicated across all NAIC patients; no in vitro functional reconstitution of mechanism","pmids":["12417987"],"is_preprint":false},{"year":2005,"finding":"Cirhin/UTP4 localizes to the nucleolus (not mitochondria as predicted), mediated by an active C-terminal monopartite nuclear localization signal (NLS) and a unique nucleolar localization signal (NrLS) between residues 315 and 432. The R565W mutation does not affect subcellular localization.","method":"EGFP and His-tagged fusion protein expression in HeLa and HepG2 cells, direct fluorescence microscopy","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with functional domain mapping using tagged constructs; single lab but multiple constructs and cell lines tested","pmids":["16225863"],"is_preprint":false},{"year":2009,"finding":"Cirhin/UTP4 interacts with Cirip (identical to the C-terminal domain of HIVEP1) via its C-terminus, and this complex upregulates a canonical NF-κB element. The R565W mutation weakens the Cirhin-Cirip interaction and reduces the NF-κB transcriptional activation effect.","method":"Yeast two-hybrid screening, co-immunoprecipitation from HeLa nuclear extracts, in vitro NF-κB reporter assay in mammalian cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal co-IP combined with functional reporter assay, single lab, two orthogonal methods","pmids":["19732766"],"is_preprint":false},{"year":2010,"finding":"The intact C-terminus of Utp4 is required for cell growth and maturation of 18S and 25S rRNAs. Utp8 interacts with the C-terminus of Utp4 and this interaction is essential for SSU processome assembly and Utp4 function in ribosome biogenesis. The homologous NAIC mutation (R565W) does not cause growth defects or aberrant ribosome biogenesis in yeast.","method":"Saccharomyces cerevisiae mutagenesis (C-terminal truncations), rRNA processing assays, yeast two-hybrid protein-protein interaction mapping of t-Utp subcomplex","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo mutagenesis with specific rRNA processing readout combined with protein interaction mapping and epistasis in yeast; multiple orthogonal methods in single rigorous study","pmids":["20385600"],"is_preprint":false},{"year":2012,"finding":"hUTP4/Cirhin interacts with NOL11, a novel metazoan-specific nucleolar protein. NOL11 is a component of the human SSU processome (co-immunoprecipitation). The C-terminal R565W mutation in hUTP4/Cirhin partially disrupts interaction with NOL11 as shown by yeast two-hybrid analysis.","method":"Yeast two-hybrid cDNA library screen, affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, AP-MS, Co-IP) identifying the interaction, plus functional siRNA knockdown confirming SSU processome membership; single lab but rigorous","pmids":["22916032"],"is_preprint":false},{"year":2013,"finding":"Knockdown of cirh1a (zebrafish ortholog of UTP4) causes defects in canalicular and biliary morphology and hepatobiliary function. These biliary defects are completely abrogated by tp53 mutation, placing Cirhin/UTP4 upstream of a p53-mediated stress response pathway in biliary development.","method":"Morpholino oligonucleotide knockdown in zebrafish, fluorescent lipid reporter assay for hepatobiliary function, genetic epistasis with tp53 mutant, transcriptional target analysis of p53","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function with specific cellular phenotype, genetic epistasis confirming pathway placement, two independent morpholinos, in vivo model","pmids":["24147052"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of Utp4 from Chaetomium thermophilum resolved at 2.15 Å reveals two orthogonal, highly basic β-propellers. An unusual Velcro-closure of the C-terminal β-propeller is relevant for protein integrity and potentially Utp8 recognition. CRAC (UV RNA-crosslinking) analysis demonstrates specific Utp4/5'-ETS RNA interaction; Utp4 binds the 5'-ETS of pre-ribosomal RNA.","method":"X-ray crystallography (2.15 Å), UV RNA-crosslinking (CRAC analysis), cryo-EM structure fitting","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at high resolution combined with orthogonal RNA-crosslinking validation of function; single lab but multiple rigorous methods","pmids":["28575120"],"is_preprint":false},{"year":2016,"finding":"Yeast Utp4 is a substrate of the arginine methyltransferase Hmt1, as validated by ex vivo methylation and MS/MS analysis.","method":"Proteome array screen, ex vivo methylation assay, MS/MS validation","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — validated by ex vivo methylation and MS/MS but single lab; the specific methylation site(s) and functional consequence are not described in the abstract","pmids":["26572822"],"is_preprint":false},{"year":2020,"finding":"NOL11 forms a protein complex with WDR43 and Cirhin/UTP4 (the NWC complex) in mitotic cells. This complex resides in the nucleolus during interphase and translocates to perichromosomal regions during mitosis. Absence of the NWC complex impairs chromosome congression, sister chromatid cohesion, centromeric enrichment of Aurora B, and phosphorylation of histone H3 at threonine 3.","method":"Co-immunoprecipitation, live-cell imaging, RNAi knockdown with mitotic phenotype readout, immunofluorescence for Aurora B and H3T3 phosphorylation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for complex identification, live imaging for localization, RNAi with multiple specific mitotic phenotype readouts; multiple orthogonal methods in a single study","pmids":["32479628"],"is_preprint":false},{"year":2023,"finding":"UTP4 knockdown in HeLa cells does not cause nucleolar structural segregation or alter intranuclear locations of specific genomic loci, centromere-nucleolus interactions, perinucleolar compartment, or Cajal body morphology — demonstrating that these global nuclear reorganization effects are specific to loss of nucleolar structure (via RPA194 knockdown) rather than cessation of ribosome synthesis.","method":"siRNA knockdown of UTP4 in HeLa cells, fluorescence microscopy, nuclear organization analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function experiment with specific nuclear phenotype readouts, but the primary finding is a NEGATIVE result (no nuclear reorganization), which is mechanistically informative as a functional distinction","pmids":["37610836"],"is_preprint":false},{"year":2026,"finding":"UTP4 knockdown in gastric cancer cells significantly inhibited cell proliferation, migration, and invasion, establishing a functional role for UTP4 in gastric cancer cell behavior.","method":"CRISPR-Cas9 screening predictions followed by siRNA/shRNA knockdown with cell proliferation, migration, and invasion assays","journal":"Molecular and clinical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with phenotypic readouts but no molecular pathway placement or mechanistic follow-up described in abstract","pmids":["41822801"],"is_preprint":false}],"current_model":"UTP4/Cirhin is a WD40-repeat nucleolar protein and core component of the t-Utp subcomplex of the SSU processome, where it binds the 5'-ETS of pre-ribosomal RNA (via its two basic β-propellers) and interacts with Utp8/NOL11/WDR43 to drive 18S rRNA maturation; it also forms the mitotic NWC complex that translocates to perichromosomal regions to support Aurora B centromeric enrichment and faithful chromosome segregation, interacts with HIVEP1/Cirip to modulate NF-κB transcriptional activity, and is subject to arginine methylation by Hmt1; the disease-causing R565W mutation weakens its C-terminal protein-protein interactions without affecting nucleolar localization, linking impaired SSU processome assembly to a p53-mediated biliary developmental defect."},"narrative":{"mechanistic_narrative":"UTP4 (Cirhin) is a WD40-repeat nucleolar protein that functions as a core component of the t-Utp/SSU processome subcomplex required for maturation of the small-subunit ribosomal RNA [PMID:20385600, PMID:28575120]. Its crystal structure reveals two orthogonal, highly basic β-propellers, and UV RNA-crosslinking demonstrates that UTP4 binds directly to the 5'-ETS of pre-ribosomal RNA, while a Velcro-closure of the C-terminal propeller supports protein integrity and partner recognition [PMID:28575120]. The intact C-terminus is essential for cell growth and 18S/25S rRNA processing, mediating interactions with Utp8 and with the metazoan-specific nucleolar protein NOL11 that drive SSU processome assembly [PMID:20385600, PMID:22916032]. Beyond ribosome biogenesis, UTP4 forms the mitotic NWC complex with NOL11 and WDR43, which relocalizes from the nucleolus to perichromosomal regions to support centromeric enrichment of Aurora B, histone H3 threonine-3 phosphorylation, sister chromatid cohesion, and chromosome congression [PMID:32479628]. UTP4 also interacts via its C-terminus with Cirip (the C-terminal domain of HIVEP1) to upregulate a canonical NF-κB element [PMID:19732766]. The R565W missense mutation causes North American Indian childhood cirrhosis (NAIC); this allele leaves nucleolar localization intact but weakens C-terminal protein-protein interactions, and loss of the zebrafish ortholog cirh1a produces biliary defects that are fully suppressed by tp53 mutation, placing UTP4 upstream of a p53-mediated stress response in biliary development [PMID:12417987, PMID:16225863, PMID:24147052].","teleology":[{"year":2002,"claim":"Established UTP4/Cirhin as a disease gene by identifying the R565W missense mutation as the cause of North American Indian childhood cirrhosis, framing the protein as relevant to embryonic liver biology.","evidence":"Genetic mapping and patient sequencing with bioinformatic domain analysis","pmids":["12417987"],"confidence":"Medium","gaps":["No functional mechanism for how R565W causes disease","WD-repeat function not tested"]},{"year":2005,"claim":"Resolved the long-standing question of where Cirhin acts by showing it is nucleolar rather than mitochondrial, defining the NLS and nucleolar localization signal and demonstrating that R565W does not perturb localization.","evidence":"EGFP/His-tagged fusion expression in HeLa and HepG2 cells with fluorescence microscopy","pmids":["16225863"],"confidence":"Medium","gaps":["Nucleolar function not yet identified","Disease mechanism still unexplained since localization is normal"]},{"year":2009,"claim":"Linked Cirhin to transcriptional signaling by identifying the HIVEP1-derived Cirip as a C-terminal partner that together activate an NF-κB element, and showed R565W weakens this interaction.","evidence":"Yeast two-hybrid, co-IP from nuclear extracts, and NF-κB reporter assay","pmids":["19732766"],"confidence":"Medium","gaps":["Relationship between NF-κB activity and ribosome biogenesis role unclear","In vivo relevance to disease untested"]},{"year":2010,"claim":"Defined the core molecular function by showing the Utp4 C-terminus is required for cell growth and 18S/25S rRNA maturation and interacts with Utp8 for SSU processome assembly.","evidence":"Yeast C-terminal truncation mutagenesis, rRNA processing assays, and Y2H interaction mapping","pmids":["20385600"],"confidence":"High","gaps":["Homologous R565W did not reproduce defects in yeast, leaving disease mechanism unresolved","Direct RNA binding not yet demonstrated"]},{"year":2012,"claim":"Extended SSU processome membership to humans by identifying NOL11 as a Cirhin/UTP4 partner and SSU processome component, with R565W partially disrupting the interaction.","evidence":"Y2H cDNA screen, AP-MS, co-IP, and siRNA knockdown in human cells","pmids":["22916032"],"confidence":"High","gaps":["Quantitative contribution of NOL11 disruption to disease not established","Structural basis of interaction unknown"]},{"year":2016,"claim":"Identified UTP4 as a substrate of the arginine methyltransferase Hmt1, introducing a post-translational regulatory layer.","evidence":"Proteome array screen with ex vivo methylation and MS/MS validation in yeast","pmids":["26572822"],"confidence":"Medium","gaps":["Specific methylation sites not mapped","Functional consequence of methylation unknown"]},{"year":2013,"claim":"Placed UTP4 in a developmental pathway by showing zebrafish cirh1a loss causes biliary defects that are fully suppressed by tp53 mutation, linking impaired UTP4 function to a p53-mediated stress response.","evidence":"Morpholino knockdown in zebrafish, hepatobiliary reporter assays, and genetic epistasis with tp53 mutant","pmids":["24147052"],"confidence":"High","gaps":["How ribosome biogenesis defect triggers p53 in biliary cells not defined","Tissue specificity of the phenotype unexplained"]},{"year":2017,"claim":"Provided the structural and biochemical basis of UTP4 function, showing two basic β-propellers and direct binding to the 5'-ETS of pre-rRNA.","evidence":"X-ray crystallography at 2.15 Å, CRAC UV RNA-crosslinking, and cryo-EM fitting in Chaetomium thermophilum","pmids":["28575120"],"confidence":"High","gaps":["Structure of the human protein and disease residue not determined","Mechanism of Utp8 recognition by the Velcro closure not directly shown"]},{"year":2020,"claim":"Revealed a moonlighting mitotic role by defining the NWC complex (NOL11–WDR43–Cirhin/UTP4) that translocates to perichromosomal regions to support Aurora B enrichment, H3T3 phosphorylation, and faithful chromosome segregation.","evidence":"Reciprocal co-IP, live-cell imaging, and RNAi with multiple mitotic phenotype readouts","pmids":["32479628"],"confidence":"High","gaps":["Whether the mitotic role contributes to NAIC unknown","Mechanism coupling nucleolar release to perichromosomal targeting undefined"]},{"year":2023,"claim":"Distinguished UTP4 loss from loss of nucleolar structure by showing UTP4 knockdown does not trigger global nuclear reorganization, isolating its effect to ribosome synthesis rather than nucleolar architecture.","evidence":"siRNA knockdown in HeLa cells with fluorescence microscopy of nuclear organization","pmids":["37610836"],"confidence":"Medium","gaps":["Negative result limits mechanistic conclusions","No assessment of subtler functional consequences"]},{"year":2026,"claim":"Implicated UTP4 in cancer cell behavior by showing knockdown inhibits gastric cancer cell proliferation, migration, and invasion.","evidence":"CRISPR screen prediction followed by siRNA/shRNA knockdown with proliferation, migration, and invasion assays","pmids":["41822801"],"confidence":"Low","gaps":["No molecular pathway placement or mechanistic follow-up","Connection to ribosome biogenesis or NWC functions not tested"]},{"year":null,"claim":"It remains unresolved how a single nucleolar SSU processome protein mechanistically produces a tissue-specific biliary disease via R565W when the mutation leaves localization intact and only partially weakens partner interactions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Quantitative link between weakened C-terminal interactions and human disease severity","Whether the NF-κB or mitotic NWC functions contribute to NAIC","Cell-type basis of the p53-dependent biliary phenotype"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8]}],"complexes":["SSU processome (t-Utp subcomplex)","NWC complex (NOL11-WDR43-Cirhin/UTP4)"],"partners":["NOL11","WDR43","UTP8","HIVEP1","HMT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969X6","full_name":"U3 small nucleolar RNA-associated protein 4 homolog","aliases":["Cirhin","UTP4 small subunit processome component"],"length_aa":686,"mass_kda":76.9,"function":"Ribosome biogenesis factor. Involved in nucleolar processing of pre-18S ribosomal RNA. 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 d Involved in SSU pre-rRNA processing at sites A', A0, 1 and 2b. Required for optimal pre-ribosomal RNA transcription by RNA polymerase (PubMed:17699751, PubMed:19732766, PubMed:34516797). May be a transcriptional regulator (PubMed:22916032) (Microbial infection) Acts as a positive regulator of HIVEP1 which specifically binds to the DNA sequence 5'-GGGACTTTCC-3' found in enhancer elements of numerous viral promoters such as those of HIV-1, SV40, or CMV","subcellular_location":"Nucleus, nucleolus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q969X6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/UTP4","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000141076","cell_line_id":"CID001079","localizations":[{"compartment":"nucleolus_fc_dfc","grade":3}],"interactors":[{"gene":"NOL11","stoichiometry":10.0},{"gene":"CIRH1A","stoichiometry":10.0},{"gene":"WDR43","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001079","total_profiled":1310},"omim":[{"mim_id":"612935","title":"MYOSIN PHOSPHATASE RHO-INTERACTING PROTEIN; MPRIP","url":"https://www.omim.org/entry/612935"},{"mim_id":"607456","title":"UTP4 SMALL SUBUNIT PROCESSOME COMPONENT; UTP4","url":"https://www.omim.org/entry/607456"},{"mim_id":"604901","title":"NORTH AMERICAN INDIAN CHILDHOOD CIRRHOSIS; NAIC","url":"https://www.omim.org/entry/604901"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli fibrillar center","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UTP4"},"hgnc":{"alias_symbol":["NAIC","FLJ14728","KIAA1988","TEX292","CIRHIN"],"prev_symbol":["CIRH1A"]},"alphafold":{"accession":"Q969X6","domains":[{"cath_id":"2.130.10.10","chopping":"20-331","consensus_level":"medium","plddt":93.1725,"start":20,"end":331}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969X6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969X6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969X6-F1-predicted_aligned_error_v6.png","plddt_mean":91.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UTP4","jax_strain_url":"https://www.jax.org/strain/search?query=UTP4"},"sequence":{"accession":"Q969X6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969X6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969X6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969X6"}},"corpus_meta":[{"pmid":"22916032","id":"PMC_22916032","title":"NOL11, implicated in the pathogenesis of North American Indian childhood cirrhosis, is required for pre-rRNA transcription and processing.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22916032","citation_count":81,"is_preprint":false},{"pmid":"12417987","id":"PMC_12417987","title":"A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis.","date":"2002","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12417987","citation_count":69,"is_preprint":false},{"pmid":"1320376","id":"PMC_1320376","title":"A nucleotide receptor in vascular endothelial cells is specifically activated by the fully ionized forms of ATP and UTP.","date":"1992","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/1320376","citation_count":56,"is_preprint":false},{"pmid":"20385600","id":"PMC_20385600","title":"The C-terminus of Utp4, mutated in childhood cirrhosis, is essential for ribosome biogenesis.","date":"2010","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/20385600","citation_count":54,"is_preprint":false},{"pmid":"11853319","id":"PMC_11853319","title":"Prediction of the coding sequences of unidentified human genes. 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The complete sequences of 50 new cDNA clones which code for large proteins.","date":"2001","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/11853319","citation_count":49,"is_preprint":false},{"pmid":"39221992","id":"PMC_39221992","title":"Perioperative toripalimab plus neoadjuvant chemotherapy might improve outcomes in resectable esophageal cancer: an interim analysis of a phase III randomized clinical trial.","date":"2024","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39221992","citation_count":44,"is_preprint":false},{"pmid":"24240090","id":"PMC_24240090","title":"Human diseases of the SSU processome.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24240090","citation_count":40,"is_preprint":false},{"pmid":"38933281","id":"PMC_38933281","title":"CT-based quantification of intratumoral heterogeneity for predicting pathologic complete response to neoadjuvant immunochemotherapy in non-small cell lung cancer.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38933281","citation_count":35,"is_preprint":false},{"pmid":"15768832","id":"PMC_15768832","title":"Molecular basis of intrahepatic cholestasis.","date":"2004","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15768832","citation_count":33,"is_preprint":false},{"pmid":"24147052","id":"PMC_24147052","title":"p53-mediated biliary defects caused by knockdown of cirh1a, the zebrafish homolog of the gene responsible for North American Indian Childhood Cirrhosis.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24147052","citation_count":31,"is_preprint":false},{"pmid":"11045837","id":"PMC_11045837","title":"North American Indian cirrhosis in children: a review of 30 cases.","date":"2000","source":"Journal of pediatric gastroenterology and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/11045837","citation_count":28,"is_preprint":false},{"pmid":"10820129","id":"PMC_10820129","title":"Localization of a recessive gene for North American Indian childhood cirrhosis to chromosome region 16q22-and identification of a shared haplotype.","date":"2000","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10820129","citation_count":22,"is_preprint":false},{"pmid":"32479628","id":"PMC_32479628","title":"Identification of a novel nucleolar protein complex required for mitotic chromosome segregation through centromeric accumulation of Aurora B.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/32479628","citation_count":20,"is_preprint":false},{"pmid":"16225863","id":"PMC_16225863","title":"Nucleolar localization of cirhin, the protein mutated in North American Indian childhood cirrhosis.","date":"2005","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/16225863","citation_count":16,"is_preprint":false},{"pmid":"40295492","id":"PMC_40295492","title":"Efficacy, safety and single-cell analysis of neoadjuvant immunochemotherapy in locally advanced oral squamous cell carcinoma: a phase II trial.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40295492","citation_count":16,"is_preprint":false},{"pmid":"4017265","id":"PMC_4017265","title":"Arguments for the presence of a Na-K ATPase pump inhibitor in the plasma of uremic and essential hypertensive patients.","date":"1985","source":"Clinical and experimental hypertension. 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Immunochemotherapy.","date":"2023","source":"Annals of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37093412","citation_count":3,"is_preprint":false},{"pmid":"40406099","id":"PMC_40406099","title":"Neoadjuvant immunochemotherapy versus neoadjuvant immunoradiotherapy in locally advanced oral squamous cell carcinoma.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40406099","citation_count":2,"is_preprint":false},{"pmid":"10192172","id":"PMC_10192172","title":"Effects of UTP on Na+, Cl- and K+ transport in primary cultures from human sweat gland coils.","date":"1999","source":"Acta physiologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/10192172","citation_count":2,"is_preprint":false},{"pmid":"41822801","id":"PMC_41822801","title":"Pan-cancer analysis and experimental validation reveal UTP4 as a novel biomarker for gastric cancer.","date":"2026","source":"Molecular and clinical 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immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/41591567","citation_count":0,"is_preprint":false},{"pmid":"41251915","id":"PMC_41251915","title":"Neoadjuvant Chemoimmunotherapy for Elderly Patients with Locally Advanced Resectable Esophageal Squamous Cell Carcinoma.","date":"2025","source":"Annals of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41251915","citation_count":0,"is_preprint":false},{"pmid":"41158039","id":"PMC_41158039","title":"[Prediction of Spatial Distance of CAFs-TAECs for Pathological Response 
to Neoadjuvant Chemoimmunotherapy in Lung Squamous Cell Carcinoma].","date":"2025","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41158039","citation_count":0,"is_preprint":false},{"pmid":"41727640","id":"PMC_41727640","title":"Optimal timing of surgery in head and neck squamous cell carcinoma after neoadjuvant immunochemotherapy.","date":"2026","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41727640","citation_count":0,"is_preprint":false},{"pmid":"41018074","id":"PMC_41018074","title":"De-escalating adjuvant therapy after pathologic complete response in oral squamous cell carcinoma: Chemoradiotherapy benefits only high-risk subgroups.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41018074","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26267,"output_tokens":2781,"usd":0.060258,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10159,"output_tokens":3534,"usd":0.069572,"stage2_stop_reason":"end_turn"},"total_usd":0.12983,"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\": 2002,\n      \"finding\": \"UTP4/Cirhin contains WD repeats and the R565W missense mutation in its C-terminus causes North American Indian childhood cirrhosis (NAIC); the protein is preferentially expressed in embryonic liver.\",\n      \"method\": \"Genetic mapping, sequencing of patient samples, bioinformatic domain analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct identification of disease-causing mutation with genetic mapping and sequencing, replicated across all NAIC patients; no in vitro functional reconstitution of mechanism\",\n      \"pmids\": [\"12417987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cirhin/UTP4 localizes to the nucleolus (not mitochondria as predicted), mediated by an active C-terminal monopartite nuclear localization signal (NLS) and a unique nucleolar localization signal (NrLS) between residues 315 and 432. The R565W mutation does not affect subcellular localization.\",\n      \"method\": \"EGFP and His-tagged fusion protein expression in HeLa and HepG2 cells, direct fluorescence microscopy\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with functional domain mapping using tagged constructs; single lab but multiple constructs and cell lines tested\",\n      \"pmids\": [\"16225863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cirhin/UTP4 interacts with Cirip (identical to the C-terminal domain of HIVEP1) via its C-terminus, and this complex upregulates a canonical NF-κB element. The R565W mutation weakens the Cirhin-Cirip interaction and reduces the NF-κB transcriptional activation effect.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation from HeLa nuclear extracts, in vitro NF-κB reporter assay in mammalian cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal co-IP combined with functional reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"19732766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The intact C-terminus of Utp4 is required for cell growth and maturation of 18S and 25S rRNAs. Utp8 interacts with the C-terminus of Utp4 and this interaction is essential for SSU processome assembly and Utp4 function in ribosome biogenesis. The homologous NAIC mutation (R565W) does not cause growth defects or aberrant ribosome biogenesis in yeast.\",\n      \"method\": \"Saccharomyces cerevisiae mutagenesis (C-terminal truncations), rRNA processing assays, yeast two-hybrid protein-protein interaction mapping of t-Utp subcomplex\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo mutagenesis with specific rRNA processing readout combined with protein interaction mapping and epistasis in yeast; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"20385600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"hUTP4/Cirhin interacts with NOL11, a novel metazoan-specific nucleolar protein. NOL11 is a component of the human SSU processome (co-immunoprecipitation). The C-terminal R565W mutation in hUTP4/Cirhin partially disrupts interaction with NOL11 as shown by yeast two-hybrid analysis.\",\n      \"method\": \"Yeast two-hybrid cDNA library screen, affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, AP-MS, Co-IP) identifying the interaction, plus functional siRNA knockdown confirming SSU processome membership; single lab but rigorous\",\n      \"pmids\": [\"22916032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of cirh1a (zebrafish ortholog of UTP4) causes defects in canalicular and biliary morphology and hepatobiliary function. These biliary defects are completely abrogated by tp53 mutation, placing Cirhin/UTP4 upstream of a p53-mediated stress response pathway in biliary development.\",\n      \"method\": \"Morpholino oligonucleotide knockdown in zebrafish, fluorescent lipid reporter assay for hepatobiliary function, genetic epistasis with tp53 mutant, transcriptional target analysis of p53\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function with specific cellular phenotype, genetic epistasis confirming pathway placement, two independent morpholinos, in vivo model\",\n      \"pmids\": [\"24147052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of Utp4 from Chaetomium thermophilum resolved at 2.15 Å reveals two orthogonal, highly basic β-propellers. An unusual Velcro-closure of the C-terminal β-propeller is relevant for protein integrity and potentially Utp8 recognition. CRAC (UV RNA-crosslinking) analysis demonstrates specific Utp4/5'-ETS RNA interaction; Utp4 binds the 5'-ETS of pre-ribosomal RNA.\",\n      \"method\": \"X-ray crystallography (2.15 Å), UV RNA-crosslinking (CRAC analysis), cryo-EM structure fitting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at high resolution combined with orthogonal RNA-crosslinking validation of function; single lab but multiple rigorous methods\",\n      \"pmids\": [\"28575120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Yeast Utp4 is a substrate of the arginine methyltransferase Hmt1, as validated by ex vivo methylation and MS/MS analysis.\",\n      \"method\": \"Proteome array screen, ex vivo methylation assay, MS/MS validation\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — validated by ex vivo methylation and MS/MS but single lab; the specific methylation site(s) and functional consequence are not described in the abstract\",\n      \"pmids\": [\"26572822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NOL11 forms a protein complex with WDR43 and Cirhin/UTP4 (the NWC complex) in mitotic cells. This complex resides in the nucleolus during interphase and translocates to perichromosomal regions during mitosis. Absence of the NWC complex impairs chromosome congression, sister chromatid cohesion, centromeric enrichment of Aurora B, and phosphorylation of histone H3 at threonine 3.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, RNAi knockdown with mitotic phenotype readout, immunofluorescence for Aurora B and H3T3 phosphorylation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for complex identification, live imaging for localization, RNAi with multiple specific mitotic phenotype readouts; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"32479628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UTP4 knockdown in HeLa cells does not cause nucleolar structural segregation or alter intranuclear locations of specific genomic loci, centromere-nucleolus interactions, perinucleolar compartment, or Cajal body morphology — demonstrating that these global nuclear reorganization effects are specific to loss of nucleolar structure (via RPA194 knockdown) rather than cessation of ribosome synthesis.\",\n      \"method\": \"siRNA knockdown of UTP4 in HeLa cells, fluorescence microscopy, nuclear organization analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function experiment with specific nuclear phenotype readouts, but the primary finding is a NEGATIVE result (no nuclear reorganization), which is mechanistically informative as a functional distinction\",\n      \"pmids\": [\"37610836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"UTP4 knockdown in gastric cancer cells significantly inhibited cell proliferation, migration, and invasion, establishing a functional role for UTP4 in gastric cancer cell behavior.\",\n      \"method\": \"CRISPR-Cas9 screening predictions followed by siRNA/shRNA knockdown with cell proliferation, migration, and invasion assays\",\n      \"journal\": \"Molecular and clinical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with phenotypic readouts but no molecular pathway placement or mechanistic follow-up described in abstract\",\n      \"pmids\": [\"41822801\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UTP4/Cirhin is a WD40-repeat nucleolar protein and core component of the t-Utp subcomplex of the SSU processome, where it binds the 5'-ETS of pre-ribosomal RNA (via its two basic β-propellers) and interacts with Utp8/NOL11/WDR43 to drive 18S rRNA maturation; it also forms the mitotic NWC complex that translocates to perichromosomal regions to support Aurora B centromeric enrichment and faithful chromosome segregation, interacts with HIVEP1/Cirip to modulate NF-κB transcriptional activity, and is subject to arginine methylation by Hmt1; the disease-causing R565W mutation weakens its C-terminal protein-protein interactions without affecting nucleolar localization, linking impaired SSU processome assembly to a p53-mediated biliary developmental defect.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UTP4 (Cirhin) is a WD40-repeat nucleolar protein that functions as a core component of the t-Utp/SSU processome subcomplex required for maturation of the small-subunit ribosomal RNA [#3, #6]. Its crystal structure reveals two orthogonal, highly basic β-propellers, and UV RNA-crosslinking demonstrates that UTP4 binds directly to the 5'-ETS of pre-ribosomal RNA, while a Velcro-closure of the C-terminal propeller supports protein integrity and partner recognition [#6]. The intact C-terminus is essential for cell growth and 18S/25S rRNA processing, mediating interactions with Utp8 and with the metazoan-specific nucleolar protein NOL11 that drive SSU processome assembly [#3, #4]. Beyond ribosome biogenesis, UTP4 forms the mitotic NWC complex with NOL11 and WDR43, which relocalizes from the nucleolus to perichromosomal regions to support centromeric enrichment of Aurora B, histone H3 threonine-3 phosphorylation, sister chromatid cohesion, and chromosome congression [#8]. UTP4 also interacts via its C-terminus with Cirip (the C-terminal domain of HIVEP1) to upregulate a canonical NF-κB element [#2]. The R565W missense mutation causes North American Indian childhood cirrhosis (NAIC); this allele leaves nucleolar localization intact but weakens C-terminal protein-protein interactions, and loss of the zebrafish ortholog cirh1a produces biliary defects that are fully suppressed by tp53 mutation, placing UTP4 upstream of a p53-mediated stress response in biliary development [#0, #1, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established UTP4/Cirhin as a disease gene by identifying the R565W missense mutation as the cause of North American Indian childhood cirrhosis, framing the protein as relevant to embryonic liver biology.\",\n      \"evidence\": \"Genetic mapping and patient sequencing with bioinformatic domain analysis\",\n      \"pmids\": [\"12417987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional mechanism for how R565W causes disease\", \"WD-repeat function not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the long-standing question of where Cirhin acts by showing it is nucleolar rather than mitochondrial, defining the NLS and nucleolar localization signal and demonstrating that R565W does not perturb localization.\",\n      \"evidence\": \"EGFP/His-tagged fusion expression in HeLa and HepG2 cells with fluorescence microscopy\",\n      \"pmids\": [\"16225863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nucleolar function not yet identified\", \"Disease mechanism still unexplained since localization is normal\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked Cirhin to transcriptional signaling by identifying the HIVEP1-derived Cirip as a C-terminal partner that together activate an NF-κB element, and showed R565W weakens this interaction.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP from nuclear extracts, and NF-κB reporter assay\",\n      \"pmids\": [\"19732766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between NF-κB activity and ribosome biogenesis role unclear\", \"In vivo relevance to disease untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the core molecular function by showing the Utp4 C-terminus is required for cell growth and 18S/25S rRNA maturation and interacts with Utp8 for SSU processome assembly.\",\n      \"evidence\": \"Yeast C-terminal truncation mutagenesis, rRNA processing assays, and Y2H interaction mapping\",\n      \"pmids\": [\"20385600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Homologous R565W did not reproduce defects in yeast, leaving disease mechanism unresolved\", \"Direct RNA binding not yet demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended SSU processome membership to humans by identifying NOL11 as a Cirhin/UTP4 partner and SSU processome component, with R565W partially disrupting the interaction.\",\n      \"evidence\": \"Y2H cDNA screen, AP-MS, co-IP, and siRNA knockdown in human cells\",\n      \"pmids\": [\"22916032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of NOL11 disruption to disease not established\", \"Structural basis of interaction unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified UTP4 as a substrate of the arginine methyltransferase Hmt1, introducing a post-translational regulatory layer.\",\n      \"evidence\": \"Proteome array screen with ex vivo methylation and MS/MS validation in yeast\",\n      \"pmids\": [\"26572822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific methylation sites not mapped\", \"Functional consequence of methylation unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed UTP4 in a developmental pathway by showing zebrafish cirh1a loss causes biliary defects that are fully suppressed by tp53 mutation, linking impaired UTP4 function to a p53-mediated stress response.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish, hepatobiliary reporter assays, and genetic epistasis with tp53 mutant\",\n      \"pmids\": [\"24147052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ribosome biogenesis defect triggers p53 in biliary cells not defined\", \"Tissue specificity of the phenotype unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the structural and biochemical basis of UTP4 function, showing two basic β-propellers and direct binding to the 5'-ETS of pre-rRNA.\",\n      \"evidence\": \"X-ray crystallography at 2.15 Å, CRAC UV RNA-crosslinking, and cryo-EM fitting in Chaetomium thermophilum\",\n      \"pmids\": [\"28575120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the human protein and disease residue not determined\", \"Mechanism of Utp8 recognition by the Velcro closure not directly shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a moonlighting mitotic role by defining the NWC complex (NOL11–WDR43–Cirhin/UTP4) that translocates to perichromosomal regions to support Aurora B enrichment, H3T3 phosphorylation, and faithful chromosome segregation.\",\n      \"evidence\": \"Reciprocal co-IP, live-cell imaging, and RNAi with multiple mitotic phenotype readouts\",\n      \"pmids\": [\"32479628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the mitotic role contributes to NAIC unknown\", \"Mechanism coupling nucleolar release to perichromosomal targeting undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguished UTP4 loss from loss of nucleolar structure by showing UTP4 knockdown does not trigger global nuclear reorganization, isolating its effect to ribosome synthesis rather than nucleolar architecture.\",\n      \"evidence\": \"siRNA knockdown in HeLa cells with fluorescence microscopy of nuclear organization\",\n      \"pmids\": [\"37610836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result limits mechanistic conclusions\", \"No assessment of subtler functional consequences\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated UTP4 in cancer cell behavior by showing knockdown inhibits gastric cancer cell proliferation, migration, and invasion.\",\n      \"evidence\": \"CRISPR screen prediction followed by siRNA/shRNA knockdown with proliferation, migration, and invasion assays\",\n      \"pmids\": [\"41822801\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular pathway placement or mechanistic follow-up\", \"Connection to ribosome biogenesis or NWC functions not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single nucleolar SSU processome protein mechanistically produces a tissue-specific biliary disease via R565W when the mutation leaves localization intact and only partially weakens partner interactions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative link between weakened C-terminal interactions and human disease severity\", \"Whether the NF-κB or mitotic NWC functions contribute to NAIC\", \"Cell-type basis of the p53-dependent biliary phenotype\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"SSU processome (t-Utp subcomplex)\", \"NWC complex (NOL11-WDR43-Cirhin/UTP4)\"],\n    \"partners\": [\"NOL11\", \"WDR43\", \"Utp8\", \"HIVEP1\", \"Hmt1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}