{"gene":"BOP1","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2000,"finding":"Bop1 is a WD40 repeat nucleolar protein that cosediments with 50S-80S ribonucleoprotein particles containing 32S rRNA precursor; expression of dominant-negative Bop1Delta (lacking 231 N-terminal amino acids) specifically blocks conversion of 36S to 32S pre-rRNA and completely inhibits processing of 32S pre-rRNA to mature 28S and 5.8S rRNAs, causing deficiency of cytosolic 60S ribosomal subunits and G1 cell cycle arrest.","method":"Immunofluorescence, sucrose density gradient fractionation, pulse-chase rRNA processing analysis, dominant-negative expression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, pulse-chase, dominant-negative) in foundational paper, replicated by subsequent studies","pmids":["10891491"],"is_preprint":false},{"year":2001,"finding":"Perturbation of Bop1 by dominant-negative Bop1Delta induces p53-dependent G1 cell cycle arrest; inactivation of p53 abrogates this arrest without restoring normal rRNA processing, demonstrating that deficiencies in ribosome synthesis trigger cell cycle arrest via a p53-dependent nucleolar stress pathway, and that rRNA processing defects can be uncoupled from cell cycle arrest.","method":"Dominant-negative expression, p53 inactivation, CDK kinase activity assays, pRb phosphorylation analysis, p21/p27 western blotting","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (p53 inactivation rescues arrest but not rRNA defect), multiple biochemical readouts, replicated in subsequent studies","pmids":["11390653"],"is_preprint":false},{"year":2001,"finding":"The yeast homolog of Bop1, Erb1p (encoded by YMR049C), is essential for viability and required for processing of 27SB pre-rRNA to 25S and 5.8S rRNAs; Erb1p depletion causes loss of 25S and 5.8S rRNAs with underaccumulation of 27SB pre-rRNA, demonstrating evolutionary conservation of Bop1/Erb1p function in large ribosomal subunit maturation.","method":"Gene disruption, conditional depletion, rRNA processing analysis in S. cerevisiae","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic disruption plus processing analysis, ortholog confirms conserved mechanism","pmids":["11522832"],"is_preprint":false},{"year":2002,"finding":"Bop1 is required for pre-rRNA processing at four distinct sites within ITS1, ITS2, and the 3' external spacer; both C-terminal (Bop1N2) and N-terminal (Bop1Delta) deletion mutants localize to the nucleolus and inhibit rRNA processing and cell cycle progression, and antisense oligonucleotide knockdown of endogenous Bop1 recapitulates processing defects.","method":"Deletion mutagenesis, antisense oligonucleotide knockdown, immunofluorescence, rRNA processing analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple dominant-negative mutants plus antisense KD, consistent results across methods","pmids":["12048210"],"is_preprint":false},{"year":2004,"finding":"Bop1 physically interacts with Pes1 (mouse homolog of yeast Nop7p); this interaction is essential for efficient incorporation of Pes1 into nucleolar preribosomal complexes, and Pes1 mutants defective for Bop1 interaction lose the ability to affect rRNA maturation and the cell cycle.","method":"Co-immunoprecipitation, dominant-negative Pes1 mutant panel, rRNA processing analysis, cell cycle assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction mapping with multiple mutants, functional epistasis established","pmids":["15225545"],"is_preprint":false},{"year":2005,"finding":"Bop1 and Pes1 form a stable trimeric complex with WDR12 (a novel WD40 repeat protein), termed the PeBoW complex; endogenous WDR12 is required for processing of 32S precursor rRNA and cell proliferation, and a dominant-negative WDR12 mutant blocks rRNA processing and induces p53 accumulation in a p19ARF-independent manner.","method":"Co-immunoprecipitation, dominant-negative expression, rRNA processing assays, p53 accumulation analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — complex identified by co-IP, functional validation with dominant-negative and knockdown, multiple orthogonal methods","pmids":["16043514"],"is_preprint":false},{"year":2007,"finding":"Bop1 is the integral/central component of the PeBoW complex: recombinant expression of Pes1, Bop1, and WDR12 is sufficient for complex formation; Bop1 knockdown abolishes copurification of Pes1 with WDR12; overexpressed Bop1 inhibits cell proliferation and rRNA processing (rescuable by WDR12 co-expression but not Pes1); nucleolar transport of Bop1 from cytoplasm is Pes1-dependent, while Pes1 migrates to nucleolus independently of Bop1.","method":"Recombinant protein expression, co-immunoprecipitation, siRNA knockdown, immunofluorescence, cell fractionation, sucrose gradient centrifugation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reconstitution of complex from recombinant subunits plus multiple orthogonal localization and biochemical methods","pmids":["17353269"],"is_preprint":false},{"year":2020,"finding":"BOP1 promotes chromosomal instability by increasing the active form of Aurora kinase B (AURKB), which regulates chromosomal segregation; CCAT2 lncRNA directly binds and stabilizes BOP1 protein and also activates MYC-driven BOP1 transcription, leading to BOP1 overexpression that causes chromosomal missegregation errors.","method":"MS2 pull-down, RNA immunoprecipitation, SHAPE analysis, BOP1 overexpression/knockdown, cytogenetic analysis, immunofluorescence","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-protein interaction confirmed by multiple pulldown methods, AURKB activation shown by BOP1 overexpression; single lab","pmids":["32805281"],"is_preprint":false},{"year":2019,"finding":"Loss of BOP1 confers resistance to BRAF kinase inhibitors in melanoma by downregulating MAPK phosphatases DUSP4 and DUSP6 via a transcription-based mechanism, leading to increased MAPK signaling.","method":"shRNA screen (363 epigenetic regulators), BOP1 knockdown, DUSP4/DUSP6 expression analysis, MAPK pathway activity assays, in vivo mouse studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale functional screen plus mechanistic follow-up in cell culture and mouse models; single lab","pmids":["30782837"],"is_preprint":false},{"year":2011,"finding":"BOP1 promotes epithelial-to-mesenchymal transition (EMT) in hepatocellular carcinoma cells, stimulates actin stress fiber assembly, and activates RhoA; siRNA-mediated BOP1 knockdown upregulates epithelial markers (E-cadherin, cytokeratin 18, γ-catenin) and downregulates mesenchymal markers (fibronectin, vimentin), while ectopic BOP1 expression in hepatocytes increases invasiveness and migration.","method":"siRNA knockdown, ectopic overexpression, invasion/migration assays, EMT marker western blotting, RhoA activation assay, actin staining","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotypes and molecular markers; single lab","pmids":["21520196"],"is_preprint":false},{"year":2021,"finding":"BOP1 activates Wnt/β-catenin signaling in triple-negative breast cancer by increasing recruitment of CBP (CREB-binding protein) to β-catenin, enhancing CBP-mediated acetylation of β-catenin, and increasing transcription of stemness-related genes CD133 and ALDH1A1, thereby promoting cancer stem cell-like phenotype and chemoresistance.","method":"BOP1 overexpression/knockdown, Co-immunoprecipitation (BOP1-CBP-β-catenin), acetylation assay, gene expression analysis, in vitro and in vivo drug resistance assays","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for complex, acetylation assay, functional rescue with CBP/β-catenin inhibitor; single lab","pmids":["33797754"],"is_preprint":false},{"year":2021,"finding":"BOP1 knockdown in vascular smooth muscle cells activates nucleolar stress, causing RPL11 release from nucleolus to nucleoplasm, which inhibits MDM2 E3 ubiquitin ligase activity, stabilizes p53, and subsequently inhibits VSMC proliferation and migration; siRNA knockdown of RPL11 or p53 inhibition with pifithrin-α partially reverses these effects.","method":"siRNA knockdown of BOP1 and RPL11, p53 inhibitor (pifithrin-α), proliferation/migration assays, nascent protein synthesis assay, rat balloon injury model","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (RPL11 KD and p53 inhibition rescue BOP1 KD phenotype), in vivo model; single lab","pmids":["33510838"],"is_preprint":false},{"year":2024,"finding":"BOP1 knockdown triggers nucleolar stress response causing RPL11 release from nucleolus into nucleoplasm, inhibiting MDM2, stabilizing p53, which then inhibits mTOR phosphorylation, activating autophagy in granulosa cells; BOP1 overexpression in vivo suppresses this pathway and alleviates PCOS phenotypes.","method":"BOP1 knockdown/overexpression (lentiviral), RPL11 localization, MDM2 inhibition, p53/mTOR pathway analysis, in vivo PCOS mouse model","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway defined via epistasis (RPL11-MDM2-p53-mTOR), in vivo rescue, single lab","pmids":["38409361"],"is_preprint":false},{"year":2006,"finding":"Transient overexpression of BOP1 in human cells increases the percentage of multipolar spindles, indicating a role for BOP1 in proper chromosome segregation beyond its function in ribosome biogenesis.","method":"BOP1 overexpression, immunofluorescence analysis of spindle morphology","journal":"Genes, chromosomes & cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment, single method, single lab","pmids":["16804918"],"is_preprint":false},{"year":2023,"finding":"BOP1 promotes prostate cancer cell viability and metastasis via regulation of DUSP6 expression and activation of the MAPK pathway; BOP1 knockout inhibits DUSP6 expression and MAPK signaling, and DUSP6 overexpression reverses the effects of BOP1 siRNA.","method":"BOP1 knockout/siRNA, DUSP6 overexpression, MAPK pathway western blotting, Transwell invasion assay, apoptosis assay","journal":"Archivos espanoles de urologia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, no direct BOP1-DUSP6 interaction demonstrated","pmids":["37681336"],"is_preprint":false},{"year":2022,"finding":"lncRNA SNHG6 binds BOP1 protein and enhances its stability, promoting glycolysis and proliferation in hepatocellular carcinoma cells; BOP1 overexpression rescues proliferation and glycolysis changes caused by SNHG6 manipulation.","method":"MS2 pull-down, RNA pull-down, RNA immunoprecipitation (RIP), western blotting, glucose uptake/lactate/OCR/ECAR assays","journal":"Animal cells and systems","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNA-protein interaction shown by pulldown methods but protein stabilization mechanism not detailed; single lab","pmids":["36605586"],"is_preprint":false},{"year":2025,"finding":"BOP1 depletion reduces overall ribosome availability, which preferentially upregulates translation of non-optimal codon transcripts (including several ISGs) during IFN-β stimulation, demonstrating that ribosome biogenesis controlled by BOP1 regulates translational fine-tuning through codon optimality.","method":"RNA-seq, LC-MS/MS proteomics (multi-omics), BOP1 knockdown, codon usage analysis, reporter constructs (codon-optimal vs non-optimal)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, reporter assays support codon optimality model but mechanistic link to BOP1 is indirect","pmids":["bio_10.1101_2025.09.05.673799"],"is_preprint":true}],"current_model":"BOP1 is a conserved WD40 repeat nucleolar protein that functions as the integral scaffold of the trimeric PeBoW complex (with Pes1 and WDR12), where it coordinates processing of pre-rRNA at multiple ITS1, ITS2, and 3' ETS sites to generate mature 28S and 5.8S rRNAs and biogenesis of 60S ribosomal subunits; disruption of BOP1 function triggers nucleolar stress, leading to RPL11 release from the nucleolus, MDM2 inhibition, p53 stabilization, and p53-dependent G1 cell cycle arrest, while BOP1 overexpression promotes chromosomal instability via Aurora kinase B activation, EMT via RhoA, and Wnt/β-catenin signaling via CBP-mediated β-catenin acetylation."},"narrative":{"mechanistic_narrative":"BOP1 is a conserved WD40-repeat nucleolar protein that serves as the integral scaffold of the trimeric PeBoW complex (BOP1–Pes1–WDR12) and drives maturation of the large (60S) ribosomal subunit [PMID:10891491, PMID:16043514, PMID:17353269]. It cosediments with pre-ribosomal particles containing the 32S rRNA precursor and is required for pre-rRNA processing at four distinct sites within ITS1, ITS2, and the 3' external spacer, generating mature 28S and 5.8S rRNAs; dominant-negative or antisense disruption blocks the 36S→32S conversion and 32S processing, depleting cytosolic 60S subunits and arresting cells in G1 [PMID:10891491, PMID:12048210]. This function is evolutionarily conserved, as the yeast homolog Erb1p is essential for processing 27SB pre-rRNA to 25S and 5.8S rRNAs [PMID:11522832]. Within PeBoW, BOP1 directly binds Pes1 to license Pes1 incorporation into pre-ribosomal complexes, and BOP1 is the central subunit whose loss abolishes copurification of Pes1 with WDR12; BOP1 itself depends on Pes1 for nucleolar import [PMID:15225545, PMID:17353269]. Disruption of BOP1-dependent ribosome biogenesis triggers a nucleolar stress response in which RPL11 is released from the nucleolus to the nucleoplasm, inhibiting MDM2, stabilizing p53, and imposing p53-dependent G1 arrest; this stress pathway is genetically separable from the rRNA processing defect itself [PMID:11390653, PMID:33510838]. Downstream of stabilized p53, BOP1 loss inhibits mTOR phosphorylation to activate autophagy [PMID:38409361]. In cancer contexts, BOP1 overexpression promotes chromosomal instability through activation of Aurora kinase B [PMID:32805281], drives epithelial-to-mesenchymal transition and invasion via RhoA activation [PMID:21520196], and enhances Wnt/β-catenin signaling by recruiting CBP to β-catenin to increase its acetylation and stemness gene transcription [PMID:33797754].","teleology":[{"year":2000,"claim":"Established BOP1 as a nucleolar factor physically and functionally tied to large-subunit rRNA maturation, answering what cellular process it serves.","evidence":"Sucrose gradient fractionation, pulse-chase rRNA processing, and dominant-negative Bop1Delta in mammalian cells","pmids":["10891491"],"confidence":"High","gaps":["Does not identify partner proteins in the pre-ribosomal particle","Catalytic versus scaffold role left undefined"]},{"year":2001,"claim":"Showed that the cell cycle arrest caused by BOP1 perturbation is mediated by a p53-dependent nucleolar stress pathway and is uncoupled from the rRNA processing defect itself.","evidence":"Dominant-negative expression with p53 inactivation epistasis, CDK/pRb and p21/p27 readouts","pmids":["11390653"],"confidence":"High","gaps":["Molecular sensor linking biogenesis defect to p53 not yet identified","Does not define which ribosomal protein relays the signal"]},{"year":2001,"claim":"Demonstrated evolutionary conservation by showing the yeast ortholog Erb1p is essential for 27SB pre-rRNA processing, generalizing the large-subunit maturation role.","evidence":"Gene disruption and conditional depletion with rRNA processing analysis in S. cerevisiae","pmids":["11522832"],"confidence":"High","gaps":["Conservation of the human p53 stress link not addressable in yeast"]},{"year":2002,"claim":"Mapped the precise processing sites requiring BOP1 and confirmed the requirement with endogenous knockdown, sharpening its biochemical role.","evidence":"Deletion mutagenesis, antisense knockdown, immunofluorescence and rRNA processing analysis","pmids":["12048210"],"confidence":"High","gaps":["Whether BOP1 acts catalytically or recruits processing nucleases unresolved"]},{"year":2004,"claim":"Defined a direct BOP1–Pes1 interaction required for Pes1 entry into pre-ribosomal complexes, identifying the first physical partner.","evidence":"Co-immunoprecipitation and dominant-negative Pes1 mutant panel with rRNA and cell cycle assays","pmids":["15225545"],"confidence":"High","gaps":["Interaction interface not structurally resolved","Stoichiometry not defined"]},{"year":2005,"claim":"Identified the trimeric PeBoW complex (BOP1–Pes1–WDR12) and showed WDR12 is also required for 32S processing and proliferation.","evidence":"Co-immunoprecipitation, dominant-negative WDR12, rRNA processing and p53 accumulation assays","pmids":["16043514"],"confidence":"High","gaps":["Order of assembly not yet established","p19ARF-independent route to p53 not mechanistically detailed"]},{"year":2007,"claim":"Established BOP1 as the central, complex-organizing subunit and defined Pes1-dependent nucleolar import, clarifying assembly architecture and trafficking.","evidence":"Recombinant reconstitution, co-IP, siRNA, fractionation and sucrose gradient centrifugation","pmids":["17353269"],"confidence":"High","gaps":["No high-resolution structure of the assembled complex","Mechanism of Pes1-dependent transport unknown"]},{"year":2006,"claim":"First hint of a mitotic role: BOP1 overexpression increased multipolar spindles, suggesting function beyond ribosome biogenesis.","evidence":"BOP1 overexpression with immunofluorescence of spindle morphology","pmids":["16804918"],"confidence":"Low","gaps":["Single overexpression experiment, single method","Molecular link to spindle defects not defined"]},{"year":2011,"claim":"Connected BOP1 overexpression to EMT and motility via RhoA activation in hepatocellular carcinoma, extending its biology to a pro-metastatic axis.","evidence":"siRNA and ectopic expression with invasion/migration assays, EMT markers and RhoA activation assay","pmids":["21520196"],"confidence":"Medium","gaps":["Mechanism linking BOP1 to RhoA not defined","Single-lab cancer-cell context"]},{"year":2019,"claim":"Identified BOP1 loss as a driver of BRAF-inhibitor resistance through transcriptional downregulation of DUSP4/DUSP6 and elevated MAPK signaling.","evidence":"shRNA epigenetic-regulator screen, knockdown, DUSP expression and MAPK assays, mouse studies","pmids":["30782837"],"confidence":"Medium","gaps":["Direct mechanism by which BOP1 controls DUSP transcription unknown","Relationship to ribosome biogenesis role unclear"]},{"year":2020,"claim":"Linked CCAT2-driven BOP1 overexpression to chromosomal instability via Aurora kinase B activation, providing a mechanism for the earlier spindle phenotype.","evidence":"MS2/RIP/SHAPE RNA-protein analysis, overexpression/knockdown, cytogenetics and immunofluorescence","pmids":["32805281"],"confidence":"Medium","gaps":["How BOP1 activates AURKB mechanistically not resolved","Single lab"]},{"year":2021,"claim":"Demonstrated that BOP1 overexpression amplifies Wnt/β-catenin signaling by recruiting CBP to β-catenin to enhance acetylation and stemness, defining a transcriptional oncogenic axis.","evidence":"Overexpression/knockdown, BOP1-CBP-β-catenin co-IP, acetylation assay, drug-resistance assays in vitro and in vivo","pmids":["33797754"],"confidence":"Medium","gaps":["Whether BOP1 directly contacts β-catenin or CBP not fully resolved","Single lab"]},{"year":2021,"claim":"Mapped the nucleolar stress effector chain in vascular smooth muscle: BOP1 loss → RPL11 release → MDM2 inhibition → p53 stabilization → suppressed proliferation.","evidence":"BOP1/RPL11 siRNA, pifithrin-α p53 inhibition, proliferation/migration assays and rat balloon injury model","pmids":["33510838"],"confidence":"Medium","gaps":["Generality across cell types not established by this study alone","Single lab"]},{"year":2024,"claim":"Extended the RPL11–MDM2–p53 axis downstream to mTOR inhibition and autophagy activation, with in vivo rescue of PCOS phenotypes.","evidence":"Lentiviral knockdown/overexpression, pathway analysis and in vivo PCOS mouse model","pmids":["38409361"],"confidence":"Medium","gaps":["Direct versus indirect coupling of p53 to mTOR not dissected","Single lab"]},{"year":null,"claim":"How BOP1's non-canonical signaling activities (AURKB, RhoA, CBP/β-catenin, DUSP/MAPK) mechanistically arise from or are independent of its core ribosome-biogenesis scaffold function remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PeBoW","No demonstrated direct enzymatic substrate for BOP1","Whether signaling roles require nucleolar localization is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,5,6]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[11,12]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3,5]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,11]}],"complexes":["PeBoW complex"],"partners":["PES1","WDR12","RPL11","CREBBP","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14137","full_name":"Ribosome biogenesis protein BOP1","aliases":["Block of proliferation 1 protein"],"length_aa":746,"mass_kda":83.6,"function":"Component of the PeBoW complex, which is required for maturation of 28S and 5.8S ribosomal RNAs and formation of the 60S ribosome","subcellular_location":"Nucleus, nucleolus; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q14137/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/BOP1","classification":"Common Essential","n_dependent_lines":1197,"n_total_lines":1208,"dependency_fraction":0.9908940397350994},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000261236","cell_line_id":"CID001061","localizations":[{"compartment":"nucleolus_gc","grade":3}],"interactors":[{"gene":"WIZ","stoichiometry":10.0},{"gene":"PES1","stoichiometry":10.0},{"gene":"WDR12","stoichiometry":10.0},{"gene":"RAD50","stoichiometry":4.0},{"gene":"ARPC2","stoichiometry":0.2},{"gene":"CSNK2A1","stoichiometry":0.2},{"gene":"CSNK2A2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"NPM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001061","total_profiled":1310},"omim":[{"mim_id":"619403","title":"COLON CANCER-ASSOCIATED TRANSCRIPT 2, NONCODING; CCAT2","url":"https://www.omim.org/entry/619403"},{"mim_id":"616621","title":"DEAD-BOX HELICASE 27; DDX27","url":"https://www.omim.org/entry/616621"},{"mim_id":"616620","title":"WD REPEAT-CONTAINING PROTEIN 12; WDR12","url":"https://www.omim.org/entry/616620"},{"mim_id":"610597","title":"GLUTAMATE-RICH WD REPEAT-CONTAINING PROTEIN 1; GRWD1","url":"https://www.omim.org/entry/610597"},{"mim_id":"610596","title":"BLOCK OF PROLIFERATION 1; BOP1","url":"https://www.omim.org/entry/610596"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Nucleoli rim","reliability":"Enhanced"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Mitotic chromosome","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":69.1}],"url":"https://www.proteinatlas.org/search/BOP1"},"hgnc":{"alias_symbol":["KIAA0124"],"prev_symbol":[]},"alphafold":{"accession":"Q14137","domains":[{"cath_id":"2.130.10.10","chopping":"396-503_511-746","consensus_level":"medium","plddt":93.869,"start":396,"end":746}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14137","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14137-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14137-F1-predicted_aligned_error_v6.png","plddt_mean":79.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BOP1","jax_strain_url":"https://www.jax.org/strain/search?query=BOP1"},"sequence":{"accession":"Q14137","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14137.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14137/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14137"}},"corpus_meta":[{"pmid":"11390653","id":"PMC_11390653","title":"Evidence of p53-dependent cross-talk between ribosome biogenesis and the cell cycle: effects of nucleolar protein Bop1 on G(1)/S transition.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11390653","citation_count":297,"is_preprint":false},{"pmid":"16043514","id":"PMC_16043514","title":"Mammalian WDR12 is a novel member of the Pes1-Bop1 complex and is required for ribosome biogenesis and cell proliferation.","date":"2005","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16043514","citation_count":165,"is_preprint":false},{"pmid":"10891491","id":"PMC_10891491","title":"Bop1 is a mouse WD40 repeat nucleolar protein involved in 28S and 5. 8S RRNA processing and 60S ribosome biogenesis.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10891491","citation_count":156,"is_preprint":false},{"pmid":"32805281","id":"PMC_32805281","title":"The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling.","date":"2020","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/32805281","citation_count":113,"is_preprint":false},{"pmid":"15225545","id":"PMC_15225545","title":"Physical and functional interaction between Pes1 and Bop1 in mammalian ribosome biogenesis.","date":"2004","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15225545","citation_count":113,"is_preprint":false},{"pmid":"17353269","id":"PMC_17353269","title":"Interdependence of Pes1, Bop1, and WDR12 controls nucleolar localization and assembly of the PeBoW complex required for maturation of the 60S ribosomal subunit.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17353269","citation_count":112,"is_preprint":false},{"pmid":"12048210","id":"PMC_12048210","title":"Functional inactivation of the mouse nucleolar protein Bop1 inhibits multiple steps in pre-rRNA processing and blocks cell cycle progression.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12048210","citation_count":91,"is_preprint":false},{"pmid":"11522832","id":"PMC_11522832","title":"ERB1, the yeast homolog of mammalian Bop1, is an essential gene required for maturation of the 25S and 5.8S ribosomal RNAs.","date":"2001","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/11522832","citation_count":65,"is_preprint":false},{"pmid":"21520196","id":"PMC_21520196","title":"Block of proliferation 1 (BOP1) plays an oncogenic role in hepatocellular carcinoma by promoting epithelial-to-mesenchymal transition.","date":"2011","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/21520196","citation_count":64,"is_preprint":false},{"pmid":"16804918","id":"PMC_16804918","title":"Contribution of the BOP1 gene, located on 8q24, to colorectal tumorigenesis.","date":"2006","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16804918","citation_count":55,"is_preprint":false},{"pmid":"27208226","id":"PMC_27208226","title":"A Homolog of Blade-On-Petiole 1 and 2 (BOP1/2) Controls Internode Length and Homeotic Changes of the Barley Inflorescence.","date":"2016","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27208226","citation_count":41,"is_preprint":false},{"pmid":"30782837","id":"PMC_30782837","title":"Loss of BOP1 confers resistance to BRAF kinase inhibitors in melanoma by activating MAP kinase pathway.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30782837","citation_count":34,"is_preprint":false},{"pmid":"33797754","id":"PMC_33797754","title":"BOP1 confers chemoresistance of triple-negative breast cancer by promoting CBP-mediated β-catenin acetylation.","date":"2021","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33797754","citation_count":23,"is_preprint":false},{"pmid":"38409361","id":"PMC_38409361","title":"BOP1 contributes to the activation of autophagy in polycystic ovary syndrome via nucleolar stress response.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38409361","citation_count":12,"is_preprint":false},{"pmid":"36605586","id":"PMC_36605586","title":"LncRNA SNHG6 promotes glycolysis reprogramming in hepatocellular carcinoma by stabilizing the BOP1 protein.","date":"2022","source":"Animal cells and systems","url":"https://pubmed.ncbi.nlm.nih.gov/36605586","citation_count":12,"is_preprint":false},{"pmid":"33510838","id":"PMC_33510838","title":"BOP1 Knockdown Attenuates Neointimal Hyperplasia by Activating p53 and Inhibiting Nascent Protein Synthesis.","date":"2021","source":"Oxidative medicine and cellular 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research","url":"https://pubmed.ncbi.nlm.nih.gov/18670790","citation_count":7,"is_preprint":false},{"pmid":"16362343","id":"PMC_16362343","title":"Interaction of beta-giardin with the Bop1 protein in Giardia lamblia.","date":"2005","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/16362343","citation_count":7,"is_preprint":false},{"pmid":"33877544","id":"PMC_33877544","title":"BOP1 Silencing Suppresses Gastric Cancer Proliferation through p53 Modulation.","date":"2021","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/33877544","citation_count":6,"is_preprint":false},{"pmid":"39003587","id":"PMC_39003587","title":"Cotton BOP1 mediates SUMOylation of GhBES1 to regulate fibre development and plant architecture.","date":"2024","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/39003587","citation_count":4,"is_preprint":false},{"pmid":"37974491","id":"PMC_37974491","title":"Bop1 is required to establish precursor domains of craniofacial tissues.","date":"2023","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/37974491","citation_count":2,"is_preprint":false},{"pmid":"37681336","id":"PMC_37681336","title":"BOP1 Promotes Prostate Cancer through the DUSP6/MAPK Pathway.","date":"2023","source":"Archivos espanoles de urologia","url":"https://pubmed.ncbi.nlm.nih.gov/37681336","citation_count":2,"is_preprint":false},{"pmid":"37615370","id":"PMC_37615370","title":"PDGF-C promotes cell proliferation partially via downregulating BOP1.","date":"2023","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/37615370","citation_count":2,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.05.673799","title":"Ribosome biogenesis mediates the translational increase of non-optimal codon transcripts during IFN stimulation","date":"2025-09-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.05.673799","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14633,"output_tokens":4340,"usd":0.054499,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12374,"output_tokens":4117,"usd":0.082397,"stage2_stop_reason":"end_turn"},"total_usd":0.136896,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Bop1 is a WD40 repeat nucleolar protein that cosediments with 50S-80S ribonucleoprotein particles containing 32S rRNA precursor; expression of dominant-negative Bop1Delta (lacking 231 N-terminal amino acids) specifically blocks conversion of 36S to 32S pre-rRNA and completely inhibits processing of 32S pre-rRNA to mature 28S and 5.8S rRNAs, causing deficiency of cytosolic 60S ribosomal subunits and G1 cell cycle arrest.\",\n      \"method\": \"Immunofluorescence, sucrose density gradient fractionation, pulse-chase rRNA processing analysis, dominant-negative expression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, pulse-chase, dominant-negative) in foundational paper, replicated by subsequent studies\",\n      \"pmids\": [\"10891491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Perturbation of Bop1 by dominant-negative Bop1Delta induces p53-dependent G1 cell cycle arrest; inactivation of p53 abrogates this arrest without restoring normal rRNA processing, demonstrating that deficiencies in ribosome synthesis trigger cell cycle arrest via a p53-dependent nucleolar stress pathway, and that rRNA processing defects can be uncoupled from cell cycle arrest.\",\n      \"method\": \"Dominant-negative expression, p53 inactivation, CDK kinase activity assays, pRb phosphorylation analysis, p21/p27 western blotting\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (p53 inactivation rescues arrest but not rRNA defect), multiple biochemical readouts, replicated in subsequent studies\",\n      \"pmids\": [\"11390653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The yeast homolog of Bop1, Erb1p (encoded by YMR049C), is essential for viability and required for processing of 27SB pre-rRNA to 25S and 5.8S rRNAs; Erb1p depletion causes loss of 25S and 5.8S rRNAs with underaccumulation of 27SB pre-rRNA, demonstrating evolutionary conservation of Bop1/Erb1p function in large ribosomal subunit maturation.\",\n      \"method\": \"Gene disruption, conditional depletion, rRNA processing analysis in S. cerevisiae\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic disruption plus processing analysis, ortholog confirms conserved mechanism\",\n      \"pmids\": [\"11522832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Bop1 is required for pre-rRNA processing at four distinct sites within ITS1, ITS2, and the 3' external spacer; both C-terminal (Bop1N2) and N-terminal (Bop1Delta) deletion mutants localize to the nucleolus and inhibit rRNA processing and cell cycle progression, and antisense oligonucleotide knockdown of endogenous Bop1 recapitulates processing defects.\",\n      \"method\": \"Deletion mutagenesis, antisense oligonucleotide knockdown, immunofluorescence, rRNA processing analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple dominant-negative mutants plus antisense KD, consistent results across methods\",\n      \"pmids\": [\"12048210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Bop1 physically interacts with Pes1 (mouse homolog of yeast Nop7p); this interaction is essential for efficient incorporation of Pes1 into nucleolar preribosomal complexes, and Pes1 mutants defective for Bop1 interaction lose the ability to affect rRNA maturation and the cell cycle.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative Pes1 mutant panel, rRNA processing analysis, cell cycle assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction mapping with multiple mutants, functional epistasis established\",\n      \"pmids\": [\"15225545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Bop1 and Pes1 form a stable trimeric complex with WDR12 (a novel WD40 repeat protein), termed the PeBoW complex; endogenous WDR12 is required for processing of 32S precursor rRNA and cell proliferation, and a dominant-negative WDR12 mutant blocks rRNA processing and induces p53 accumulation in a p19ARF-independent manner.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative expression, rRNA processing assays, p53 accumulation analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complex identified by co-IP, functional validation with dominant-negative and knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"16043514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Bop1 is the integral/central component of the PeBoW complex: recombinant expression of Pes1, Bop1, and WDR12 is sufficient for complex formation; Bop1 knockdown abolishes copurification of Pes1 with WDR12; overexpressed Bop1 inhibits cell proliferation and rRNA processing (rescuable by WDR12 co-expression but not Pes1); nucleolar transport of Bop1 from cytoplasm is Pes1-dependent, while Pes1 migrates to nucleolus independently of Bop1.\",\n      \"method\": \"Recombinant protein expression, co-immunoprecipitation, siRNA knockdown, immunofluorescence, cell fractionation, sucrose gradient centrifugation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reconstitution of complex from recombinant subunits plus multiple orthogonal localization and biochemical methods\",\n      \"pmids\": [\"17353269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BOP1 promotes chromosomal instability by increasing the active form of Aurora kinase B (AURKB), which regulates chromosomal segregation; CCAT2 lncRNA directly binds and stabilizes BOP1 protein and also activates MYC-driven BOP1 transcription, leading to BOP1 overexpression that causes chromosomal missegregation errors.\",\n      \"method\": \"MS2 pull-down, RNA immunoprecipitation, SHAPE analysis, BOP1 overexpression/knockdown, cytogenetic analysis, immunofluorescence\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-protein interaction confirmed by multiple pulldown methods, AURKB activation shown by BOP1 overexpression; single lab\",\n      \"pmids\": [\"32805281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of BOP1 confers resistance to BRAF kinase inhibitors in melanoma by downregulating MAPK phosphatases DUSP4 and DUSP6 via a transcription-based mechanism, leading to increased MAPK signaling.\",\n      \"method\": \"shRNA screen (363 epigenetic regulators), BOP1 knockdown, DUSP4/DUSP6 expression analysis, MAPK pathway activity assays, in vivo mouse studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale functional screen plus mechanistic follow-up in cell culture and mouse models; single lab\",\n      \"pmids\": [\"30782837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BOP1 promotes epithelial-to-mesenchymal transition (EMT) in hepatocellular carcinoma cells, stimulates actin stress fiber assembly, and activates RhoA; siRNA-mediated BOP1 knockdown upregulates epithelial markers (E-cadherin, cytokeratin 18, γ-catenin) and downregulates mesenchymal markers (fibronectin, vimentin), while ectopic BOP1 expression in hepatocytes increases invasiveness and migration.\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, invasion/migration assays, EMT marker western blotting, RhoA activation assay, actin staining\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotypes and molecular markers; single lab\",\n      \"pmids\": [\"21520196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BOP1 activates Wnt/β-catenin signaling in triple-negative breast cancer by increasing recruitment of CBP (CREB-binding protein) to β-catenin, enhancing CBP-mediated acetylation of β-catenin, and increasing transcription of stemness-related genes CD133 and ALDH1A1, thereby promoting cancer stem cell-like phenotype and chemoresistance.\",\n      \"method\": \"BOP1 overexpression/knockdown, Co-immunoprecipitation (BOP1-CBP-β-catenin), acetylation assay, gene expression analysis, in vitro and in vivo drug resistance assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for complex, acetylation assay, functional rescue with CBP/β-catenin inhibitor; single lab\",\n      \"pmids\": [\"33797754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BOP1 knockdown in vascular smooth muscle cells activates nucleolar stress, causing RPL11 release from nucleolus to nucleoplasm, which inhibits MDM2 E3 ubiquitin ligase activity, stabilizes p53, and subsequently inhibits VSMC proliferation and migration; siRNA knockdown of RPL11 or p53 inhibition with pifithrin-α partially reverses these effects.\",\n      \"method\": \"siRNA knockdown of BOP1 and RPL11, p53 inhibitor (pifithrin-α), proliferation/migration assays, nascent protein synthesis assay, rat balloon injury model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (RPL11 KD and p53 inhibition rescue BOP1 KD phenotype), in vivo model; single lab\",\n      \"pmids\": [\"33510838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BOP1 knockdown triggers nucleolar stress response causing RPL11 release from nucleolus into nucleoplasm, inhibiting MDM2, stabilizing p53, which then inhibits mTOR phosphorylation, activating autophagy in granulosa cells; BOP1 overexpression in vivo suppresses this pathway and alleviates PCOS phenotypes.\",\n      \"method\": \"BOP1 knockdown/overexpression (lentiviral), RPL11 localization, MDM2 inhibition, p53/mTOR pathway analysis, in vivo PCOS mouse model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway defined via epistasis (RPL11-MDM2-p53-mTOR), in vivo rescue, single lab\",\n      \"pmids\": [\"38409361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Transient overexpression of BOP1 in human cells increases the percentage of multipolar spindles, indicating a role for BOP1 in proper chromosome segregation beyond its function in ribosome biogenesis.\",\n      \"method\": \"BOP1 overexpression, immunofluorescence analysis of spindle morphology\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment, single method, single lab\",\n      \"pmids\": [\"16804918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BOP1 promotes prostate cancer cell viability and metastasis via regulation of DUSP6 expression and activation of the MAPK pathway; BOP1 knockout inhibits DUSP6 expression and MAPK signaling, and DUSP6 overexpression reverses the effects of BOP1 siRNA.\",\n      \"method\": \"BOP1 knockout/siRNA, DUSP6 overexpression, MAPK pathway western blotting, Transwell invasion assay, apoptosis assay\",\n      \"journal\": \"Archivos espanoles de urologia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, no direct BOP1-DUSP6 interaction demonstrated\",\n      \"pmids\": [\"37681336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"lncRNA SNHG6 binds BOP1 protein and enhances its stability, promoting glycolysis and proliferation in hepatocellular carcinoma cells; BOP1 overexpression rescues proliferation and glycolysis changes caused by SNHG6 manipulation.\",\n      \"method\": \"MS2 pull-down, RNA pull-down, RNA immunoprecipitation (RIP), western blotting, glucose uptake/lactate/OCR/ECAR assays\",\n      \"journal\": \"Animal cells and systems\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNA-protein interaction shown by pulldown methods but protein stabilization mechanism not detailed; single lab\",\n      \"pmids\": [\"36605586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BOP1 depletion reduces overall ribosome availability, which preferentially upregulates translation of non-optimal codon transcripts (including several ISGs) during IFN-β stimulation, demonstrating that ribosome biogenesis controlled by BOP1 regulates translational fine-tuning through codon optimality.\",\n      \"method\": \"RNA-seq, LC-MS/MS proteomics (multi-omics), BOP1 knockdown, codon usage analysis, reporter constructs (codon-optimal vs non-optimal)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, reporter assays support codon optimality model but mechanistic link to BOP1 is indirect\",\n      \"pmids\": [\"bio_10.1101_2025.09.05.673799\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"BOP1 is a conserved WD40 repeat nucleolar protein that functions as the integral scaffold of the trimeric PeBoW complex (with Pes1 and WDR12), where it coordinates processing of pre-rRNA at multiple ITS1, ITS2, and 3' ETS sites to generate mature 28S and 5.8S rRNAs and biogenesis of 60S ribosomal subunits; disruption of BOP1 function triggers nucleolar stress, leading to RPL11 release from the nucleolus, MDM2 inhibition, p53 stabilization, and p53-dependent G1 cell cycle arrest, while BOP1 overexpression promotes chromosomal instability via Aurora kinase B activation, EMT via RhoA, and Wnt/β-catenin signaling via CBP-mediated β-catenin acetylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BOP1 is a conserved WD40-repeat nucleolar protein that serves as the integral scaffold of the trimeric PeBoW complex (BOP1–Pes1–WDR12) and drives maturation of the large (60S) ribosomal subunit [#0, #5, #6]. It cosediments with pre-ribosomal particles containing the 32S rRNA precursor and is required for pre-rRNA processing at four distinct sites within ITS1, ITS2, and the 3' external spacer, generating mature 28S and 5.8S rRNAs; dominant-negative or antisense disruption blocks the 36S→32S conversion and 32S processing, depleting cytosolic 60S subunits and arresting cells in G1 [#0, #3]. This function is evolutionarily conserved, as the yeast homolog Erb1p is essential for processing 27SB pre-rRNA to 25S and 5.8S rRNAs [#2]. Within PeBoW, BOP1 directly binds Pes1 to license Pes1 incorporation into pre-ribosomal complexes, and BOP1 is the central subunit whose loss abolishes copurification of Pes1 with WDR12; BOP1 itself depends on Pes1 for nucleolar import [#4, #6]. Disruption of BOP1-dependent ribosome biogenesis triggers a nucleolar stress response in which RPL11 is released from the nucleolus to the nucleoplasm, inhibiting MDM2, stabilizing p53, and imposing p53-dependent G1 arrest; this stress pathway is genetically separable from the rRNA processing defect itself [#1, #11]. Downstream of stabilized p53, BOP1 loss inhibits mTOR phosphorylation to activate autophagy [#12]. In cancer contexts, BOP1 overexpression promotes chromosomal instability through activation of Aurora kinase B [#7], drives epithelial-to-mesenchymal transition and invasion via RhoA activation [#9], and enhances Wnt/β-catenin signaling by recruiting CBP to β-catenin to increase its acetylation and stemness gene transcription [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established BOP1 as a nucleolar factor physically and functionally tied to large-subunit rRNA maturation, answering what cellular process it serves.\",\n      \"evidence\": \"Sucrose gradient fractionation, pulse-chase rRNA processing, and dominant-negative Bop1Delta in mammalian cells\",\n      \"pmids\": [\"10891491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify partner proteins in the pre-ribosomal particle\", \"Catalytic versus scaffold role left undefined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that the cell cycle arrest caused by BOP1 perturbation is mediated by a p53-dependent nucleolar stress pathway and is uncoupled from the rRNA processing defect itself.\",\n      \"evidence\": \"Dominant-negative expression with p53 inactivation epistasis, CDK/pRb and p21/p27 readouts\",\n      \"pmids\": [\"11390653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor linking biogenesis defect to p53 not yet identified\", \"Does not define which ribosomal protein relays the signal\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated evolutionary conservation by showing the yeast ortholog Erb1p is essential for 27SB pre-rRNA processing, generalizing the large-subunit maturation role.\",\n      \"evidence\": \"Gene disruption and conditional depletion with rRNA processing analysis in S. cerevisiae\",\n      \"pmids\": [\"11522832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of the human p53 stress link not addressable in yeast\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped the precise processing sites requiring BOP1 and confirmed the requirement with endogenous knockdown, sharpening its biochemical role.\",\n      \"evidence\": \"Deletion mutagenesis, antisense knockdown, immunofluorescence and rRNA processing analysis\",\n      \"pmids\": [\"12048210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BOP1 acts catalytically or recruits processing nucleases unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined a direct BOP1–Pes1 interaction required for Pes1 entry into pre-ribosomal complexes, identifying the first physical partner.\",\n      \"evidence\": \"Co-immunoprecipitation and dominant-negative Pes1 mutant panel with rRNA and cell cycle assays\",\n      \"pmids\": [\"15225545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interaction interface not structurally resolved\", \"Stoichiometry not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified the trimeric PeBoW complex (BOP1–Pes1–WDR12) and showed WDR12 is also required for 32S processing and proliferation.\",\n      \"evidence\": \"Co-immunoprecipitation, dominant-negative WDR12, rRNA processing and p53 accumulation assays\",\n      \"pmids\": [\"16043514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of assembly not yet established\", \"p19ARF-independent route to p53 not mechanistically detailed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established BOP1 as the central, complex-organizing subunit and defined Pes1-dependent nucleolar import, clarifying assembly architecture and trafficking.\",\n      \"evidence\": \"Recombinant reconstitution, co-IP, siRNA, fractionation and sucrose gradient centrifugation\",\n      \"pmids\": [\"17353269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the assembled complex\", \"Mechanism of Pes1-dependent transport unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"First hint of a mitotic role: BOP1 overexpression increased multipolar spindles, suggesting function beyond ribosome biogenesis.\",\n      \"evidence\": \"BOP1 overexpression with immunofluorescence of spindle morphology\",\n      \"pmids\": [\"16804918\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single overexpression experiment, single method\", \"Molecular link to spindle defects not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected BOP1 overexpression to EMT and motility via RhoA activation in hepatocellular carcinoma, extending its biology to a pro-metastatic axis.\",\n      \"evidence\": \"siRNA and ectopic expression with invasion/migration assays, EMT markers and RhoA activation assay\",\n      \"pmids\": [\"21520196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking BOP1 to RhoA not defined\", \"Single-lab cancer-cell context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified BOP1 loss as a driver of BRAF-inhibitor resistance through transcriptional downregulation of DUSP4/DUSP6 and elevated MAPK signaling.\",\n      \"evidence\": \"shRNA epigenetic-regulator screen, knockdown, DUSP expression and MAPK assays, mouse studies\",\n      \"pmids\": [\"30782837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which BOP1 controls DUSP transcription unknown\", \"Relationship to ribosome biogenesis role unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked CCAT2-driven BOP1 overexpression to chromosomal instability via Aurora kinase B activation, providing a mechanism for the earlier spindle phenotype.\",\n      \"evidence\": \"MS2/RIP/SHAPE RNA-protein analysis, overexpression/knockdown, cytogenetics and immunofluorescence\",\n      \"pmids\": [\"32805281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How BOP1 activates AURKB mechanistically not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that BOP1 overexpression amplifies Wnt/β-catenin signaling by recruiting CBP to β-catenin to enhance acetylation and stemness, defining a transcriptional oncogenic axis.\",\n      \"evidence\": \"Overexpression/knockdown, BOP1-CBP-β-catenin co-IP, acetylation assay, drug-resistance assays in vitro and in vivo\",\n      \"pmids\": [\"33797754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BOP1 directly contacts β-catenin or CBP not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the nucleolar stress effector chain in vascular smooth muscle: BOP1 loss → RPL11 release → MDM2 inhibition → p53 stabilization → suppressed proliferation.\",\n      \"evidence\": \"BOP1/RPL11 siRNA, pifithrin-α p53 inhibition, proliferation/migration assays and rat balloon injury model\",\n      \"pmids\": [\"33510838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality across cell types not established by this study alone\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the RPL11–MDM2–p53 axis downstream to mTOR inhibition and autophagy activation, with in vivo rescue of PCOS phenotypes.\",\n      \"evidence\": \"Lentiviral knockdown/overexpression, pathway analysis and in vivo PCOS mouse model\",\n      \"pmids\": [\"38409361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect coupling of p53 to mTOR not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BOP1's non-canonical signaling activities (AURKB, RhoA, CBP/β-catenin, DUSP/MAPK) mechanistically arise from or are independent of its core ribosome-biogenesis scaffold function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PeBoW\", \"No demonstrated direct enzymatic substrate for BOP1\", \"Whether signaling roles require nucleolar localization is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 5]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"complexes\": [\"PeBoW complex\"],\n    \"partners\": [\"PES1\", \"WDR12\", \"RPL11\", \"CREBBP\", \"CTNNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}