{"gene":"UTP14A","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2016,"finding":"Yeast Utp14 (ortholog of human UTP14A) directly interacts with the DEAH/RHA RNA helicase Dhr1 and stimulates its RNA unwinding activity in vitro. Mutations in a discrete region of Utp14 that reduced Dhr1 interaction also reduced Utp14 function in vivo, causing accumulation of Dhr1 and U3 snoRNA in a pre-40S particle—phenocopying a helicase-inactive Dhr1 mutant. Together with Bud23, Utp14 is required for stable recruitment of Dhr1 to the preribosome.","method":"In vitro unwinding assay, yeast two-hybrid, co-immunoprecipitation, site-directed mutagenesis, genetic epistasis with bud23 mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of helicase stimulation with mutagenesis correlating in vitro and in vivo phenotypes; multiple orthogonal methods in a single rigorous study","pmids":["26729466"],"is_preprint":false},{"year":2019,"finding":"A conserved sequence motif in human UTP14A directly interacts with DHX37 (human ortholog of Dhr1), stimulates its ATPase activity, and enhances its RNA binding. The carboxy-terminal domain (CTD) of DHX37 is required (but not sufficient) for interaction with UTP14A in vitro and is essential for ribosome biogenesis in vivo. Crystal structure of DHX37 with single-stranded RNA revealed a canonical DEAH architecture plus a structurally unique CTD, and conformational comparisons suggested an ATP-dependent 3′→5′ RNA translocation mechanism.","method":"Crystal structure (X-ray crystallography), in vitro ATPase assay, RNA-binding assay, pull-down, mutagenesis, in vivo complementation assay","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with in vitro enzymatic assays and mutagenesis, multiple orthogonal methods in one study","pmids":["30910870"],"is_preprint":false},{"year":2018,"finding":"Utp14 cross-links to the pre-rRNA by UV crosslinking and analysis of cDNA (CRAC), and yeast two-hybrid interactions position it within the SSU processome. Proteomic analysis of SSU particles lacking Utp14 showed that Utp14 is needed for efficient recruitment of the RNA exosome to the preribosome, suggesting Utp14 communicates assembly status to the exosome as well as to Dhr1.","method":"UV crosslinking and analysis of cDNA (CRAC), yeast two-hybrid, quantitative proteomics of SSU particles","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (CRAC, Y2H, proteomics) in a single lab study","pmids":["29925570"],"is_preprint":false},{"year":2018,"finding":"Human UTP14a (hUTP14a) interacts with c-Myc and protects c-Myc from ubiquitination and degradation in a USP36-dependent manner. hUTP14a forms a complex with USP36 and Fbw7γ to inhibit Fbw7γ-mediated c-Myc degradation. Ectopic hUTP14a expression enriches c-Myc in the nucleolus. Reciprocally, c-Myc activates transcription of hUTP14a, forming a positive feedback loop.","method":"Mass spectrometry identification of complex components, co-immunoprecipitation, ubiquitination assay, shRNA knockdown in mouse xenografts, ectopic overexpression with localization analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, MS complex identification, ubiquitination assay, in vivo xenograft knockdown; single lab","pmids":["30343112"],"is_preprint":false},{"year":2019,"finding":"hUTP14a upregulates transcription and secretion of platelet-derived growth factor subunit A (PDGFA) in colorectal cancer cells. Conditioned medium from hUTP14a-depleted cells inhibits PDGFA-mediated signaling, tube formation, and migration in HUVECs; these effects are rescued by Flag-hUTP14a expression and blocked by PDGFR inhibitor imatinib.","method":"RNA-seq, shRNA knockdown, conditioned medium assay, HUVEC tube formation and migration assay, in vivo Matrigel plug assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus multiple functional assays (tube formation, migration, in vivo plug) with rescue; single lab","pmids":["30929921"],"is_preprint":false},{"year":2024,"finding":"P16INK4A upregulates UTP14A E3 ligase activity, which catalyzes ubiquitination of RB1 at lysine 810 (K810), leading to RB1 degradation. Loss of P16INK4A disrupts UTP14A-mediated RB1 ubiquitination and causes RB1 accumulation.","method":"Ubiquitination assay with site identification (K810 mutant), knockdown/overexpression of P16INK4A and UTP14A, proteome-scale ubiquitination analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific ubiquitination site identified with mutagenesis, loss-of-function phenotype, single lab","pmids":["39351198"],"is_preprint":false},{"year":2021,"finding":"UTP14A activates the PERK/eIF2α/GRP78 endoplasmic reticulum stress signalling pathway in esophageal squamous cell carcinoma cells; knockdown suppresses and overexpression enhances migration and proliferation via this pathway.","method":"shRNA knockdown, overexpression, in vitro cell proliferation and migration assays, in vivo xenograft, pathway readout by western blot","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD/OE phenotype with pathway readout but no direct biochemical interaction demonstrated between UTP14A and PERK pathway components","pmids":["33391409"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of 16 native SSU processome intermediates show that Utp14 probes evolving surfaces of the preribosome as it matures, ultimately positioning and activating Dhr1 to unwind U3 snoRNA and initiate nucleolar pre-40S release. The RNA exosome is redundantly tethered to the SSU processome, and irreversible pre-rRNA degradation by the exosome drives compositional changes that are communicated to Dhr1 via Utp14.","method":"Cryo-EM of native SSU processome intermediates, genetic data","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural data with genetic support, but preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.09.29.679232"],"is_preprint":true}],"current_model":"UTP14A is a bifunctional ribosome biogenesis factor that (1) recruits and activates the DEAH helicase DHX37/Dhr1 via direct interaction to unwind U3 snoRNA from the pre-ribosome—thereby enabling pre-40S maturation—and also facilitates exosome recruitment to the SSU processome; (2) acts as an E3 ubiquitin ligase that catalyzes K810 ubiquitination and degradation of RB1 downstream of P16INK4A; and (3) stabilizes c-Myc in the nucleolus by forming a complex with USP36/Fbw7γ to inhibit c-Myc ubiquitination, while also promoting angiogenesis through upregulation of PDGFA."},"narrative":{"mechanistic_narrative":"UTP14A is a ribosome biogenesis factor of the small subunit (SSU) processome that couples assembly status of the maturing pre-ribosome to the activation of the DEAH-box helicase that triggers pre-40S release [PMID:26729466, PMID:bio_10.1101_2025.09.29.679232]. It directly binds the helicase Dhr1/DHX37 through a conserved sequence motif, stimulating its RNA unwinding and ATPase activities and enhancing its RNA binding; this interaction, together with Bud23, is required for stable recruitment of the helicase to the pre-ribosome so that it can unwind U3 snoRNA and initiate nucleolar pre-40S release [PMID:26729466, PMID:30910870]. UTP14A crosslinks to pre-rRNA within the SSU processome and is additionally required for efficient recruitment of the RNA exosome, positioning it as a sensor that communicates compositional maturation state to both the exosome and the helicase [PMID:29925570, PMID:bio_10.1101_2025.09.29.679232]. Beyond ribosome assembly, human UTP14A has been implicated in oncogenic protein homeostasis: it forms a complex with USP36 and Fbw7γ to inhibit Fbw7γ-mediated ubiquitination of c-Myc, enriching c-Myc in the nucleolus within a c-Myc/UTP14A positive feedback loop [PMID:30343112], and it acts downstream of P16INK4A as an E3 ligase activity that ubiquitinates RB1 at K810 to drive its degradation [PMID:39351198]. It also promotes angiogenesis by upregulating PDGFA transcription and secretion [PMID:30929921].","teleology":[{"year":2016,"claim":"Established that Utp14 is not merely a structural processome component but a direct activator of the Dhr1 helicase, defining the mechanistic link between Utp14 and U3 snoRNA removal during pre-40S maturation.","evidence":"In vitro unwinding assay, yeast two-hybrid, co-IP and site-directed mutagenesis with genetic epistasis in yeast","pmids":["26729466"],"confidence":"High","gaps":["Did not provide an atomic structure of the Utp14-Dhr1 interface","Human ortholog activity not yet tested in this study"]},{"year":2018,"claim":"Positioned Utp14 physically on the pre-rRNA and revealed a second output of its function—recruitment of the RNA exosome—implying it integrates assembly signals for both exosome and helicase.","evidence":"CRAC pre-rRNA crosslinking, yeast two-hybrid and quantitative proteomics of SSU particles","pmids":["29925570"],"confidence":"Medium","gaps":["Mechanism by which Utp14 senses assembly status not resolved","Direct vs. indirect exosome recruitment not distinguished"]},{"year":2018,"claim":"Identified a non-ribosomal role for human UTP14A in stabilizing the oncoprotein c-Myc, connecting a ribosome biogenesis factor to deubiquitination machinery and tumor-relevant signaling.","evidence":"MS complex identification, reciprocal co-IP, ubiquitination assay, shRNA xenograft and localization analysis","pmids":["30343112"],"confidence":"Medium","gaps":["Single lab without independent replication","Whether c-Myc stabilization depends on UTP14A's processome function is unclear"]},{"year":2019,"claim":"Resolved the structural basis of helicase activation, showing the human UTP14A motif stimulates DHX37 ATPase via its unique C-terminal domain and defining the helicase translocation mechanism.","evidence":"Crystal structure of DHX37 with ssRNA, in vitro ATPase and RNA-binding assays, mutagenesis and in vivo complementation","pmids":["30910870"],"confidence":"High","gaps":["No co-structure of the UTP14A-DHX37 complex","Conformational ATP-dependent translocation inferred rather than directly observed"]},{"year":2019,"claim":"Extended UTP14A oncogenic function to angiogenesis by linking it to PDGFA-driven paracrine signaling in colorectal cancer.","evidence":"RNA-seq, shRNA knockdown, conditioned-medium HUVEC tube formation/migration with rescue and imatinib block, in vivo Matrigel plug","pmids":["30929921"],"confidence":"Medium","gaps":["Mechanism of PDGFA transcriptional upregulation not defined","Single lab"]},{"year":2021,"claim":"Associated UTP14A with PERK/eIF2α/GRP78 ER stress signaling in esophageal squamous cell carcinoma, but only at the level of phenotype and pathway readout.","evidence":"shRNA knockdown, overexpression, proliferation/migration assays, xenograft and western blot pathway readout","pmids":["33391409"],"confidence":"Low","gaps":["No direct biochemical interaction demonstrated between UTP14A and PERK pathway components","Causality between UTP14A and ER stress activation not established"]},{"year":2024,"claim":"Defined an E3 ligase output for UTP14A acting downstream of P16INK4A, identifying RB1 K810 as a ubiquitination site whose modification drives RB1 degradation.","evidence":"Ubiquitination assay with K810 site mutant, P16INK4A/UTP14A loss- and gain-of-function, proteome-scale ubiquitination analysis","pmids":["39351198"],"confidence":"Medium","gaps":["Direct E3 ligase catalytic activity of UTP14A not reconstituted with purified components","Single lab"]},{"year":2025,"claim":"Captured the dynamic trajectory by which Utp14 probes maturing processome surfaces to ultimately position and activate Dhr1, and showed exosome tethering is redundant, unifying the helicase- and exosome-coupling roles into one assembly-checkpoint model.","evidence":"Cryo-EM of 16 native SSU processome intermediates with genetic data (preprint)","pmids":["bio_10.1101_2025.09.29.679232"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Molecular signal communicated from exosome to Dhr1 via Utp14 not defined at residue level"]},{"year":null,"claim":"How UTP14A's nucleolar ribosome biogenesis function mechanistically relates to its reported E3 ligase and c-Myc-stabilizing activities in cancer remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or biochemical reconciliation of processome vs. ubiquitin-pathway functions","Whether E3 ligase activity is intrinsic or complex-dependent is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3,7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,7]}],"complexes":["SSU processome"],"partners":["DHX37","USP36","FBXW7","MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BVJ6","full_name":"U3 small nucleolar RNA-associated protein 14 homolog A","aliases":["Antigen NY-CO-16","Serologically defined colon cancer antigen 16"],"length_aa":771,"mass_kda":88.0,"function":"May be required for ribosome biogenesis","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9BVJ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UTP14A","classification":"Not Classified","n_dependent_lines":163,"n_total_lines":1208,"dependency_fraction":0.13493377483443708},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000156697","cell_line_id":"CID001089","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"BYSL","stoichiometry":4.0},{"gene":"PARN","stoichiometry":4.0},{"gene":"DHX37","stoichiometry":0.2},{"gene":"MAPRE1","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"PES1","stoichiometry":0.2},{"gene":"RPAP2","stoichiometry":0.2},{"gene":"RPS11","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"TSR1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001089","total_profiled":1310},"omim":[{"mim_id":"608969","title":"UTP14C SMALL SUBUNIT PROCESSOME COMPONENT; UTP14C","url":"https://www.omim.org/entry/608969"},{"mim_id":"300508","title":"UTP14A SMALL SUBUNIT PROCESSOME COMPONENT; UTP14A","url":"https://www.omim.org/entry/300508"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UTP14A"},"hgnc":{"alias_symbol":["NY-CO-16","Utp14"],"prev_symbol":["SDCCAG16"]},"alphafold":{"accession":"Q9BVJ6","domains":[{"cath_id":"-","chopping":"676-724","consensus_level":"medium","plddt":92.0565,"start":676,"end":724}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVJ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVJ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVJ6-F1-predicted_aligned_error_v6.png","plddt_mean":66.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UTP14A","jax_strain_url":"https://www.jax.org/strain/search?query=UTP14A"},"sequence":{"accession":"Q9BVJ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BVJ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BVJ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVJ6"}},"corpus_meta":[{"pmid":"26729466","id":"PMC_26729466","title":"Utp14 Recruits and Activates the RNA Helicase Dhr1 To Undock U3 snoRNA from the Preribosome.","date":"2016","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26729466","citation_count":49,"is_preprint":false},{"pmid":"30910870","id":"PMC_30910870","title":"Molecular mechanism of the RNA helicase DHX37 and its activation by UTP14A in ribosome biogenesis.","date":"2019","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30910870","citation_count":43,"is_preprint":false},{"pmid":"30343112","id":"PMC_30343112","title":"Human UTP14a promotes colorectal cancer progression by forming a positive regulation loop with c-Myc.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30343112","citation_count":41,"is_preprint":false},{"pmid":"29925570","id":"PMC_29925570","title":"Utp14 interaction with the small subunit processome.","date":"2018","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29925570","citation_count":19,"is_preprint":false},{"pmid":"35734237","id":"PMC_35734237","title":"UTP14A, DKC1, DDX10, PinX1, and ESF1 Modulate Cardiac Angiogenesis Leading to Obesity-Induced Cardiac Injury.","date":"2022","source":"Journal of diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/35734237","citation_count":14,"is_preprint":false},{"pmid":"30929921","id":"PMC_30929921","title":"Human UTP14a promotes angiogenesis through upregulating PDGFA expression in colorectal cancer.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30929921","citation_count":13,"is_preprint":false},{"pmid":"33391409","id":"PMC_33391409","title":"U three protein 14a (UTP14A) promotes tumour proliferation and metastasis via the PERK/eIF2a/GRP78 signalling pathway in oesophageal squamous cell carcinoma.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33391409","citation_count":7,"is_preprint":false},{"pmid":"29308242","id":"PMC_29308242","title":"Lineage-independent retrotransposition of UTP14 associated with male fertility has occurred multiple times throughout mammalian evolution.","date":"2017","source":"Royal Society open science","url":"https://pubmed.ncbi.nlm.nih.gov/29308242","citation_count":4,"is_preprint":false},{"pmid":"39351198","id":"PMC_39351198","title":"P16INK4A drives RB1 degradation by UTP14A-catalyzed K810 ubiquitination.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/39351198","citation_count":2,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.29.679232","title":"Helicase-mediated mechanism of SSU processome maturation and disassembly","date":"2025-09-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.29.679232","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6636,"output_tokens":2343,"usd":0.027526,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9386,"output_tokens":2848,"usd":0.059065,"stage2_stop_reason":"end_turn"},"total_usd":0.086591,"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\": 2016,\n      \"finding\": \"Yeast Utp14 (ortholog of human UTP14A) directly interacts with the DEAH/RHA RNA helicase Dhr1 and stimulates its RNA unwinding activity in vitro. Mutations in a discrete region of Utp14 that reduced Dhr1 interaction also reduced Utp14 function in vivo, causing accumulation of Dhr1 and U3 snoRNA in a pre-40S particle—phenocopying a helicase-inactive Dhr1 mutant. Together with Bud23, Utp14 is required for stable recruitment of Dhr1 to the preribosome.\",\n      \"method\": \"In vitro unwinding assay, yeast two-hybrid, co-immunoprecipitation, site-directed mutagenesis, genetic epistasis with bud23 mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of helicase stimulation with mutagenesis correlating in vitro and in vivo phenotypes; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"26729466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A conserved sequence motif in human UTP14A directly interacts with DHX37 (human ortholog of Dhr1), stimulates its ATPase activity, and enhances its RNA binding. The carboxy-terminal domain (CTD) of DHX37 is required (but not sufficient) for interaction with UTP14A in vitro and is essential for ribosome biogenesis in vivo. Crystal structure of DHX37 with single-stranded RNA revealed a canonical DEAH architecture plus a structurally unique CTD, and conformational comparisons suggested an ATP-dependent 3′→5′ RNA translocation mechanism.\",\n      \"method\": \"Crystal structure (X-ray crystallography), in vitro ATPase assay, RNA-binding assay, pull-down, mutagenesis, in vivo complementation assay\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with in vitro enzymatic assays and mutagenesis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30910870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Utp14 cross-links to the pre-rRNA by UV crosslinking and analysis of cDNA (CRAC), and yeast two-hybrid interactions position it within the SSU processome. Proteomic analysis of SSU particles lacking Utp14 showed that Utp14 is needed for efficient recruitment of the RNA exosome to the preribosome, suggesting Utp14 communicates assembly status to the exosome as well as to Dhr1.\",\n      \"method\": \"UV crosslinking and analysis of cDNA (CRAC), yeast two-hybrid, quantitative proteomics of SSU particles\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (CRAC, Y2H, proteomics) in a single lab study\",\n      \"pmids\": [\"29925570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human UTP14a (hUTP14a) interacts with c-Myc and protects c-Myc from ubiquitination and degradation in a USP36-dependent manner. hUTP14a forms a complex with USP36 and Fbw7γ to inhibit Fbw7γ-mediated c-Myc degradation. Ectopic hUTP14a expression enriches c-Myc in the nucleolus. Reciprocally, c-Myc activates transcription of hUTP14a, forming a positive feedback loop.\",\n      \"method\": \"Mass spectrometry identification of complex components, co-immunoprecipitation, ubiquitination assay, shRNA knockdown in mouse xenografts, ectopic overexpression with localization analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, MS complex identification, ubiquitination assay, in vivo xenograft knockdown; single lab\",\n      \"pmids\": [\"30343112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hUTP14a upregulates transcription and secretion of platelet-derived growth factor subunit A (PDGFA) in colorectal cancer cells. Conditioned medium from hUTP14a-depleted cells inhibits PDGFA-mediated signaling, tube formation, and migration in HUVECs; these effects are rescued by Flag-hUTP14a expression and blocked by PDGFR inhibitor imatinib.\",\n      \"method\": \"RNA-seq, shRNA knockdown, conditioned medium assay, HUVEC tube formation and migration assay, in vivo Matrigel plug assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus multiple functional assays (tube formation, migration, in vivo plug) with rescue; single lab\",\n      \"pmids\": [\"30929921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"P16INK4A upregulates UTP14A E3 ligase activity, which catalyzes ubiquitination of RB1 at lysine 810 (K810), leading to RB1 degradation. Loss of P16INK4A disrupts UTP14A-mediated RB1 ubiquitination and causes RB1 accumulation.\",\n      \"method\": \"Ubiquitination assay with site identification (K810 mutant), knockdown/overexpression of P16INK4A and UTP14A, proteome-scale ubiquitination analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific ubiquitination site identified with mutagenesis, loss-of-function phenotype, single lab\",\n      \"pmids\": [\"39351198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UTP14A activates the PERK/eIF2α/GRP78 endoplasmic reticulum stress signalling pathway in esophageal squamous cell carcinoma cells; knockdown suppresses and overexpression enhances migration and proliferation via this pathway.\",\n      \"method\": \"shRNA knockdown, overexpression, in vitro cell proliferation and migration assays, in vivo xenograft, pathway readout by western blot\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD/OE phenotype with pathway readout but no direct biochemical interaction demonstrated between UTP14A and PERK pathway components\",\n      \"pmids\": [\"33391409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of 16 native SSU processome intermediates show that Utp14 probes evolving surfaces of the preribosome as it matures, ultimately positioning and activating Dhr1 to unwind U3 snoRNA and initiate nucleolar pre-40S release. The RNA exosome is redundantly tethered to the SSU processome, and irreversible pre-rRNA degradation by the exosome drives compositional changes that are communicated to Dhr1 via Utp14.\",\n      \"method\": \"Cryo-EM of native SSU processome intermediates, genetic data\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural data with genetic support, but preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.29.679232\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"UTP14A is a bifunctional ribosome biogenesis factor that (1) recruits and activates the DEAH helicase DHX37/Dhr1 via direct interaction to unwind U3 snoRNA from the pre-ribosome—thereby enabling pre-40S maturation—and also facilitates exosome recruitment to the SSU processome; (2) acts as an E3 ubiquitin ligase that catalyzes K810 ubiquitination and degradation of RB1 downstream of P16INK4A; and (3) stabilizes c-Myc in the nucleolus by forming a complex with USP36/Fbw7γ to inhibit c-Myc ubiquitination, while also promoting angiogenesis through upregulation of PDGFA.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UTP14A is a ribosome biogenesis factor of the small subunit (SSU) processome that couples assembly status of the maturing pre-ribosome to the activation of the DEAH-box helicase that triggers pre-40S release [#0, #7]. It directly binds the helicase Dhr1/DHX37 through a conserved sequence motif, stimulating its RNA unwinding and ATPase activities and enhancing its RNA binding; this interaction, together with Bud23, is required for stable recruitment of the helicase to the pre-ribosome so that it can unwind U3 snoRNA and initiate nucleolar pre-40S release [#0, #1]. UTP14A crosslinks to pre-rRNA within the SSU processome and is additionally required for efficient recruitment of the RNA exosome, positioning it as a sensor that communicates compositional maturation state to both the exosome and the helicase [#2, #7]. Beyond ribosome assembly, human UTP14A has been implicated in oncogenic protein homeostasis: it forms a complex with USP36 and Fbw7\\u03b3 to inhibit Fbw7\\u03b3-mediated ubiquitination of c-Myc, enriching c-Myc in the nucleolus within a c-Myc/UTP14A positive feedback loop [#3], and it acts downstream of P16INK4A as an E3 ligase activity that ubiquitinates RB1 at K810 to drive its degradation [#5]. It also promotes angiogenesis by upregulating PDGFA transcription and secretion [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that Utp14 is not merely a structural processome component but a direct activator of the Dhr1 helicase, defining the mechanistic link between Utp14 and U3 snoRNA removal during pre-40S maturation.\",\n      \"evidence\": \"In vitro unwinding assay, yeast two-hybrid, co-IP and site-directed mutagenesis with genetic epistasis in yeast\",\n      \"pmids\": [\"26729466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not provide an atomic structure of the Utp14-Dhr1 interface\", \"Human ortholog activity not yet tested in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioned Utp14 physically on the pre-rRNA and revealed a second output of its function\\u2014recruitment of the RNA exosome\\u2014implying it integrates assembly signals for both exosome and helicase.\",\n      \"evidence\": \"CRAC pre-rRNA crosslinking, yeast two-hybrid and quantitative proteomics of SSU particles\",\n      \"pmids\": [\"29925570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Utp14 senses assembly status not resolved\", \"Direct vs. indirect exosome recruitment not distinguished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a non-ribosomal role for human UTP14A in stabilizing the oncoprotein c-Myc, connecting a ribosome biogenesis factor to deubiquitination machinery and tumor-relevant signaling.\",\n      \"evidence\": \"MS complex identification, reciprocal co-IP, ubiquitination assay, shRNA xenograft and localization analysis\",\n      \"pmids\": [\"30343112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without independent replication\", \"Whether c-Myc stabilization depends on UTP14A's processome function is unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the structural basis of helicase activation, showing the human UTP14A motif stimulates DHX37 ATPase via its unique C-terminal domain and defining the helicase translocation mechanism.\",\n      \"evidence\": \"Crystal structure of DHX37 with ssRNA, in vitro ATPase and RNA-binding assays, mutagenesis and in vivo complementation\",\n      \"pmids\": [\"30910870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure of the UTP14A-DHX37 complex\", \"Conformational ATP-dependent translocation inferred rather than directly observed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended UTP14A oncogenic function to angiogenesis by linking it to PDGFA-driven paracrine signaling in colorectal cancer.\",\n      \"evidence\": \"RNA-seq, shRNA knockdown, conditioned-medium HUVEC tube formation/migration with rescue and imatinib block, in vivo Matrigel plug\",\n      \"pmids\": [\"30929921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PDGFA transcriptional upregulation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Associated UTP14A with PERK/eIF2\\u03b1/GRP78 ER stress signaling in esophageal squamous cell carcinoma, but only at the level of phenotype and pathway readout.\",\n      \"evidence\": \"shRNA knockdown, overexpression, proliferation/migration assays, xenograft and western blot pathway readout\",\n      \"pmids\": [\"33391409\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical interaction demonstrated between UTP14A and PERK pathway components\", \"Causality between UTP14A and ER stress activation not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an E3 ligase output for UTP14A acting downstream of P16INK4A, identifying RB1 K810 as a ubiquitination site whose modification drives RB1 degradation.\",\n      \"evidence\": \"Ubiquitination assay with K810 site mutant, P16INK4A/UTP14A loss- and gain-of-function, proteome-scale ubiquitination analysis\",\n      \"pmids\": [\"39351198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct E3 ligase catalytic activity of UTP14A not reconstituted with purified components\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Captured the dynamic trajectory by which Utp14 probes maturing processome surfaces to ultimately position and activate Dhr1, and showed exosome tethering is redundant, unifying the helicase- and exosome-coupling roles into one assembly-checkpoint model.\",\n      \"evidence\": \"Cryo-EM of 16 native SSU processome intermediates with genetic data (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.29.679232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Molecular signal communicated from exosome to Dhr1 via Utp14 not defined at residue level\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UTP14A's nucleolar ribosome biogenesis function mechanistically relates to its reported E3 ligase and c-Myc-stabilizing activities in cancer remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or biochemical reconciliation of processome vs. ubiquitin-pathway functions\", \"Whether E3 ligase activity is intrinsic or complex-dependent is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 7]}\n    ],\n    \"complexes\": [\"SSU processome\"],\n    \"partners\": [\"DHX37\", \"USP36\", \"FBXW7\", \"MYC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":5,"faith_pct":80.0}}