{"gene":"PDCD11","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1996,"finding":"RRP5 (yeast ortholog of PDCD11) is essential for pre-rRNA processing at sites A0, A1, and A2 (required for 18S rRNA synthesis) and at site A3 (required for the major short form of 5.8S rRNA synthesis), making it the first cellular component simultaneously required for both snoRNP-dependent and RNase MRP-dependent cleavage events in ribosome biogenesis.","method":"Genetic depletion of Rrp5p in S. cerevisiae followed by pre-rRNA processing analysis; synthetic lethality screen with snR10 deletion","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic depletion with defined molecular phenotype, multiple pre-rRNA processing sites analyzed, replicated by multiple subsequent studies","pmids":["8896463"],"is_preprint":false},{"year":2008,"finding":"Human NFBP (PDCD11) colocalizes with and co-precipitates U3 snoRNA in the nucleolus, and is essential for 18S rRNA maturation via cleavages at sites A0, 1, and 2, as demonstrated by accumulation of unprocessed rRNA intermediates upon NFBP knockdown.","method":"Co-immunoprecipitation, immunofluorescence colocalization, Northern blot analysis of pre-rRNA processing upon NFBP depletion","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and localization plus loss-of-function with specific molecular phenotype (rRNA processing defect), two orthogonal methods","pmids":["17654514"],"is_preprint":false},{"year":2009,"finding":"Human RRP5 (PDCD11) associates with the U3 snoRNP as part of a 50S SSU processome assembly intermediate, together with nucleolin and DBP4, and is likely recruited to pre-rRNA through RNA-binding activity to form this intermediate before tUTP, bUTP, MPP10 and BMS1/RCL1 subcomplexes join.","method":"Sucrose gradient sedimentation, co-immunoprecipitation, depletion of tUTP proteins to accumulate intermediate complex","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and sedimentation identifying complex membership, single lab, two orthogonal methods","pmids":["19332556"],"is_preprint":false},{"year":2011,"finding":"Yeast Rrp5 binds pre-rRNA at three distinct regions within ITS1 using its 12 tandem S1 RNA-binding domains; the first nine S1 motifs contribute high-affinity but non-specific RNA binding, while the last three S1 domains provide specificity for pre-rRNA. Two truncated forms (Rrp5N and Rrp5C) together fully restore growth in vivo.","method":"In vitro RNA binding assays, DMS probing of RNA-protein interactions, quantitative affinity measurements with truncated protein fragments, complementation assays in yeast","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of RNA binding with mutagenesis/truncation analysis plus in vivo complementation, single lab with multiple orthogonal methods","pmids":["21233221"],"is_preprint":false},{"year":2013,"finding":"Rrp5 binds pre-rRNA at multiple sites in vivo: the C-terminal domain (CTD) crosslinks to sequences flanking cleavage site A2 and to snoRNAs U3, U14, snR30, and snR10 (required for A0-A2 cleavage), while the N-terminal domain (NTD) crosslinks to sequences flanking site A3 and to the RNA component of RNase MRP. Rrp5 depletion abolishes cotranscriptional cleavage and greatly reduces preribosome compaction.","method":"In vivo UV crosslinking and site identification, intramolecular complementation analysis, chromatin spreads (electron microscopy)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo UV crosslinking with nucleotide resolution, complementation genetics, and chromatin spread EM; multiple orthogonal methods; independently consistent with earlier genetic and biochemical data","pmids":["24239293"],"is_preprint":false},{"year":2016,"finding":"The DEAD-box protein Rok1, when ATP-bound, stabilizes Rrp5 binding to pre-40S ribosomes; ATP hydrolysis by Rok1 is required for release of Rrp5 from pre-40S ribosomes in vivo, allowing Rrp5 to subsequently participate in 60S subunit assembly. Rrp5 also interacts with the DEAD-box protein Has1, and blocking Rrp5 release from pre-40S subunits causes accumulation of snR30.","method":"In vivo and in vitro biochemical analyses; ATP vs ADP-bound Rok1 binding assays; co-immunoprecipitation; genetic experiments with inactivation mutants","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of ATP-dependent binding, in vivo genetic validation, multiple orthogonal methods in single rigorous study","pmids":["27280440"],"is_preprint":false},{"year":2018,"finding":"The crystal structure of the Rrp5 TPR (TetratricoPeptide Repeat) module was solved (PDB: 5NLG). In vitro assays demonstrated that the TPR region alone does not bind RNA, whereas the three S1 domains preceding the TPR module can associate with homopolymeric RNA. Association of Rrp5 constructs with several proposed interactors was tested in support of cryo-EM-based models.","method":"X-ray crystallography, in vitro RNA binding assays with domain deletion constructs, protein interaction assays","journal":"FEBS open bio","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination plus in vitro functional RNA binding assays with domain-specific constructs","pmids":["30338212"],"is_preprint":false},{"year":2019,"finding":"Rrp5 functions as a checkpoint coupling 40S and 60S ribosome assembly: early in transcription, Rrp5 blocks access of Rcl1 to the nascent rRNA, inhibiting pre-40S rRNA cleavage and separation of the two subunit precursors. Upon transcription of domain I of 25S rRNA, the 60S assembly factors Noc1/Noc2 bind both this RNA and Rrp5, altering Rrp5's RNA-binding mode to allow Rcl1-mediated pre-40S rRNA processing. Noc1 HEAT-repeat domain mutants deficient in subunit separation are rescued by overexpression of wild-type but not catalytically inactive Rcl1.","method":"Quantitative RNA binding assays, pre-rRNA cleavage assays, genetic epistasis (Noc1 mutants rescued by Rcl1 overexpression), in vivo co-immunoprecipitation","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro RNA binding and cleavage assays combined with genetic epistasis (mutant rescue), multiple orthogonal methods in single study","pmids":["31217256"],"is_preprint":false},{"year":2002,"finding":"High-dosage snR10 suppresses defects of a bipartite rrp5 allele in yeast; suppression does not restore cleavage at A2 but improves overall pre-rRNA processing rate and increases active ribosome levels, indicating a functional connection between snR10 and Rrp5 in ribosome biogenesis.","method":"Multicopy suppressor screen, phenotypic analysis (growth, temperature sensitivity), Northern blot analysis of pre-rRNA processing, polysome profiling","journal":"Molecular genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic suppressor analysis with molecular phenotype readouts, two orthogonal methods, single lab","pmids":["12242501"],"is_preprint":false},{"year":2005,"finding":"Human NFBP (PDCD11) physically interacts with HIV-1 Tat protein via Tat residues 37–48, and this interaction is modulated by RNA molecules. NFBP colocalizes with Tat in the nucleus and nucleoli. Functionally, NFBP augments TAR-dependent LTR activation by Tat in the absence of κB-binding sites, but interferes with the synergistic activation of LTR transcription by P65 and Tat together.","method":"Co-immunoprecipitation, immunofluorescence colocalization, domain mapping with deletion mutants, LTR reporter transcription assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping and functional reporter assays, single lab, two orthogonal methods","pmids":["15887232"],"is_preprint":false},{"year":2020,"finding":"In zebrafish, PDCD11 is required for microglia differentiation; pdcd11 deficiency prevents maturation of precursors to brain microglia while augmenting inflammatory macrophage brain colonization. Mechanistically, PDCD11 differentially regulates NF-κB family members: suppressing P65-mediated expression of inflammatory cytokines (e.g., tnfα) and enhancing c-Rel-dependent expression of tgfβ1.","method":"Zebrafish genetic loss-of-function (pdcd11 deficiency), immunofluorescence, transcriptional pathway analysis, cytokine expression assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish loss-of-function with defined cellular phenotype and pathway placement (NF-κB members), single lab, multiple readouts","pmids":["32709934"],"is_preprint":false},{"year":2022,"finding":"In Drosophila, Rrp5 (PDCD11 ortholog) localizes to the nucleolus and is required for pre-rRNA processing; depletion of Rok1 causes Rrp5 to become enriched in the core of the nucleolus, indicating that Rok1 is required for accurate subcellular localization of Rrp5 within the nucleolus and for its role in ITS1 and ITS2 rRNA processing.","method":"Genetics (rok1 mutant analysis), fluorescence in situ hybridization (FISH) for ITS1/ITS2 signals, immunofluorescence localization of Rrp5 in nucleolus","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with direct localization imaging and FISH for pre-rRNA processing, single lab, two orthogonal methods","pmids":["35628496"],"is_preprint":false},{"year":2025,"finding":"In p53-mutant breast and colon cancer cells, extra-nucleolar PDCD11 binds the transactivation domain (TAD) of C-MYC in the nucleoplasm, preventing SKP2 (an E3 ligase component and transcriptional target of C-MYC) from interacting with and ubiquitinating C-MYC, thereby stabilizing C-MYC and activating downstream signaling for G1/S transition, proliferation, and migration. PDCD11 silencing restores SKP2-mediated C-MYC degradation and suppresses tumor growth and metastasis in vivo.","method":"Co-immunoprecipitation, domain mapping of C-MYC TAD interaction, ubiquitination assays, PDCD11 knockdown with C-MYC stability and SKP2 interaction readouts, xenograft mouse tumor models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping plus ubiquitination assays and in vivo xenograft rescue, single lab, multiple orthogonal methods","pmids":["40051297"],"is_preprint":false},{"year":2025,"finding":"PDCD11 was identified as a carrier of HBV RNA/DNA into extracellular vesicles in HBV-infected HCC cells; depletion of PDCD11 reduced accumulation of HBV RNAs (pre-genomic RNA, HBx, HBc, HBs mRNAs) and intact virions in EVs. MRPL2 was found to interact with PDCD11 in the nucleus, where MRPL2 nuclear localization enhances intracellular calcium signaling through this interaction.","method":"ASO-mediated depletion of PDCD11, qRT-PCR for HBV RNAs in EVs, proteome profiling by LC-MS/MS, protein-protein interaction network analysis, nuclear localization assays","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, depletion assay with qRT-PCR readout for RNA packaging; MRPL2-PDCD11 nuclear interaction based on co-localization and network analysis without direct binding validation","pmids":["41425093"],"is_preprint":false}],"current_model":"PDCD11 (human homolog of yeast Rrp5) is a large multi-domain RNA-binding protein with 12 tandem S1 domains and a C-terminal TPR domain that resides in the nucleolus and functions as a central coordinator of ribosome biogenesis: its C-terminal domain binds pre-rRNA near cleavage site A2 and associates with U3/U14/snR30/snR10 snoRNAs to promote 18S rRNA maturation, while its N-terminal domain binds near site A3 and the RNase MRP RNA to enable 5.8S/28S rRNA synthesis; the DEAD-box helicase Rok1 regulates Rrp5/PDCD11 release from pre-40S ribosomes in an ATP hydrolysis-dependent manner to allow 60S assembly, and Noc1/Noc2 binding to nascent 25S rRNA repositions Rrp5 to license pre-40S processing, establishing Rrp5 as a checkpoint coupling the two ribosomal subunit assembly pathways; additionally, extra-nucleolar PDCD11 in cancer cells stabilizes C-MYC by blocking SKP2-mediated ubiquitination, and in zebrafish PDCD11 modulates microglia differentiation by differentially regulating NF-κB subunits P65 and c-Rel."},"narrative":{"mechanistic_narrative":"PDCD11 (the human homolog of yeast Rrp5) is a large multi-domain RNA-binding protein and a central coordinator of nucleolar ribosome biogenesis, uniquely required for both 18S rRNA maturation and 5.8S/28S rRNA synthesis [PMID:8896463, PMID:17654514]. Acting through 12 tandem S1 RNA-binding domains, it binds pre-rRNA at multiple sites: its C-terminal domain crosslinks to sequences flanking cleavage site A2 and to the U3, U14, snR30, and snR10 snoRNAs that direct A0–A2 cleavage, while its N-terminal domain binds near site A3 and the RNase MRP RNA component required for 5.8S/28S synthesis [PMID:21233221, PMID:24239293]. In humans it associates with the U3 snoRNP within an early 50S SSU processome intermediate before later subcomplexes join [PMID:17654514, PMID:19332556]. Mechanistically, Rrp5/PDCD11 functions as a checkpoint coupling the 40S and 60S assembly pathways: early in transcription it blocks Rcl1 access to nascent rRNA, and binding of the 60S factors Noc1/Noc2 to domain I of 25S rRNA alters its RNA-binding mode to license pre-40S cleavage, while ATP hydrolysis by the DEAD-box helicase Rok1 drives its release from pre-40S particles so it can join 60S assembly [PMID:27280440, PMID:31217256]. Beyond the nucleolus, extra-nucleolar PDCD11 in p53-mutant cancer cells binds the C-MYC transactivation domain to block SKP2-mediated ubiquitination, stabilizing C-MYC and promoting proliferation and metastasis [PMID:40051297], and in zebrafish it directs microglia differentiation by differentially regulating the NF-κB subunits P65 and c-Rel [PMID:32709934].","teleology":[{"year":1996,"claim":"Established that a single factor could be simultaneously required for the two divergent cleavage pathways of ribosome biogenesis, defining Rrp5 as a candidate coordinator linking 18S and 5.8S/28S synthesis.","evidence":"Genetic depletion of Rrp5p in S. cerevisiae with pre-rRNA processing analysis and a synthetic-lethality screen with snR10","pmids":["8896463"],"confidence":"High","gaps":["Molecular basis of dual-site requirement not resolved","Domain architecture responsible for each cleavage not mapped"]},{"year":2002,"claim":"Connected snR10 function to Rrp5 genetically, refining how snoRNA partners contribute to Rrp5-dependent processing efficiency rather than the A2 cleavage step itself.","evidence":"Multicopy suppressor screen with Northern and polysome readouts in yeast","pmids":["12242501"],"confidence":"Medium","gaps":["Suppression did not restore A2 cleavage, leaving the mechanism of rate improvement unclear","Physical Rrp5–snR10 contact not demonstrated here"]},{"year":2008,"claim":"Extended Rrp5 function to humans, showing PDCD11/NFBP is a nucleolar U3 snoRNA-associated factor required for 18S maturation, conserving the yeast role.","evidence":"Co-IP, immunofluorescence colocalization, and Northern analysis of pre-rRNA upon NFBP knockdown in human cells","pmids":["17654514"],"confidence":"High","gaps":["Direct vs indirect U3 association not distinguished","Role in 5.8S/28S synthesis in human cells not tested here"]},{"year":2009,"claim":"Placed human PDCD11 within a defined early assembly intermediate, showing it joins the U3 snoRNP and a 50S SSU processome before later subcomplexes assemble.","evidence":"Sucrose gradient sedimentation and co-IP with tUTP depletion in human cells","pmids":["19332556"],"confidence":"Medium","gaps":["Recruitment order inferred, not directly ordered","Single lab, complex membership not reconstituted"]},{"year":2011,"claim":"Resolved how the 12 tandem S1 domains partition labor, showing the first nine provide high-affinity non-specific binding and the last three confer pre-rRNA specificity, and that separable N/C fragments together support viability.","evidence":"In vitro RNA binding, DMS probing, truncation affinity measurements, and yeast complementation","pmids":["21233221"],"confidence":"High","gaps":["Structural basis of S1 specificity not solved here","How the two fragments coordinate in vivo unclear"]},{"year":2013,"claim":"Mapped Rrp5's two domains to distinct functional sites in vivo, explaining its dual role: the CTD contacts site A2 and A0–A2 snoRNAs while the NTD contacts site A3 and the RNase MRP RNA.","evidence":"In vivo UV crosslinking with nucleotide resolution, intramolecular complementation, and chromatin-spread EM","pmids":["24239293"],"confidence":"High","gaps":["Direct vs bridged contacts with snoRNAs/MRP RNA not fully separated","How compaction defect arises mechanistically not detailed"]},{"year":2016,"claim":"Identified the ATPase switch governing Rrp5 dynamics, showing Rok1 ATP hydrolysis releases Rrp5 from pre-40S particles to enable its 60S role.","evidence":"In vitro ATP/ADP-bound Rok1 binding assays, co-IP, and yeast genetics with inactivation mutants","pmids":["27280440"],"confidence":"High","gaps":["Structural detail of the Rok1–Rrp5 interface not resolved","How Has1 interaction contributes mechanistically unclear"]},{"year":2018,"claim":"Provided structural and biochemical dissection of the C-terminal region, showing the TPR module lacks RNA binding while preceding S1 domains bind RNA.","evidence":"X-ray crystallography (PDB 5NLG) and in vitro RNA binding with domain-deletion constructs","pmids":["30338212"],"confidence":"High","gaps":["Functional role of the TPR module not defined","Full-length structure on pre-ribosome not determined"]},{"year":2019,"claim":"Defined Rrp5 as a transcription-coupled checkpoint that couples the two subunit pathways, blocking Rcl1 access until Noc1/Noc2 binding of 25S domain I licenses pre-40S cleavage.","evidence":"Quantitative RNA binding and cleavage assays plus genetic epistasis (Noc1 mutants rescued by Rcl1 overexpression) and in vivo co-IP","pmids":["31217256"],"confidence":"High","gaps":["Conservation of this checkpoint logic in humans not shown","Structural transition of Rrp5 RNA-binding mode not visualized"]},{"year":2022,"claim":"Linked helicase activity to subnucleolar positioning, showing Rok1 is required for accurate intranucleolar localization of Rrp5 and for ITS1/ITS2 processing in Drosophila.","evidence":"rok1 mutant genetics, FISH for ITS1/ITS2, and immunofluorescence localization","pmids":["35628496"],"confidence":"Medium","gaps":["Direct cause of mislocalization not established","Relationship to the yeast release mechanism not connected experimentally"]},{"year":2005,"claim":"Revealed an early non-ribosomal activity, with NFBP/PDCD11 binding HIV-1 Tat and modulating LTR transcription, hinting at extra-nucleolar regulatory roles.","evidence":"Co-IP, colocalization, Tat domain mapping, and LTR reporter assays in human cells","pmids":["15887232"],"confidence":"Medium","gaps":["Physiological relevance to viral replication not established","Mechanism of differential LTR effects unclear"]},{"year":2020,"claim":"Demonstrated an organismal developmental role beyond ribosome biogenesis, with PDCD11 directing microglia differentiation through differential NF-κB subunit regulation.","evidence":"Zebrafish pdcd11 loss-of-function with immunofluorescence and cytokine/transcriptional readouts","pmids":["32709934"],"confidence":"Medium","gaps":["Direct molecular target linking PDCD11 to P65 vs c-Rel not identified","Conservation in mammalian microglia not tested"]},{"year":2025,"claim":"Defined a pro-oncogenic moonlighting function, with extra-nucleolar PDCD11 stabilizing C-MYC by shielding it from SKP2-mediated ubiquitination in p53-mutant cancers.","evidence":"Co-IP, C-MYC TAD domain mapping, ubiquitination assays, knockdown stability readouts, and xenograft tumor models","pmids":["40051297"],"confidence":"Medium","gaps":["How nucleolar vs nucleoplasmic PDCD11 partitioning is regulated unclear","Dependence on p53 status mechanistically undefined"]},{"year":2025,"claim":"Implicated PDCD11 in viral packaging into extracellular vesicles and a putative nuclear MRPL2 interaction affecting calcium signaling.","evidence":"ASO depletion with qRT-PCR for HBV RNAs in EVs, LC-MS/MS proteomics, and interaction network/localization analysis","pmids":["41425093"],"confidence":"Low","gaps":["MRPL2–PDCD11 interaction based on colocalization/network analysis without direct binding validation","Mechanism of HBV RNA loading into EVs not established","Not independently confirmed"]},{"year":null,"claim":"How the conserved ribosome-assembly machine is repurposed for extra-nucleolar functions, and what governs PDCD11's partitioning between the nucleolus and nucleoplasm, remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length human PDCD11 on a pre-ribosome","Regulatory cues directing PDCD11 to non-ribosomal substrates (C-MYC, NF-κB) unknown","Human relevance of yeast Noc1/Noc2/Rok1 checkpoint not directly tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,3,4,6]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1,2,11]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,4,7]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,5]}],"complexes":["SSU processome / U3 snoRNP","RNase MRP (RNA association)"],"partners":["ROK1","HAS1","NOC1","NOC2","MYC","SKP2","U3 SNORNA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14690","full_name":"Protein RRP5 homolog","aliases":["NF-kappa-B-binding protein","NFBP","Programmed cell death protein 11"],"length_aa":1871,"mass_kda":208.7,"function":"Essential for the generation of mature 18S rRNA, specifically necessary for cleavages at sites A0, 1 and 2 of the 47S precursor. Directly interacts with U3 snoRNA Involved in the biogenesis of rRNA","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q14690/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PDCD11","classification":"Common Essential","n_dependent_lines":1200,"n_total_lines":1208,"dependency_fraction":0.9933774834437086},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000148843","cell_line_id":"CID001098","localizations":[{"compartment":"nucleolus_gc","grade":3}],"interactors":[{"gene":"PKN2","stoichiometry":10.0},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001098","total_profiled":1310},"omim":[{"mim_id":"612333","title":"PROGRAMMED CELL DEATH 11; PDCD11","url":"https://www.omim.org/entry/612333"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli rim","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PDCD11"},"hgnc":{"alias_symbol":["KIAA0185","ALG-4","RRP5","NFBP"],"prev_symbol":[]},"alphafold":{"accession":"Q14690","domains":[{"cath_id":"2.40.50.140","chopping":"74-171","consensus_level":"medium","plddt":83.487,"start":74,"end":171},{"cath_id":"2.40.50.140","chopping":"548-613","consensus_level":"medium","plddt":87.5323,"start":548,"end":613},{"cath_id":"2.40.50.140","chopping":"638-803","consensus_level":"medium","plddt":86.7257,"start":638,"end":803},{"cath_id":"2.40.50.140","chopping":"808-996","consensus_level":"medium","plddt":82.9262,"start":808,"end":996},{"cath_id":"2.40.50.140","chopping":"1140-1226","consensus_level":"medium","plddt":82.761,"start":1140,"end":1226},{"cath_id":"2.40.50.140","chopping":"1316-1406","consensus_level":"medium","plddt":81.7176,"start":1316,"end":1406},{"cath_id":"1.25.40,1.25.40","chopping":"1532-1544_1603-1688","consensus_level":"medium","plddt":81.8459,"start":1532,"end":1688}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14690","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14690-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14690-F1-predicted_aligned_error_v6.png","plddt_mean":74.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDCD11","jax_strain_url":"https://www.jax.org/strain/search?query=PDCD11"},"sequence":{"accession":"Q14690","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14690.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14690/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14690"}},"corpus_meta":[{"pmid":"20133686","id":"PMC_20133686","title":"Argonautes ALG-3 and ALG-4 are required for spermatogenesis-specific 26G-RNAs and thermotolerant sperm in Caenorhabditis elegans.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20133686","citation_count":186,"is_preprint":false},{"pmid":"8896463","id":"PMC_8896463","title":"RRP5 is required for formation of both 18S and 5.8S rRNA in yeast.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8896463","citation_count":135,"is_preprint":false},{"pmid":"24239293","id":"PMC_24239293","title":"Rrp5 binding at multiple sites coordinates pre-rRNA processing and assembly.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24239293","citation_count":62,"is_preprint":false},{"pmid":"19332556","id":"PMC_19332556","title":"A novel small-subunit processome assembly intermediate that contains the U3 snoRNP, nucleolin, RRP5, and DBP4.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19332556","citation_count":59,"is_preprint":false},{"pmid":"34420029","id":"PMC_34420029","title":"CircRNA circ-PDCD11 promotes triple-negative breast cancer progression via enhancing aerobic glycolysis.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34420029","citation_count":41,"is_preprint":false},{"pmid":"27280440","id":"PMC_27280440","title":"The DEAD-box Protein Rok1 Orchestrates 40S and 60S Ribosome Assembly by Promoting the Release of Rrp5 from Pre-40S Ribosomes to Allow for 60S Maturation.","date":"2016","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/27280440","citation_count":38,"is_preprint":false},{"pmid":"14551810","id":"PMC_14551810","title":"Kinetics and mechanism of iron release from the bacterial ferric binding protein nFbp: exogenous anion influence and comparison with mammalian transferrin.","date":"2003","source":"Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14551810","citation_count":24,"is_preprint":false},{"pmid":"21233221","id":"PMC_21233221","title":"The roles of S1 RNA-binding domains in Rrp5's interactions with pre-rRNA.","date":"2011","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21233221","citation_count":22,"is_preprint":false},{"pmid":"29507658","id":"PMC_29507658","title":"Elevation of autoantibody level against PDCD11 in patients with transient ischemic attack.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29507658","citation_count":21,"is_preprint":false},{"pmid":"17654514","id":"PMC_17654514","title":"Evidence for involvement of NFBP in processing of ribosomal RNA.","date":"2008","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17654514","citation_count":15,"is_preprint":false},{"pmid":"15887232","id":"PMC_15887232","title":"Interplay between NFBP and NF-kappaB modulates tat activation of the LTR.","date":"2005","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15887232","citation_count":15,"is_preprint":false},{"pmid":"31217256","id":"PMC_31217256","title":"Rrp5 establishes a checkpoint for 60S assembly during 40S maturation.","date":"2019","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/31217256","citation_count":14,"is_preprint":false},{"pmid":"32709934","id":"PMC_32709934","title":"Yolk sac-derived Pdcd11-positive cells modulate zebrafish microglia differentiation through the NF-κB-Tgfβ1 pathway.","date":"2020","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/32709934","citation_count":13,"is_preprint":false},{"pmid":"40051297","id":"PMC_40051297","title":"PDCD11 Stabilizes C-MYC Oncoprotein by Hindering C-MYC-SKP2 Negative Feedback Loop to Facilitate Progression of p53-Mutant Breast and Colon Malignancies.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40051297","citation_count":7,"is_preprint":false},{"pmid":"28657695","id":"PMC_28657695","title":"Rare PDCD11 variations are not associated with risk of schizophrenia in Japan.","date":"2017","source":"Psychiatry and clinical neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/28657695","citation_count":7,"is_preprint":false},{"pmid":"34549171","id":"PMC_34549171","title":"Meiotic H3K9me2 distribution is influenced by the ALG-3 and ALG-4 pathway and by poly(U) polymerase activity.","date":"2021","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/34549171","citation_count":6,"is_preprint":false},{"pmid":"12242501","id":"PMC_12242501","title":"High dosage of the small nucleolar RNA snR10 specifically suppresses defects of a yeast rrp5 mutant.","date":"2002","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/12242501","citation_count":5,"is_preprint":false},{"pmid":"30338212","id":"PMC_30338212","title":"Structural and interaction analysis of the Rrp5 C-terminal region.","date":"2018","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/30338212","citation_count":3,"is_preprint":false},{"pmid":"41558196","id":"PMC_41558196","title":"Lometrexol targets MRPL2 to suppress NSCLC via dual regulation of mitochondrial ribosomal activity and nuclear PDCD11/ Ca2+ signaling.","date":"2026","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41558196","citation_count":2,"is_preprint":false},{"pmid":"35628496","id":"PMC_35628496","title":"The DEAD-Box Protein Rok1 Coordinates Ribosomal RNA Processing in Association with Rrp5 in Drosophila.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35628496","citation_count":1,"is_preprint":false},{"pmid":"41425093","id":"PMC_41425093","title":"Proteome profiling of extracellular vesicles-derived from hepatitis B virus-infected hepatocellular carcinoma cell lines identifies PDCD11 as a carrier of viral RNAs.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/41425093","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12251,"output_tokens":4157,"usd":0.049554,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11965,"output_tokens":4328,"usd":0.084013,"stage2_stop_reason":"end_turn"},"total_usd":0.133567,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"RRP5 (yeast ortholog of PDCD11) is essential for pre-rRNA processing at sites A0, A1, and A2 (required for 18S rRNA synthesis) and at site A3 (required for the major short form of 5.8S rRNA synthesis), making it the first cellular component simultaneously required for both snoRNP-dependent and RNase MRP-dependent cleavage events in ribosome biogenesis.\",\n      \"method\": \"Genetic depletion of Rrp5p in S. cerevisiae followed by pre-rRNA processing analysis; synthetic lethality screen with snR10 deletion\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic depletion with defined molecular phenotype, multiple pre-rRNA processing sites analyzed, replicated by multiple subsequent studies\",\n      \"pmids\": [\"8896463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human NFBP (PDCD11) colocalizes with and co-precipitates U3 snoRNA in the nucleolus, and is essential for 18S rRNA maturation via cleavages at sites A0, 1, and 2, as demonstrated by accumulation of unprocessed rRNA intermediates upon NFBP knockdown.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, Northern blot analysis of pre-rRNA processing upon NFBP depletion\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and localization plus loss-of-function with specific molecular phenotype (rRNA processing defect), two orthogonal methods\",\n      \"pmids\": [\"17654514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human RRP5 (PDCD11) associates with the U3 snoRNP as part of a 50S SSU processome assembly intermediate, together with nucleolin and DBP4, and is likely recruited to pre-rRNA through RNA-binding activity to form this intermediate before tUTP, bUTP, MPP10 and BMS1/RCL1 subcomplexes join.\",\n      \"method\": \"Sucrose gradient sedimentation, co-immunoprecipitation, depletion of tUTP proteins to accumulate intermediate complex\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and sedimentation identifying complex membership, single lab, two orthogonal methods\",\n      \"pmids\": [\"19332556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Yeast Rrp5 binds pre-rRNA at three distinct regions within ITS1 using its 12 tandem S1 RNA-binding domains; the first nine S1 motifs contribute high-affinity but non-specific RNA binding, while the last three S1 domains provide specificity for pre-rRNA. Two truncated forms (Rrp5N and Rrp5C) together fully restore growth in vivo.\",\n      \"method\": \"In vitro RNA binding assays, DMS probing of RNA-protein interactions, quantitative affinity measurements with truncated protein fragments, complementation assays in yeast\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of RNA binding with mutagenesis/truncation analysis plus in vivo complementation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21233221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rrp5 binds pre-rRNA at multiple sites in vivo: the C-terminal domain (CTD) crosslinks to sequences flanking cleavage site A2 and to snoRNAs U3, U14, snR30, and snR10 (required for A0-A2 cleavage), while the N-terminal domain (NTD) crosslinks to sequences flanking site A3 and to the RNA component of RNase MRP. Rrp5 depletion abolishes cotranscriptional cleavage and greatly reduces preribosome compaction.\",\n      \"method\": \"In vivo UV crosslinking and site identification, intramolecular complementation analysis, chromatin spreads (electron microscopy)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo UV crosslinking with nucleotide resolution, complementation genetics, and chromatin spread EM; multiple orthogonal methods; independently consistent with earlier genetic and biochemical data\",\n      \"pmids\": [\"24239293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The DEAD-box protein Rok1, when ATP-bound, stabilizes Rrp5 binding to pre-40S ribosomes; ATP hydrolysis by Rok1 is required for release of Rrp5 from pre-40S ribosomes in vivo, allowing Rrp5 to subsequently participate in 60S subunit assembly. Rrp5 also interacts with the DEAD-box protein Has1, and blocking Rrp5 release from pre-40S subunits causes accumulation of snR30.\",\n      \"method\": \"In vivo and in vitro biochemical analyses; ATP vs ADP-bound Rok1 binding assays; co-immunoprecipitation; genetic experiments with inactivation mutants\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ATP-dependent binding, in vivo genetic validation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"27280440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The crystal structure of the Rrp5 TPR (TetratricoPeptide Repeat) module was solved (PDB: 5NLG). In vitro assays demonstrated that the TPR region alone does not bind RNA, whereas the three S1 domains preceding the TPR module can associate with homopolymeric RNA. Association of Rrp5 constructs with several proposed interactors was tested in support of cryo-EM-based models.\",\n      \"method\": \"X-ray crystallography, in vitro RNA binding assays with domain deletion constructs, protein interaction assays\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination plus in vitro functional RNA binding assays with domain-specific constructs\",\n      \"pmids\": [\"30338212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rrp5 functions as a checkpoint coupling 40S and 60S ribosome assembly: early in transcription, Rrp5 blocks access of Rcl1 to the nascent rRNA, inhibiting pre-40S rRNA cleavage and separation of the two subunit precursors. Upon transcription of domain I of 25S rRNA, the 60S assembly factors Noc1/Noc2 bind both this RNA and Rrp5, altering Rrp5's RNA-binding mode to allow Rcl1-mediated pre-40S rRNA processing. Noc1 HEAT-repeat domain mutants deficient in subunit separation are rescued by overexpression of wild-type but not catalytically inactive Rcl1.\",\n      \"method\": \"Quantitative RNA binding assays, pre-rRNA cleavage assays, genetic epistasis (Noc1 mutants rescued by Rcl1 overexpression), in vivo co-immunoprecipitation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro RNA binding and cleavage assays combined with genetic epistasis (mutant rescue), multiple orthogonal methods in single study\",\n      \"pmids\": [\"31217256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"High-dosage snR10 suppresses defects of a bipartite rrp5 allele in yeast; suppression does not restore cleavage at A2 but improves overall pre-rRNA processing rate and increases active ribosome levels, indicating a functional connection between snR10 and Rrp5 in ribosome biogenesis.\",\n      \"method\": \"Multicopy suppressor screen, phenotypic analysis (growth, temperature sensitivity), Northern blot analysis of pre-rRNA processing, polysome profiling\",\n      \"journal\": \"Molecular genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic suppressor analysis with molecular phenotype readouts, two orthogonal methods, single lab\",\n      \"pmids\": [\"12242501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human NFBP (PDCD11) physically interacts with HIV-1 Tat protein via Tat residues 37–48, and this interaction is modulated by RNA molecules. NFBP colocalizes with Tat in the nucleus and nucleoli. Functionally, NFBP augments TAR-dependent LTR activation by Tat in the absence of κB-binding sites, but interferes with the synergistic activation of LTR transcription by P65 and Tat together.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, domain mapping with deletion mutants, LTR reporter transcription assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping and functional reporter assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"15887232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In zebrafish, PDCD11 is required for microglia differentiation; pdcd11 deficiency prevents maturation of precursors to brain microglia while augmenting inflammatory macrophage brain colonization. Mechanistically, PDCD11 differentially regulates NF-κB family members: suppressing P65-mediated expression of inflammatory cytokines (e.g., tnfα) and enhancing c-Rel-dependent expression of tgfβ1.\",\n      \"method\": \"Zebrafish genetic loss-of-function (pdcd11 deficiency), immunofluorescence, transcriptional pathway analysis, cytokine expression assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish loss-of-function with defined cellular phenotype and pathway placement (NF-κB members), single lab, multiple readouts\",\n      \"pmids\": [\"32709934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Drosophila, Rrp5 (PDCD11 ortholog) localizes to the nucleolus and is required for pre-rRNA processing; depletion of Rok1 causes Rrp5 to become enriched in the core of the nucleolus, indicating that Rok1 is required for accurate subcellular localization of Rrp5 within the nucleolus and for its role in ITS1 and ITS2 rRNA processing.\",\n      \"method\": \"Genetics (rok1 mutant analysis), fluorescence in situ hybridization (FISH) for ITS1/ITS2 signals, immunofluorescence localization of Rrp5 in nucleolus\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with direct localization imaging and FISH for pre-rRNA processing, single lab, two orthogonal methods\",\n      \"pmids\": [\"35628496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In p53-mutant breast and colon cancer cells, extra-nucleolar PDCD11 binds the transactivation domain (TAD) of C-MYC in the nucleoplasm, preventing SKP2 (an E3 ligase component and transcriptional target of C-MYC) from interacting with and ubiquitinating C-MYC, thereby stabilizing C-MYC and activating downstream signaling for G1/S transition, proliferation, and migration. PDCD11 silencing restores SKP2-mediated C-MYC degradation and suppresses tumor growth and metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping of C-MYC TAD interaction, ubiquitination assays, PDCD11 knockdown with C-MYC stability and SKP2 interaction readouts, xenograft mouse tumor models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping plus ubiquitination assays and in vivo xenograft rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40051297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PDCD11 was identified as a carrier of HBV RNA/DNA into extracellular vesicles in HBV-infected HCC cells; depletion of PDCD11 reduced accumulation of HBV RNAs (pre-genomic RNA, HBx, HBc, HBs mRNAs) and intact virions in EVs. MRPL2 was found to interact with PDCD11 in the nucleus, where MRPL2 nuclear localization enhances intracellular calcium signaling through this interaction.\",\n      \"method\": \"ASO-mediated depletion of PDCD11, qRT-PCR for HBV RNAs in EVs, proteome profiling by LC-MS/MS, protein-protein interaction network analysis, nuclear localization assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, depletion assay with qRT-PCR readout for RNA packaging; MRPL2-PDCD11 nuclear interaction based on co-localization and network analysis without direct binding validation\",\n      \"pmids\": [\"41425093\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDCD11 (human homolog of yeast Rrp5) is a large multi-domain RNA-binding protein with 12 tandem S1 domains and a C-terminal TPR domain that resides in the nucleolus and functions as a central coordinator of ribosome biogenesis: its C-terminal domain binds pre-rRNA near cleavage site A2 and associates with U3/U14/snR30/snR10 snoRNAs to promote 18S rRNA maturation, while its N-terminal domain binds near site A3 and the RNase MRP RNA to enable 5.8S/28S rRNA synthesis; the DEAD-box helicase Rok1 regulates Rrp5/PDCD11 release from pre-40S ribosomes in an ATP hydrolysis-dependent manner to allow 60S assembly, and Noc1/Noc2 binding to nascent 25S rRNA repositions Rrp5 to license pre-40S processing, establishing Rrp5 as a checkpoint coupling the two ribosomal subunit assembly pathways; additionally, extra-nucleolar PDCD11 in cancer cells stabilizes C-MYC by blocking SKP2-mediated ubiquitination, and in zebrafish PDCD11 modulates microglia differentiation by differentially regulating NF-κB subunits P65 and c-Rel.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDCD11 (the human homolog of yeast Rrp5) is a large multi-domain RNA-binding protein and a central coordinator of nucleolar ribosome biogenesis, uniquely required for both 18S rRNA maturation and 5.8S/28S rRNA synthesis [#0, #1]. Acting through 12 tandem S1 RNA-binding domains, it binds pre-rRNA at multiple sites: its C-terminal domain crosslinks to sequences flanking cleavage site A2 and to the U3, U14, snR30, and snR10 snoRNAs that direct A0–A2 cleavage, while its N-terminal domain binds near site A3 and the RNase MRP RNA component required for 5.8S/28S synthesis [#3, #4]. In humans it associates with the U3 snoRNP within an early 50S SSU processome intermediate before later subcomplexes join [#1, #2]. Mechanistically, Rrp5/PDCD11 functions as a checkpoint coupling the 40S and 60S assembly pathways: early in transcription it blocks Rcl1 access to nascent rRNA, and binding of the 60S factors Noc1/Noc2 to domain I of 25S rRNA alters its RNA-binding mode to license pre-40S cleavage, while ATP hydrolysis by the DEAD-box helicase Rok1 drives its release from pre-40S particles so it can join 60S assembly [#5, #7]. Beyond the nucleolus, extra-nucleolar PDCD11 in p53-mutant cancer cells binds the C-MYC transactivation domain to block SKP2-mediated ubiquitination, stabilizing C-MYC and promoting proliferation and metastasis [#12], and in zebrafish it directs microglia differentiation by differentially regulating the NF-\\u03baB subunits P65 and c-Rel [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that a single factor could be simultaneously required for the two divergent cleavage pathways of ribosome biogenesis, defining Rrp5 as a candidate coordinator linking 18S and 5.8S/28S synthesis.\",\n      \"evidence\": \"Genetic depletion of Rrp5p in S. cerevisiae with pre-rRNA processing analysis and a synthetic-lethality screen with snR10\",\n      \"pmids\": [\"8896463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of dual-site requirement not resolved\", \"Domain architecture responsible for each cleavage not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected snR10 function to Rrp5 genetically, refining how snoRNA partners contribute to Rrp5-dependent processing efficiency rather than the A2 cleavage step itself.\",\n      \"evidence\": \"Multicopy suppressor screen with Northern and polysome readouts in yeast\",\n      \"pmids\": [\"12242501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Suppression did not restore A2 cleavage, leaving the mechanism of rate improvement unclear\", \"Physical Rrp5\\u2013snR10 contact not demonstrated here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended Rrp5 function to humans, showing PDCD11/NFBP is a nucleolar U3 snoRNA-associated factor required for 18S maturation, conserving the yeast role.\",\n      \"evidence\": \"Co-IP, immunofluorescence colocalization, and Northern analysis of pre-rRNA upon NFBP knockdown in human cells\",\n      \"pmids\": [\"17654514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect U3 association not distinguished\", \"Role in 5.8S/28S synthesis in human cells not tested here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed human PDCD11 within a defined early assembly intermediate, showing it joins the U3 snoRNP and a 50S SSU processome before later subcomplexes assemble.\",\n      \"evidence\": \"Sucrose gradient sedimentation and co-IP with tUTP depletion in human cells\",\n      \"pmids\": [\"19332556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recruitment order inferred, not directly ordered\", \"Single lab, complex membership not reconstituted\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how the 12 tandem S1 domains partition labor, showing the first nine provide high-affinity non-specific binding and the last three confer pre-rRNA specificity, and that separable N/C fragments together support viability.\",\n      \"evidence\": \"In vitro RNA binding, DMS probing, truncation affinity measurements, and yeast complementation\",\n      \"pmids\": [\"21233221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of S1 specificity not solved here\", \"How the two fragments coordinate in vivo unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped Rrp5's two domains to distinct functional sites in vivo, explaining its dual role: the CTD contacts site A2 and A0\\u2013A2 snoRNAs while the NTD contacts site A3 and the RNase MRP RNA.\",\n      \"evidence\": \"In vivo UV crosslinking with nucleotide resolution, intramolecular complementation, and chromatin-spread EM\",\n      \"pmids\": [\"24239293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs bridged contacts with snoRNAs/MRP RNA not fully separated\", \"How compaction defect arises mechanistically not detailed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the ATPase switch governing Rrp5 dynamics, showing Rok1 ATP hydrolysis releases Rrp5 from pre-40S particles to enable its 60S role.\",\n      \"evidence\": \"In vitro ATP/ADP-bound Rok1 binding assays, co-IP, and yeast genetics with inactivation mutants\",\n      \"pmids\": [\"27280440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the Rok1\\u2013Rrp5 interface not resolved\", \"How Has1 interaction contributes mechanistically unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided structural and biochemical dissection of the C-terminal region, showing the TPR module lacks RNA binding while preceding S1 domains bind RNA.\",\n      \"evidence\": \"X-ray crystallography (PDB 5NLG) and in vitro RNA binding with domain-deletion constructs\",\n      \"pmids\": [\"30338212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of the TPR module not defined\", \"Full-length structure on pre-ribosome not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined Rrp5 as a transcription-coupled checkpoint that couples the two subunit pathways, blocking Rcl1 access until Noc1/Noc2 binding of 25S domain I licenses pre-40S cleavage.\",\n      \"evidence\": \"Quantitative RNA binding and cleavage assays plus genetic epistasis (Noc1 mutants rescued by Rcl1 overexpression) and in vivo co-IP\",\n      \"pmids\": [\"31217256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of this checkpoint logic in humans not shown\", \"Structural transition of Rrp5 RNA-binding mode not visualized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked helicase activity to subnucleolar positioning, showing Rok1 is required for accurate intranucleolar localization of Rrp5 and for ITS1/ITS2 processing in Drosophila.\",\n      \"evidence\": \"rok1 mutant genetics, FISH for ITS1/ITS2, and immunofluorescence localization\",\n      \"pmids\": [\"35628496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cause of mislocalization not established\", \"Relationship to the yeast release mechanism not connected experimentally\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed an early non-ribosomal activity, with NFBP/PDCD11 binding HIV-1 Tat and modulating LTR transcription, hinting at extra-nucleolar regulatory roles.\",\n      \"evidence\": \"Co-IP, colocalization, Tat domain mapping, and LTR reporter assays in human cells\",\n      \"pmids\": [\"15887232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance to viral replication not established\", \"Mechanism of differential LTR effects unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated an organismal developmental role beyond ribosome biogenesis, with PDCD11 directing microglia differentiation through differential NF-\\u03baB subunit regulation.\",\n      \"evidence\": \"Zebrafish pdcd11 loss-of-function with immunofluorescence and cytokine/transcriptional readouts\",\n      \"pmids\": [\"32709934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target linking PDCD11 to P65 vs c-Rel not identified\", \"Conservation in mammalian microglia not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a pro-oncogenic moonlighting function, with extra-nucleolar PDCD11 stabilizing C-MYC by shielding it from SKP2-mediated ubiquitination in p53-mutant cancers.\",\n      \"evidence\": \"Co-IP, C-MYC TAD domain mapping, ubiquitination assays, knockdown stability readouts, and xenograft tumor models\",\n      \"pmids\": [\"40051297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How nucleolar vs nucleoplasmic PDCD11 partitioning is regulated unclear\", \"Dependence on p53 status mechanistically undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated PDCD11 in viral packaging into extracellular vesicles and a putative nuclear MRPL2 interaction affecting calcium signaling.\",\n      \"evidence\": \"ASO depletion with qRT-PCR for HBV RNAs in EVs, LC-MS/MS proteomics, and interaction network/localization analysis\",\n      \"pmids\": [\"41425093\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"MRPL2\\u2013PDCD11 interaction based on colocalization/network analysis without direct binding validation\", \"Mechanism of HBV RNA loading into EVs not established\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the conserved ribosome-assembly machine is repurposed for extra-nucleolar functions, and what governs PDCD11's partitioning between the nucleolus and nucleoplasm, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length human PDCD11 on a pre-ribosome\", \"Regulatory cues directing PDCD11 to non-ribosomal substrates (C-MYC, NF-\\u03baB) unknown\", \"Human relevance of yeast Noc1/Noc2/Rok1 checkpoint not directly tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 3, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 4, 7]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"complexes\": [\"SSU processome / U3 snoRNP\", \"RNase MRP (RNA association)\"],\n    \"partners\": [\"Rok1\", \"Has1\", \"Noc1\", \"Noc2\", \"MYC\", \"SKP2\", \"U3 snoRNA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}