{"gene":"TBL3","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2004,"finding":"Utp13 (yeast ortholog of TBL3) is a component of the 90S pre-ribosomal particle. In Pwp2-depleted yeast cells, Utp13 is part of a stable Pwp2 subcomplex (with Dip2, Utp6, Utp18, and Utp21) that can interact directly with the 35S pre-rRNA 5' end independently of the U3 snoRNP. Loss of Pwp2 prevents U3 snoRNP association with pre-rRNA, blocking 90S pre-ribosome assembly and impairing pre-rRNA processing at sites A0, A1, and A2, reducing 18S rRNA and 40S subunit levels.","method":"Conditional depletion in yeast, immunoprecipitation, gradient sedimentation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and gradient sedimentation with functional depletion phenotype, replicated across multiple orthogonal methods in one rigorous study","pmids":["15231838"],"is_preprint":false},{"year":2008,"finding":"TBL3 (human) preferentially binds to the N-terminal domain of TBL1 and TBLR1 (components of the SMRT/NCoR nuclear receptor corepressor complex) and forms oligomers with other WD-40 proteins via LisH domain interactions.","method":"Co-immunoprecipitation, Gal4 fusion transcriptional repression assay, LisH domain mutagenesis","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP binding demonstrated in single study; oligomerization and domain requirement supported by mutagenesis but full mechanistic context of TBL3's own role not deeply characterized","pmids":["18202150"],"is_preprint":false},{"year":2012,"finding":"Zebrafish tbl3 loss-of-function (ceylon mutant and morpholino knockdown) causes a slowing of the cell cycle in hematopoietic stem/progenitor cells and retinal progenitors, resulting in tissue-specific reduction in differentiated cells. This cell cycle slowing occurs without a corresponding increase in p53-induced cell death (in contrast to yeast), as confirmed by phenocopy in p53-/- embryos.","method":"Zebrafish forward genetic mutant characterization, morpholino knockdown, p53-/- epistasis, cell cycle analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, epistasis with p53 mutant, morpholino phenocopy across orthogonal approaches","pmids":["22659140"],"is_preprint":false},{"year":2014,"finding":"TBL3-GFP (human) localizes predominantly to the dense fibrillar component and granular component regions of nucleoli. When rRNA transcription is suppressed, TBL3-GFP redistributes to cap and body regions of nucleoli. FRAP analysis shows TBL3-GFP has very low mobility in living cells, consistent with tight association with large macromolecular complexes, acting as a scaffold or core for SSU processome complexes.","method":"Live-cell fluorescence microscopy with GFP fusion proteins, FRAP, rRNA transcription inhibition","journal":"Biochemistry and cell biology = Biochimie et biologie cellulaire","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell localization with functional perturbation (transcription inhibition), single lab study","pmids":["24754225"],"is_preprint":false},{"year":2021,"finding":"Human TBL3, involved in rRNA processing, binds to expanded CAG repeat-containing ATXN2 (expATXN2) RNA and expanded HTT (expHTT) RNA in vitro, as shown by RNA immunoprecipitation. rRNA processing is disrupted in SCA2 and HD human brain tissue, suggesting that aberrant sequestration of TBL3 by repeat-expanded RNAs impairs rRNA processing.","method":"RNA immunoprecipitation assay, in vitro binding, quantitative PCR of rRNA processing intermediates in human brain tissue","journal":"Movement disorders : official journal of the Movement Disorder Society","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA IP binding demonstrated in vitro; functional consequence (rRNA processing disruption) shown in human tissue but mechanistic link is correlative","pmids":["34390268"],"is_preprint":false},{"year":2021,"finding":"TBL3 was identified as a potential ac4C (N4-acetylcytidine)-binding protein by RNA pulldown using HEK293T cells, suggesting TBL3 may function as a reader of this epitranscriptomic modification.","method":"Bioinformatics prediction followed by RNA pulldown in HEK293T cells","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown experiment in one study, computational prediction-assisted, no functional validation of the binding's consequence","pmids":["34395433"],"is_preprint":false},{"year":2022,"finding":"MNase tethered to Utp13 (yeast ortholog of TBL3) was used to structurally probe the pre-ribosomal RNA, revealing the relative organization of the 5'ETS and ITS1 regions of 35S pre-rRNA and U3 snoRNA around the C-terminal domain of Utp13 within the nascent small subunit processome.","method":"MNase-tethering structural probing (CRAC-like approach) in yeast","journal":"Non-coding RNA","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct structural probing method (MNase tethering) in a single study provides spatial information about Utp13's position in the pre-ribosome","pmids":["35076539"],"is_preprint":false},{"year":2024,"finding":"UTP3/SAS10 facilitates the nucleolar localization of UTP13 (human TBL3 ortholog) likely through interaction with nuclear importin α, acting as a 'ferry' to bring UTP13 into the nucleolus. Loss-of-function of utp13/tbl3 in zebrafish causes accumulation of aberrantly processed 5'ETS products, establishing a crucial role for TBL3/UTP13 in pre-rRNA 5'ETS processing.","method":"Nucleolar localization screening of 50 SSU processome components, importin interaction assay, zebrafish loss-of-function, pre-rRNA processing analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic localization screen with mechanistic follow-up (importin interaction), zebrafish loss-of-function with defined rRNA processing phenotype, conservation confirmed across human and zebrafish","pmids":["39036955"],"is_preprint":false}],"current_model":"TBL3 (UTP13) is a WD-repeat-containing component of the UTP-B sub-complex within the 90S SSU processome that localizes to the nucleolar dense fibrillar and granular components via a UTP3/importin-α-dependent trafficking pathway, where it participates in 90S pre-ribosome assembly and pre-rRNA 5'ETS processing; loss of TBL3 impairs 18S rRNA production and slows cell cycle progression in a tissue-specific, p53-independent manner in vivo, and the protein also interacts with TBL1/TBLR1 in the NCoR/SMRT corepressor complex and may act as a reader of ac4C RNA modifications."},"narrative":{"mechanistic_narrative":"TBL3 (UTP13) is a WD-repeat protein that functions in the assembly of the 90S small subunit (SSU) processome and the early processing of pre-ribosomal RNA [PMID:15231838, PMID:39036955]. Its yeast ortholog Utp13 forms a stable Pwp2-containing subcomplex (with Dip2, Utp6, Utp18, and Utp21) that binds directly to the 5' end of the 35S pre-rRNA independently of the U3 snoRNP, and this association is required for U3 snoRNP recruitment, 90S pre-ribosome assembly, and pre-rRNA cleavage at sites A0, A1, and A2 that generate 18S rRNA and the 40S subunit [PMID:15231838]. Structural probing places the C-terminal domain of Utp13 at the junction organizing the 5'ETS and ITS1 regions of the pre-rRNA and the U3 snoRNA within the nascent processome [PMID:35076539]. In human and zebrafish cells, TBL3/UTP13 concentrates in the dense fibrillar and granular components of the nucleolus, displaying very low mobility consistent with a scaffolding core for SSU processome complexes, and redistributes to nucleolar caps when rRNA transcription is blocked [PMID:24754225]; its nucleolar delivery depends on UTP3/SAS10 acting through importin-α, and its loss causes accumulation of aberrantly processed 5'ETS products [PMID:39036955]. Consistent with this role, zebrafish tbl3 loss-of-function slows the cell cycle in hematopoietic and retinal progenitors in a tissue-specific, p53-independent manner [PMID:22659140]. Beyond ribosome biogenesis, TBL3 binds the N-terminal domains of TBL1 and TBLR1 of the SMRT/NCoR corepressor complex and self-oligomerizes through LisH-domain interactions [PMID:18202150].","teleology":[{"year":2004,"claim":"Established that the TBL3 ortholog Utp13 is an integral component of the 90S pre-ribosome and defined where it acts in pre-rRNA processing, answering whether it functions before or after U3 snoRNP recruitment.","evidence":"Conditional depletion, reciprocal immunoprecipitation, and gradient sedimentation in yeast","pmids":["15231838"],"confidence":"High","gaps":["Does not define the human TBL3 contribution directly","Does not resolve atomic contacts between Utp13 and the pre-rRNA"]},{"year":2008,"claim":"Identified a ribosome-biogenesis-independent interaction, showing human TBL3 binds the N-terminal domains of corepressor subunits TBL1/TBLR1 and oligomerizes via LisH domains, raising a possible role in transcriptional repression.","evidence":"Co-immunoprecipitation, Gal4 fusion repression assay, and LisH-domain mutagenesis","pmids":["18202150"],"confidence":"Medium","gaps":["Functional consequence of TBL3 in the SMRT/NCoR complex not established","No demonstration this interaction operates in a native chromatin context"]},{"year":2012,"claim":"Showed in a vertebrate that TBL3 loss produces a tissue-specific cell-cycle defect that, unlike yeast, is uncoupled from p53-dependent death, clarifying the in vivo phenotypic logic of TBL3 deficiency.","evidence":"Zebrafish forward-genetic mutant, morpholino knockdown, and p53-/- epistasis with cell cycle analysis","pmids":["22659140"],"confidence":"High","gaps":["Does not establish the molecular basis of tissue specificity","Does not directly link the cell-cycle defect to a specific rRNA processing step"]},{"year":2014,"claim":"Determined the subnuclear behavior of human TBL3, placing it in nucleolar dense fibrillar/granular components with low mobility and transcription-dependent redistribution, consistent with a scaffolding role for SSU processome complexes.","evidence":"Live-cell GFP-fusion microscopy, FRAP, and rRNA transcription inhibition","pmids":["24754225"],"confidence":"Medium","gaps":["Scaffold role inferred from mobility, not from defined structural interactions","Single-lab observation"]},{"year":2021,"claim":"Connected TBL3 to repeat-expansion disease by showing it binds expanded CAG-repeat ATXN2 and HTT RNAs in vitro alongside disrupted rRNA processing in SCA2 and HD brain, raising a sequestration hypothesis.","evidence":"RNA immunoprecipitation, in vitro binding, and qPCR of rRNA intermediates in human brain tissue","pmids":["34390268"],"confidence":"Medium","gaps":["Link between TBL3 sequestration and rRNA defect is correlative","No demonstration that restoring TBL3 rescues processing in disease tissue"]},{"year":2021,"claim":"Nominated TBL3 as a candidate reader of the ac4C RNA modification, suggesting an epitranscriptomic input to its function.","evidence":"Bioinformatics prediction followed by RNA pulldown in HEK293T cells","pmids":["34395433"],"confidence":"Low","gaps":["Single pulldown without functional validation of the binding's consequence","No mapping of ac4C sites recognized","Prediction-assisted identification not orthogonally confirmed"]},{"year":2022,"claim":"Provided spatial information on TBL3's position within the nascent processome, mapping how the 5'ETS, ITS1, and U3 snoRNA are organized around the C-terminal domain of Utp13.","evidence":"MNase-tethering structural probing in yeast","pmids":["35076539"],"confidence":"Medium","gaps":["Spatial probing does not give atomic-resolution contacts","Conducted in yeast, not validated for human TBL3"]},{"year":2024,"claim":"Defined how TBL3/UTP13 reaches its site of action and confirmed its essential processing role, showing UTP3/SAS10 ferries it to the nucleolus via importin-α and that its loss causes aberrant 5'ETS processing.","evidence":"Nucleolar localization screen of 50 SSU processome components, importin interaction assay, and zebrafish loss-of-function with pre-rRNA processing analysis","pmids":["39036955"],"confidence":"High","gaps":["Direct importin-alpha/UTP13 binding interface not resolved","Does not reconcile the corepressor interaction with the nucleolar role"]},{"year":null,"claim":"How TBL3's nucleolar ribosome-biogenesis function relates to its proposed roles in the SMRT/NCoR corepressor complex and in ac4C recognition remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No model integrating ribosome biogenesis with transcriptional corepression","Functional significance of ac4C binding uncharacterized","No structural model of human TBL3 within the processome"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4]}],"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":[0,7]}],"complexes":["90S SSU processome","UTP-B subcomplex","SMRT/NCoR corepressor complex"],"partners":["TBL1X","TBLR1","UTP3","PWP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12788","full_name":"Transducin beta-like protein 3","aliases":["WD repeat-containing protein SAZD"],"length_aa":808,"mass_kda":89.0,"function":"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","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q12788/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TBL3","classification":"Common Essential","n_dependent_lines":1176,"n_total_lines":1208,"dependency_fraction":0.9735099337748344},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"WDR3","stoichiometry":10.0},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TBL3","total_profiled":1310},"omim":[{"mim_id":"614937","title":"MYOCLONUS, FAMILIAL, 1; MYOCL1","url":"https://www.omim.org/entry/614937"},{"mim_id":"605915","title":"TRANSDUCIN-BETA-LIKE 3; TBL3","url":"https://www.omim.org/entry/605915"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TBL3"},"hgnc":{"alias_symbol":["SAZD","UTP13"],"prev_symbol":[]},"alphafold":{"accession":"Q12788","domains":[{"cath_id":"2.130.10.10","chopping":"201-333","consensus_level":"medium","plddt":83.0926,"start":201,"end":333},{"cath_id":"-","chopping":"640-763","consensus_level":"high","plddt":83.6006,"start":640,"end":763}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12788","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12788-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12788-F1-predicted_aligned_error_v6.png","plddt_mean":84.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TBL3","jax_strain_url":"https://www.jax.org/strain/search?query=TBL3"},"sequence":{"accession":"Q12788","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12788.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12788/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12788"}},"corpus_meta":[{"pmid":"22696458","id":"PMC_22696458","title":"A comparative transcriptomic analysis reveals conserved features of stem cell pluripotency in planarians and mammals.","date":"2012","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/22696458","citation_count":161,"is_preprint":false},{"pmid":"9747972","id":"PMC_9747972","title":"Upregulation of Jun and Fos family members and permanent JNK activity lead to constitutive AP-1 activation in Theileria-transformed leukocytes.","date":"1998","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/9747972","citation_count":87,"is_preprint":false},{"pmid":"15231838","id":"PMC_15231838","title":"Functional characterization of Pwp2, a WD family protein essential for the assembly of the 90 S pre-ribosomal particle.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15231838","citation_count":75,"is_preprint":false},{"pmid":"20657172","id":"PMC_20657172","title":"Involvement of TBL/DUF231 proteins into cell wall biology.","date":"2010","source":"Plant signaling & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/20657172","citation_count":36,"is_preprint":false},{"pmid":"16761111","id":"PMC_16761111","title":"A PKA survival pathway inhibited by DPT-PKI, a new specific cell permeable PKA inhibitor, is induced by T. annulata in parasitized B-lymphocytes.","date":"2006","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/16761111","citation_count":30,"is_preprint":false},{"pmid":"34395433","id":"PMC_34395433","title":"NAT10-Mediated N4-Acetylcytidine of RNA Contributes to Post-transcriptional Regulation of Mouse Oocyte Maturation in vitro.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34395433","citation_count":28,"is_preprint":false},{"pmid":"18202150","id":"PMC_18202150","title":"Function of multiple Lis-Homology domain/WD-40 repeat-containing proteins in feed-forward transcriptional repression by silencing mediator for retinoic and thyroid receptor/nuclear receptor corepressor complexes.","date":"2008","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/18202150","citation_count":22,"is_preprint":false},{"pmid":"34390268","id":"PMC_34390268","title":"RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2.","date":"2021","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/34390268","citation_count":18,"is_preprint":false},{"pmid":"24754225","id":"PMC_24754225","title":"Dynamics of WD-repeat containing proteins in SSU processome components.","date":"2014","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/24754225","citation_count":17,"is_preprint":false},{"pmid":"8307582","id":"PMC_8307582","title":"A transducin-like gene maps to the autosomal dominant polycystic kidney disease gene region.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8307582","citation_count":17,"is_preprint":false},{"pmid":"24825433","id":"PMC_24825433","title":"CAMK1 phosphoinositide signal-mediated protein sorting and transport network in human hepatocellular carcinoma (HCC) by biocomputation.","date":"2014","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/24825433","citation_count":17,"is_preprint":false},{"pmid":"22659140","id":"PMC_22659140","title":"Tbl3 regulates cell cycle length during zebrafish development.","date":"2012","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22659140","citation_count":14,"is_preprint":false},{"pmid":"25102023","id":"PMC_25102023","title":"Luminescent vesicular nanointerface: a highly selective and sensitive \"turn-on\" sensor for guanosine triphosphate.","date":"2014","source":"ACS applied materials & 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RNA","url":"https://pubmed.ncbi.nlm.nih.gov/35076539","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11488,"output_tokens":2201,"usd":0.033739,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9215,"output_tokens":2916,"usd":0.059487,"stage2_stop_reason":"end_turn"},"total_usd":0.093226,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Utp13 (yeast ortholog of TBL3) is a component of the 90S pre-ribosomal particle. In Pwp2-depleted yeast cells, Utp13 is part of a stable Pwp2 subcomplex (with Dip2, Utp6, Utp18, and Utp21) that can interact directly with the 35S pre-rRNA 5' end independently of the U3 snoRNP. Loss of Pwp2 prevents U3 snoRNP association with pre-rRNA, blocking 90S pre-ribosome assembly and impairing pre-rRNA processing at sites A0, A1, and A2, reducing 18S rRNA and 40S subunit levels.\",\n      \"method\": \"Conditional depletion in yeast, immunoprecipitation, gradient sedimentation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and gradient sedimentation with functional depletion phenotype, replicated across multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"15231838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TBL3 (human) preferentially binds to the N-terminal domain of TBL1 and TBLR1 (components of the SMRT/NCoR nuclear receptor corepressor complex) and forms oligomers with other WD-40 proteins via LisH domain interactions.\",\n      \"method\": \"Co-immunoprecipitation, Gal4 fusion transcriptional repression assay, LisH domain mutagenesis\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP binding demonstrated in single study; oligomerization and domain requirement supported by mutagenesis but full mechanistic context of TBL3's own role not deeply characterized\",\n      \"pmids\": [\"18202150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Zebrafish tbl3 loss-of-function (ceylon mutant and morpholino knockdown) causes a slowing of the cell cycle in hematopoietic stem/progenitor cells and retinal progenitors, resulting in tissue-specific reduction in differentiated cells. This cell cycle slowing occurs without a corresponding increase in p53-induced cell death (in contrast to yeast), as confirmed by phenocopy in p53-/- embryos.\",\n      \"method\": \"Zebrafish forward genetic mutant characterization, morpholino knockdown, p53-/- epistasis, cell cycle analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, epistasis with p53 mutant, morpholino phenocopy across orthogonal approaches\",\n      \"pmids\": [\"22659140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TBL3-GFP (human) localizes predominantly to the dense fibrillar component and granular component regions of nucleoli. When rRNA transcription is suppressed, TBL3-GFP redistributes to cap and body regions of nucleoli. FRAP analysis shows TBL3-GFP has very low mobility in living cells, consistent with tight association with large macromolecular complexes, acting as a scaffold or core for SSU processome complexes.\",\n      \"method\": \"Live-cell fluorescence microscopy with GFP fusion proteins, FRAP, rRNA transcription inhibition\",\n      \"journal\": \"Biochemistry and cell biology = Biochimie et biologie cellulaire\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell localization with functional perturbation (transcription inhibition), single lab study\",\n      \"pmids\": [\"24754225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human TBL3, involved in rRNA processing, binds to expanded CAG repeat-containing ATXN2 (expATXN2) RNA and expanded HTT (expHTT) RNA in vitro, as shown by RNA immunoprecipitation. rRNA processing is disrupted in SCA2 and HD human brain tissue, suggesting that aberrant sequestration of TBL3 by repeat-expanded RNAs impairs rRNA processing.\",\n      \"method\": \"RNA immunoprecipitation assay, in vitro binding, quantitative PCR of rRNA processing intermediates in human brain tissue\",\n      \"journal\": \"Movement disorders : official journal of the Movement Disorder Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA IP binding demonstrated in vitro; functional consequence (rRNA processing disruption) shown in human tissue but mechanistic link is correlative\",\n      \"pmids\": [\"34390268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TBL3 was identified as a potential ac4C (N4-acetylcytidine)-binding protein by RNA pulldown using HEK293T cells, suggesting TBL3 may function as a reader of this epitranscriptomic modification.\",\n      \"method\": \"Bioinformatics prediction followed by RNA pulldown in HEK293T cells\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown experiment in one study, computational prediction-assisted, no functional validation of the binding's consequence\",\n      \"pmids\": [\"34395433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MNase tethered to Utp13 (yeast ortholog of TBL3) was used to structurally probe the pre-ribosomal RNA, revealing the relative organization of the 5'ETS and ITS1 regions of 35S pre-rRNA and U3 snoRNA around the C-terminal domain of Utp13 within the nascent small subunit processome.\",\n      \"method\": \"MNase-tethering structural probing (CRAC-like approach) in yeast\",\n      \"journal\": \"Non-coding RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct structural probing method (MNase tethering) in a single study provides spatial information about Utp13's position in the pre-ribosome\",\n      \"pmids\": [\"35076539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UTP3/SAS10 facilitates the nucleolar localization of UTP13 (human TBL3 ortholog) likely through interaction with nuclear importin α, acting as a 'ferry' to bring UTP13 into the nucleolus. Loss-of-function of utp13/tbl3 in zebrafish causes accumulation of aberrantly processed 5'ETS products, establishing a crucial role for TBL3/UTP13 in pre-rRNA 5'ETS processing.\",\n      \"method\": \"Nucleolar localization screening of 50 SSU processome components, importin interaction assay, zebrafish loss-of-function, pre-rRNA processing analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic localization screen with mechanistic follow-up (importin interaction), zebrafish loss-of-function with defined rRNA processing phenotype, conservation confirmed across human and zebrafish\",\n      \"pmids\": [\"39036955\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TBL3 (UTP13) is a WD-repeat-containing component of the UTP-B sub-complex within the 90S SSU processome that localizes to the nucleolar dense fibrillar and granular components via a UTP3/importin-α-dependent trafficking pathway, where it participates in 90S pre-ribosome assembly and pre-rRNA 5'ETS processing; loss of TBL3 impairs 18S rRNA production and slows cell cycle progression in a tissue-specific, p53-independent manner in vivo, and the protein also interacts with TBL1/TBLR1 in the NCoR/SMRT corepressor complex and may act as a reader of ac4C RNA modifications.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TBL3 (UTP13) is a WD-repeat protein that functions in the assembly of the 90S small subunit (SSU) processome and the early processing of pre-ribosomal RNA [#0, #7]. Its yeast ortholog Utp13 forms a stable Pwp2-containing subcomplex (with Dip2, Utp6, Utp18, and Utp21) that binds directly to the 5' end of the 35S pre-rRNA independently of the U3 snoRNP, and this association is required for U3 snoRNP recruitment, 90S pre-ribosome assembly, and pre-rRNA cleavage at sites A0, A1, and A2 that generate 18S rRNA and the 40S subunit [#0]. Structural probing places the C-terminal domain of Utp13 at the junction organizing the 5'ETS and ITS1 regions of the pre-rRNA and the U3 snoRNA within the nascent processome [#6]. In human and zebrafish cells, TBL3/UTP13 concentrates in the dense fibrillar and granular components of the nucleolus, displaying very low mobility consistent with a scaffolding core for SSU processome complexes, and redistributes to nucleolar caps when rRNA transcription is blocked [#3]; its nucleolar delivery depends on UTP3/SAS10 acting through importin-\\u03b1, and its loss causes accumulation of aberrantly processed 5'ETS products [#7]. Consistent with this role, zebrafish tbl3 loss-of-function slows the cell cycle in hematopoietic and retinal progenitors in a tissue-specific, p53-independent manner [#2]. Beyond ribosome biogenesis, TBL3 binds the N-terminal domains of TBL1 and TBLR1 of the SMRT/NCoR corepressor complex and self-oligomerizes through LisH-domain interactions [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that the TBL3 ortholog Utp13 is an integral component of the 90S pre-ribosome and defined where it acts in pre-rRNA processing, answering whether it functions before or after U3 snoRNP recruitment.\",\n      \"evidence\": \"Conditional depletion, reciprocal immunoprecipitation, and gradient sedimentation in yeast\",\n      \"pmids\": [\"15231838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the human TBL3 contribution directly\", \"Does not resolve atomic contacts between Utp13 and the pre-rRNA\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a ribosome-biogenesis-independent interaction, showing human TBL3 binds the N-terminal domains of corepressor subunits TBL1/TBLR1 and oligomerizes via LisH domains, raising a possible role in transcriptional repression.\",\n      \"evidence\": \"Co-immunoprecipitation, Gal4 fusion repression assay, and LisH-domain mutagenesis\",\n      \"pmids\": [\"18202150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of TBL3 in the SMRT/NCoR complex not established\", \"No demonstration this interaction operates in a native chromatin context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed in a vertebrate that TBL3 loss produces a tissue-specific cell-cycle defect that, unlike yeast, is uncoupled from p53-dependent death, clarifying the in vivo phenotypic logic of TBL3 deficiency.\",\n      \"evidence\": \"Zebrafish forward-genetic mutant, morpholino knockdown, and p53-/- epistasis with cell cycle analysis\",\n      \"pmids\": [\"22659140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish the molecular basis of tissue specificity\", \"Does not directly link the cell-cycle defect to a specific rRNA processing step\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Determined the subnuclear behavior of human TBL3, placing it in nucleolar dense fibrillar/granular components with low mobility and transcription-dependent redistribution, consistent with a scaffolding role for SSU processome complexes.\",\n      \"evidence\": \"Live-cell GFP-fusion microscopy, FRAP, and rRNA transcription inhibition\",\n      \"pmids\": [\"24754225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Scaffold role inferred from mobility, not from defined structural interactions\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected TBL3 to repeat-expansion disease by showing it binds expanded CAG-repeat ATXN2 and HTT RNAs in vitro alongside disrupted rRNA processing in SCA2 and HD brain, raising a sequestration hypothesis.\",\n      \"evidence\": \"RNA immunoprecipitation, in vitro binding, and qPCR of rRNA intermediates in human brain tissue\",\n      \"pmids\": [\"34390268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between TBL3 sequestration and rRNA defect is correlative\", \"No demonstration that restoring TBL3 rescues processing in disease tissue\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Nominated TBL3 as a candidate reader of the ac4C RNA modification, suggesting an epitranscriptomic input to its function.\",\n      \"evidence\": \"Bioinformatics prediction followed by RNA pulldown in HEK293T cells\",\n      \"pmids\": [\"34395433\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single pulldown without functional validation of the binding's consequence\", \"No mapping of ac4C sites recognized\", \"Prediction-assisted identification not orthogonally confirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided spatial information on TBL3's position within the nascent processome, mapping how the 5'ETS, ITS1, and U3 snoRNA are organized around the C-terminal domain of Utp13.\",\n      \"evidence\": \"MNase-tethering structural probing in yeast\",\n      \"pmids\": [\"35076539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Spatial probing does not give atomic-resolution contacts\", \"Conducted in yeast, not validated for human TBL3\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined how TBL3/UTP13 reaches its site of action and confirmed its essential processing role, showing UTP3/SAS10 ferries it to the nucleolus via importin-\\u03b1 and that its loss causes aberrant 5'ETS processing.\",\n      \"evidence\": \"Nucleolar localization screen of 50 SSU processome components, importin interaction assay, and zebrafish loss-of-function with pre-rRNA processing analysis\",\n      \"pmids\": [\"39036955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct importin-alpha/UTP13 binding interface not resolved\", \"Does not reconcile the corepressor interaction with the nucleolar role\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TBL3's nucleolar ribosome-biogenesis function relates to its proposed roles in the SMRT/NCoR corepressor complex and in ac4C recognition remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No model integrating ribosome biogenesis with transcriptional corepression\", \"Functional significance of ac4C binding uncharacterized\", \"No structural model of human TBL3 within the processome\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4]}\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, 7]}\n    ],\n    \"complexes\": [\"90S SSU processome\", \"UTP-B subcomplex\", \"SMRT/NCoR corepressor complex\"],\n    \"partners\": [\"TBL1X\", \"TBLR1\", \"UTP3\", \"PWP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}