{"gene":"PES1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2004,"finding":"Pes1 (mouse homolog of zebrafish Pescadillo/yeast Nop7p) physically interacts with the nucleolar protein Bop1; both proteins direct common pre-rRNA processing steps (maturation of 28S and 5.8S rRNAs); interaction with Bop1 is essential for efficient incorporation of Pes1 into nucleolar preribosomal complexes; Pes1 mutants defective for Bop1 interaction lose the ability to affect rRNA maturation and cell cycle arrest.","method":"Transposon-derived dominant mutants, co-immunoprecipitation, rRNA processing assays, cell cycle analysis, sucrose gradient fractionation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional mutant analysis plus rRNA processing assays in a single focused study; foundational mechanistic paper replicated by subsequent work","pmids":["15225545"],"is_preprint":false},{"year":2005,"finding":"Pes1 and Bop1 form a stable trimeric complex with a novel WD40 repeat protein, WDR12 (PeBoW complex). Endogenous WDR12 is required for processing of 32S precursor rRNA and cell proliferation. A dominant-negative WDR12 mutant blocks rRNA processing and induces p53 accumulation in a p19ARF-independent manner in proliferating but not quiescent cells.","method":"Co-immunoprecipitation, conditional dominant-negative expression, rRNA processing assays, p53/p19ARF genetic analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying trimeric complex, functional rRNA and cell-cycle assays, multiple orthogonal methods, replicated by subsequent studies","pmids":["16043514"],"is_preprint":false},{"year":2006,"finding":"Dominant-negative Pes1 deletion mutants (N- and C-terminal truncations) incorporate into the PeBoW complex, block processing of 36S/32S precursors to mature 28S rRNA, inhibit cell proliferation, and induce high p53 levels in proliferating but not resting cells. The dominant-negative effect requires proper incorporation into the PeBoW complex.","method":"Deletion mutant expression, co-immunoprecipitation with Bop1/WDR12, nucleolar localization by immunofluorescence, rRNA processing assays, p53 western blot","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple deletion mutants, Co-IP, rRNA assays, p53 measurements; mechanistically confirms PeBoW complex requirement","pmids":["16738141"],"is_preprint":false},{"year":2007,"finding":"Recombinant expression of Pes1, Bop1, and WDR12 is sufficient for PeBoW complex formation. Bop1 is the integral/central component: knockdown of Bop1 abolishes co-purification of Pes1 with WDR12; transport of Bop1 from cytoplasm to nucleolus is Pes1-dependent, while Pes1 migrates to the nucleolus and associates with preribosomal particles independently of Bop1. Overexpression of Bop1 (but not WDR12 or Pes1 alone) inhibits cell proliferation and rRNA processing.","method":"Recombinant complex reconstitution, siRNA knockdown, immunofluorescence, cell fractionation, sucrose gradient centrifugation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution of trimeric complex, knockdown epistasis, multiple orthogonal localization and functional assays","pmids":["17353269"],"is_preprint":false},{"year":2006,"finding":"The BRCT domain of mammalian Pes1 is required for nucleolar localization and rRNA processing. Deletion of the BRCT domain or point mutations of conserved residues cause diffuse nucleoplasmic distribution, failure to rescue rRNA processing in Pes1-knockdown cells, reduced protein stability, and loss of incorporation into the PeBoW complex.","method":"siRNA-based knock-down/knock-in system, Pes1 truncation and point mutants, immunofluorescence, rRNA processing assays, co-immunoprecipitation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis combined with knockdown-rescue, Co-IP, localization, and rRNA functional assays in one study","pmids":["17189298"],"is_preprint":false},{"year":2000,"finding":"Murine Pes1 encodes a nuclear protein containing a BRCT domain; recombinant Pes1 expressed in HepG2 cells localizes to the nucleus.","method":"Genomic cloning, sequence analysis, recombinant protein expression, subcellular localization by microscopy","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment, single lab, single method for localization; sequence analysis for domain identification","pmids":["11112348"],"is_preprint":false},{"year":2005,"finding":"In yeast, the Nop7 subcomplex (Nop7/Erb1/Ytm1, orthologs of Pes1/Bop1/WDR12) is present in four consecutive 66S preribosomes; Ytm1 binds directly to Erb1 and is present in a heterotrimeric subcomplex with Erb1 and Nop7 both within and independently of preribosomes; Nop7 and Erb1 assemble into preribosomes prior to Ytm1; mutations in WD40 motifs of Ytm1 disrupt binding to Erb1, destabilize the heterotrimer, and delay pre-rRNA processing and nuclear export.","method":"Affinity purification, co-immunoprecipitation, pre-rRNA processing assays, nuclear export assays, WD40 mutant analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast ortholog study with reciprocal Co-IP, mutant analysis, rRNA processing, and export assays; multiple orthogonal methods in a focused study","pmids":["16287855"],"is_preprint":false},{"year":2008,"finding":"In yeast, Ytm1, Erb1, and Nop7 (orthologs of WDR12, Bop1, Pes1) assemble into preribosomes interdependently; specific domains within each protein are necessary for interaction and sufficient for preribosome recruitment; dominant-negative truncations of each protein impair growth and ribosome biogenesis.","method":"Domain truncation analysis, co-immunoprecipitation, dominant-negative overexpression, ribosome biogenesis assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic domain mapping with Co-IP, dominant-negative genetics, and functional ribosome assays in yeast ortholog system","pmids":["18448671"],"is_preprint":false},{"year":2007,"finding":"Light chain 1 of microtubule-associated protein 1B (Mtap1b-LC1) interacts with the BRCT domain of Pes1; overexpression of Mtap1b-LC1 relocalizes Pes1 from the nucleus/nucleolus to the cytoplasm, reduces nuclear Pes1 levels, and inhibits cell proliferation—phenocopying Pes1 depletion.","method":"Yeast two-hybrid screen, co-immunoprecipitation, deletion analysis, immunofluorescence, cell proliferation assay, shRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, domain mapping, and localization with functional consequence; single lab but multiple orthogonal methods","pmids":["17308336"],"is_preprint":false},{"year":2009,"finding":"Nucleolar protein B23 (nucleophosmin) physically interacts with PES1; knockdown of B23 by RNAi increases nucleoplasmic distribution of PES1, indicating B23 is involved in the nucleolar localization of PES1.","method":"Co-immunoprecipitation of endogenous proteins, in vitro pulldown domain mapping, immunofluorescence colocalization, siRNA knockdown","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — endogenous Co-IP plus pulldown plus knockdown localization effect; single lab, two orthogonal methods","pmids":["20011973"],"is_preprint":false},{"year":2012,"finding":"PES1 differentially regulates ERα and ERβ: it enhances ERα transcriptional activity while inhibiting ERβ transcriptional activity; increases ERα protein stability and decreases ERβ protein stability via the ubiquitin-proteasome pathway mediated by CHIP (carboxyl terminus of Hsc70-interacting protein); PES1 transforms normal mammary epithelial cells and is required for estrogen-induced breast tumor growth in nude mice.","method":"Transcriptional reporter assays, co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, knockdown/overexpression, cell transformation assay, xenograft tumor model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assays, Co-IP, ubiquitination, proteasome inhibition, in vivo tumor model) in a single focused study","pmids":["22820289"],"is_preprint":false},{"year":2016,"finding":"PES1 is SUMOylated by SUMO-1, SUMO-2, and SUMO-3; the major SUMOylation site is K517 in the C-terminal Glu-rich domain; SUMOylation is stimulated by estrogen; SUMOylation stabilizes PES1 by inhibiting its ubiquitination; SUMOylated PES1 enhances ERα stability and ERα-mediated transcription, increases S-phase fraction, and promotes breast cancer cell proliferation.","method":"SUMOylation assays, site-directed mutagenesis (K517R), ubiquitination assays, estrogen treatment, reporter assays, cell cycle analysis, xenograft model","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — SUMOylation site mutagenesis confirmed by multiple assays (SUMO, ubiquitin, transcription, proliferation); single lab but orthogonal methods","pmids":["27409667"],"is_preprint":false},{"year":2019,"finding":"PES1 forms a complex with telomerase reverse transcriptase (TERT) and telomerase RNA (TR) through direct interaction with TERT; PES1 facilitates telomerase assembly by promoting direct interaction between TERT and TR without affecting their expression levels; PES1 does not interact with previously reported telomerase components Reptin, Pontin, p23, or Hsp90; depletion of PES1 reduces telomerase activity, leads to telomere shortening, and induces cellular senescence.","method":"Co-immunoprecipitation, direct interaction assays, telomerase activity assays (TRAP), telomere length measurement, cellular senescence assays, PES1 knockdown","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction demonstrated by Co-IP and pulldown, functional TRAP assays, telomere length, senescence phenotype; multiple orthogonal methods; includes explicit negative results for Reptin/Pontin/p23/Hsp90","pmids":["31106266"],"is_preprint":false},{"year":2012,"finding":"c-Jun (but not JunB, JunD, c-Fos, or dominant-negative c-Jun) directly activates PES1 promoter transcription; the c-Jun binding sequence was mapped to the -274/-264 region of the PES1 promoter; JNK kinase is upstream of c-Jun in controlling PES1 expression; PES1 silencing in colon cancer cells reduces proliferation and causes G1 arrest.","method":"Luciferase reporter assays, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), siRNA knockdown, xenograft model","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, EMSA, and reporter assays provide three orthogonal methods to define the c-Jun binding site; single lab","pmids":["22860098"],"is_preprint":false},{"year":2018,"finding":"PES1 is transcriptionally regulated by bromodomain-containing protein BRD4; PES1 knockdown decreases glycolysis (altering GLUT1, PKM2, ENO1, FBP1, PCK1 expression) in hepatocellular carcinoma cells; PES1 is partially responsible for the antitumor effect of BET inhibitors.","method":"BRD4 knockdown/inhibitor experiments, PES1 knockdown, glycolysis gene expression analysis, BET inhibitor treatment","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transcriptional regulation by BRD4 and glycolytic pathway placement shown by knockdown; single lab, limited mechanistic depth in abstract","pmids":["30172011"],"is_preprint":false},{"year":2019,"finding":"PES1 interacts with BRD4 to enhance c-Myc expression; elevated c-Myc is the primary cause of cancer cell resistance to BET inhibitors; CDK5 inhibitors destabilize PES1 and overcome resistance to BET inhibitors in pancreatic cancer cells.","method":"Co-immunoprecipitation (PES1-BRD4 interaction), western blotting, CDK5 inhibitor treatment, BET inhibitor resistance assays, xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for PES1-BRD4 interaction, CDK5 inhibitor functional assays; single lab, limited mechanistic depth in abstract","pmids":["31718704"],"is_preprint":false},{"year":2018,"finding":"NOP7 (PES1) is a binding partner of β-catenin; NOP7 strengthens interaction between β-catenin and TCF4, leading to activation of β-catenin/TCF signaling in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, β-catenin/TCF reporter assay, cell growth and migration assays","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP plus reporter assay; single lab, limited mechanistic depth","pmids":["30319277"],"is_preprint":false},{"year":2021,"finding":"SNHG17 (lncRNA) impedes PES1 degradation by inhibiting Trim23-mediated ubiquitination of PES1, thereby stabilizing PES1 protein in colorectal cancer cells.","method":"RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assays, SNHG17 knockdown/overexpression","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitination assay plus RNA pulldown/RIP identifies Trim23 as the E3 ligase and SNHG17 as its inhibitor; single lab","pmids":["34782005"],"is_preprint":false},{"year":2023,"finding":"PES1 interacts with ILF3 and interferes with the interaction between ILF3 and IL15 mRNA, impairing ILF3-mediated stabilization of IL15 mRNA and thereby reducing IL15 protein level; this suppresses CD8+ T cell infiltration in esophageal squamous cell carcinoma.","method":"Mass spectrometry (interactome), co-immunoprecipitation, proximity ligation assay, RNA immunoprecipitation, IL15 mRNA stability assays, RNA sequencing, PES1 knockdown in vitro and in vivo","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP and PLA; RNA binding mechanism via RIP; multiple methods but single lab","pmids":["36959575"],"is_preprint":false},{"year":2015,"finding":"PES1 ablation in colorectal cancer cells increases steady-state and etoposide-induced γ-H2AX levels, delays resolution of γ-H2AX after DNA damage removal, decreases DNA repair capacity by comet assay, and diminishes steady-state and DNA-damage-induced nuclear RAD51 levels, indicating a role for PES1 in the DNA damage response and chemoresistance.","method":"PES1 siRNA knockdown, γ-H2AX western blot and immunofluorescence, comet assay, RAD51 nuclear localization by fractionation, drug sensitivity assays, rescue by exogenous PES1 re-expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal DNA damage assays with knockdown-rescue; single lab","pmids":["23333390"],"is_preprint":false},{"year":2015,"finding":"In neuroblastoma cells, PES1 localizes to the dense fibrillar component of the nucleolus (not the granular component); treatment with the DNA-damaging agent camptothecin causes dramatic redistribution of PES1 to diffuse nucleoplasmic localization.","method":"Immunofluorescence with nucleolar compartment markers, camptothecin treatment, confocal microscopy","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with subnucleolar resolution and stimulus-dependent redistribution; single lab, single method","pmids":["25557119"],"is_preprint":false}],"current_model":"PES1 (Pescadillo) is a nucleolar protein that functions as a core subunit of the trimeric PeBoW complex (with Bop1/WDR12), where it is required—via its BRCT domain—for nucleolar localization and processing of 32S/36S pre-rRNA precursors into mature 28S and 5.8S rRNAs and assembly of the 60S ribosomal subunit; beyond ribosome biogenesis, PES1 directly binds TERT to facilitate telomerase assembly and activity, differentially stabilizes ERα (promoting) and ERβ (inhibiting) through CHIP-mediated ubiquitin-proteasome regulation, is itself stabilized by SUMO modification at K517 which reciprocally suppresses its ubiquitination, is transcriptionally activated by c-Jun/JNK and by BRD4, interacts with BRD4 to sustain c-Myc expression, binds β-catenin/TCF4 to activate Wnt signaling, and modulates the DNA damage response by supporting nuclear RAD51 accumulation, collectively placing PES1 at the intersection of ribosome biogenesis, telomere maintenance, estrogen signaling, oncogenic transcription, and DNA repair."},"narrative":{"mechanistic_narrative":"PES1 (Pescadillo) is a nucleolar protein that functions as a core subunit of the trimeric PeBoW complex with Bop1 and WDR12, where it directs maturation of 36S/32S pre-rRNA precursors into mature 28S and 5.8S rRNAs and supports 60S subunit assembly and cell proliferation [PMID:15225545, PMID:16043514, PMID:16738141, PMID:17353269]. Its BRCT domain is required for nucleolar localization, protein stability, and incorporation into the PeBoW complex; loss of this domain produces diffuse nucleoplasmic distribution and failure to rescue rRNA processing [PMID:17189298]. PES1 occupies the dense fibrillar component of the nucleolus and redistributes to the nucleoplasm upon DNA damage [PMID:25557119], and its nucleolar retention depends on partners including B23/nucleophosmin and is antagonized by Mtap1b-LC1, which sequesters PES1 to the cytoplasm [PMID:17308336, PMID:20011973]. Studies of the yeast Nop7/Erb1/Ytm1 subcomplex establish that these orthologs assemble interdependently into consecutive 66S preribosomes through defined interaction domains [PMID:16287855, PMID:18448671]. Beyond ribosome biogenesis, PES1 directly binds TERT to promote telomerase assembly with telomerase RNA, sustaining telomerase activity and preventing telomere shortening and senescence [PMID:31106266]. PES1 also acts as an oncogenic effector: it differentially controls estrogen receptor signaling by stabilizing ERα and destabilizing ERβ through CHIP-mediated ubiquitin-proteasome regulation, and is itself stabilized by SUMOylation at K517 which suppresses its ubiquitination [PMID:22820289, PMID:27409667]. PES1 transcription is driven by JNK/c-Jun and by BRD4, and PES1 interacts with BRD4 to sustain c-Myc expression and BET-inhibitor resistance [PMID:22860098, PMID:30172011, PMID:31718704]. Additional roles include binding β-catenin to strengthen β-catenin/TCF4 signaling [PMID:30319277] and supporting nuclear RAD51 accumulation and DNA repair capacity [PMID:23333390].","teleology":[{"year":2004,"claim":"Established that mammalian Pes1 acts in pre-rRNA processing by physically partnering with Bop1, defining a functional unit for 28S/5.8S rRNA maturation.","evidence":"Reciprocal Co-IP, dominant mutant and rRNA processing assays in mouse cells","pmids":["15225545"],"confidence":"High","gaps":["Third subunit and full complex composition not yet defined","No structural basis for the Pes1-Bop1 interaction"]},{"year":2005,"claim":"Resolved the complex composition by showing Pes1/Bop1 form a stable trimer with WDR12 (PeBoW) required for 32S processing and proliferation, linking ribosome biogenesis to p53-dependent cell-cycle control.","evidence":"Co-IP, dominant-negative WDR12 expression, rRNA and p53/p19ARF genetic analysis","pmids":["16043514"],"confidence":"High","gaps":["How rRNA processing failure signals to p53 not defined","Subunit assembly order not yet mapped"]},{"year":2006,"claim":"Defined that Pes1's dominant-negative activity and rRNA processing function require correct PeBoW incorporation, and that the BRCT domain governs nucleolar localization and stability.","evidence":"Deletion and point mutants, Co-IP, immunofluorescence, knockdown-rescue rRNA assays","pmids":["16738141","17189298"],"confidence":"High","gaps":["BRCT ligand/binding partner not identified","Structural model of PeBoW assembly absent"]},{"year":2007,"claim":"Reconstituted the PeBoW complex and established assembly hierarchy, showing Bop1 is central and its nucleolar transport is Pes1-dependent while Pes1 localizes independently.","evidence":"Recombinant reconstitution, siRNA epistasis, fractionation, sucrose gradients","pmids":["17353269"],"confidence":"High","gaps":["Enzymatic activity of the complex not defined","How the complex is released from mature ribosomes unknown"]},{"year":2008,"claim":"Yeast ortholog studies clarified that Nop7/Erb1/Ytm1 assemble interdependently into consecutive 66S preribosomes via discrete interaction domains, providing the conserved mechanistic framework for PeBoW.","evidence":"Affinity purification, Co-IP, domain truncation, dominant-negative genetics, export and rRNA assays in yeast","pmids":["16287855","18448671"],"confidence":"High","gaps":["Direct mapping of human domain requirements to yeast not fully tested","Mechanism of preribosome release not resolved"]},{"year":2009,"claim":"Identified B23/nucleophosmin and Mtap1b-LC1 as regulators of PES1 subcellular distribution, showing nucleolar retention is actively controlled.","evidence":"Endogenous Co-IP, pulldown domain mapping, yeast two-hybrid, knockdown and localization assays","pmids":["20011973","17308336"],"confidence":"Medium","gaps":["Whether these interactions affect rRNA processing not tested","Single-lab findings without reciprocal validation across studies"]},{"year":2012,"claim":"Extended PES1 beyond the nucleolus into estrogen signaling and transcriptional control, showing it differentially stabilizes ERα/ERβ via CHIP and is induced by JNK/c-Jun, placing it in oncogenic pathways.","evidence":"Reporter, Co-IP, ubiquitination, proteasome inhibition, xenograft, ChIP and EMSA","pmids":["22820289","22860098"],"confidence":"High","gaps":["How a nucleolar protein engages cytoplasmic/nuclear receptor turnover unclear","Direct vs indirect role in CHIP recruitment not resolved"]},{"year":2016,"claim":"Showed PES1 is itself stabilized by SUMOylation at K517, which suppresses ubiquitination and reinforces ERα-driven proliferation, defining a post-translational control loop.","evidence":"SUMOylation assays, K517R mutagenesis, ubiquitination assays, estrogen treatment, cell cycle and xenograft","pmids":["27409667"],"confidence":"High","gaps":["SUMO E3 ligase for PES1 not identified","Crosstalk with PeBoW function not tested"]},{"year":2019,"claim":"Revealed a telomere-maintenance function: PES1 directly binds TERT and promotes telomerase assembly with TR, distinct from known telomerase chaperones.","evidence":"Co-IP, direct interaction assays, TRAP, telomere length and senescence assays with explicit negative controls","pmids":["31106266"],"confidence":"High","gaps":["Structural basis of PES1-TERT contact unknown","Whether nucleolar PeBoW role is separable from telomerase role untested"]},{"year":2019,"claim":"Connected PES1 to BRD4-driven oncogenic transcription, showing PES1-BRD4 interaction sustains c-Myc and BET-inhibitor resistance, with CDK5 inhibition destabilizing PES1.","evidence":"Co-IP, BRD4/CDK5 inhibitor experiments, glycolysis gene profiling, BET resistance assays, xenograft","pmids":["30172011","31718704"],"confidence":"Medium","gaps":["Direct mechanism by which PES1 enhances c-Myc transcription not defined","Single-lab findings of limited mechanistic depth"]},{"year":2021,"claim":"Defined the ubiquitin-proteasome control of PES1, identifying Trim23 as its E3 ligase whose action is blocked by lncRNA SNHG17.","evidence":"RNA pull-down, RIP, Co-IP, ubiquitination assays, SNHG17 manipulation","pmids":["34782005"],"confidence":"Medium","gaps":["Trim23 ubiquitination site on PES1 not mapped","Relationship to SUMO-mediated stabilization untested"]},{"year":2023,"claim":"Expanded PES1 into immune evasion by showing it binds ILF3 to disrupt IL15 mRNA stabilization, reducing CD8+ T cell infiltration.","evidence":"Mass spectrometry, Co-IP, PLA, RIP, mRNA stability and RNA-seq, knockdown in vitro and in vivo","pmids":["36959575"],"confidence":"Medium","gaps":["Whether PES1 directly binds RNA or only ILF3 unclear","Single-lab finding without reciprocal validation"]},{"year":null,"claim":"How PES1's core nucleolar ribosome-biogenesis function mechanistically connects to its diverse extranucleolar oncogenic roles (telomerase, ER signaling, BRD4/c-Myc, Wnt, DNA repair, immune evasion) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking nucleolar and extranucleolar pools of PES1","No structural data for non-PeBoW interactions","Stimulus-dependent partitioning between functions uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,12,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,12]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,3,4,9,20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,4]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4,20]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2,3,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,2,13]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[19]}],"complexes":["PeBoW complex (PES1/Bop1/WDR12)","Nop7 subcomplex (Nop7/Erb1/Ytm1, yeast)","telomerase (PES1/TERT/TR)"],"partners":["BOP1","WDR12","TERT","BRD4","CTNNB1","ILF3","NPM1","MAP1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00541","full_name":"Pescadillo homolog","aliases":[],"length_aa":588,"mass_kda":68.0,"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; Chromosome","url":"https://www.uniprot.org/uniprotkb/O00541/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PES1","classification":"Common Essential","n_dependent_lines":1165,"n_total_lines":1208,"dependency_fraction":0.9644039735099338},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100029","cell_line_id":"CID001054","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"NXF1","stoichiometry":10.0},{"gene":"WDR12","stoichiometry":10.0},{"gene":"BOP1","stoichiometry":10.0},{"gene":"RPL7L1","stoichiometry":10.0},{"gene":"CSNK2A1","stoichiometry":0.2},{"gene":"CSNK2A2","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"LMNB1","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"NPM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001054","total_profiled":1310},"omim":[{"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":"610596","title":"BLOCK OF PROLIFERATION 1; BOP1","url":"https://www.omim.org/entry/610596"},{"mim_id":"605819","title":"PESCADILLO RIBOSOMAL BIOGENESIS FACTOR 1; PES1","url":"https://www.omim.org/entry/605819"},{"mim_id":"605078","title":"TAR DNA-BINDING PROTEIN; TARDBP","url":"https://www.omim.org/entry/605078"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Nucleoli rim","reliability":"Enhanced"},{"location":"Mitotic chromosome","reliability":"Enhanced"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Crystal morphology of melt-crystallized ultrathin film and its change after enzymatic degradation.","date":"2000","source":"Biomacromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/11710202","citation_count":9,"is_preprint":false},{"pmid":"19433282","id":"PMC_19433282","title":"Congenital pes cavus in a Charcot-Marie-tooth disease type 1A newborn.","date":"2009","source":"Pediatric neurology","url":"https://pubmed.ncbi.nlm.nih.gov/19433282","citation_count":9,"is_preprint":false},{"pmid":"36760164","id":"PMC_36760164","title":"SCARECROW-like GRAS protein PES positively regulates petunia floral scent production.","date":"2023","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/36760164","citation_count":8,"is_preprint":false},{"pmid":"17308336","id":"PMC_17308336","title":"Light chain 1 of microtubule-associated protein 1B can negatively regulate the action of Pes1.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17308336","citation_count":8,"is_preprint":false},{"pmid":"34267941","id":"PMC_34267941","title":"How to manage pes cavus in children and adolescents?","date":"2021","source":"EFORT open reviews","url":"https://pubmed.ncbi.nlm.nih.gov/34267941","citation_count":8,"is_preprint":false},{"pmid":"36361992","id":"PMC_36361992","title":"The BRCT Domain from the Homologue of the Oncogene PES1 in Leishmania major (LmjPES) Promotes Malignancy and Drug Resistance in Mammalian Cells.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36361992","citation_count":8,"is_preprint":false},{"pmid":"27467132","id":"PMC_27467132","title":"Mechanism of Alcohol-Water Dehydrogenative Coupling into Carboxylic Acid Using Milstein's Catalyst: A Detailed Investigation of the Outer-Sphere PES in the Reaction of Aldehydes with an Octahedral Ruthenium Hydroxide.","date":"2016","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27467132","citation_count":8,"is_preprint":false},{"pmid":"30319277","id":"PMC_30319277","title":"NOP7 interacts with β-catenin and activates β-catenin/TCF signaling in hepatocellular carcinoma cells.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30319277","citation_count":7,"is_preprint":false},{"pmid":"34845814","id":"PMC_34845814","title":"Licochalcone A inhibits cell growth through the downregulation of the Hippo pathway via PES1 in cholangiocarcinoma cells.","date":"2021","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34845814","citation_count":7,"is_preprint":false},{"pmid":"38345129","id":"PMC_38345129","title":"Immobilization of carbonic anhydrase on modified PES membranes for artificial lungs.","date":"2024","source":"Journal of materials chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/38345129","citation_count":7,"is_preprint":false},{"pmid":"38357260","id":"PMC_38357260","title":"Novel Insights from Clinical Practice: Xia-Gibbs Syndrome with Pes Cavus, Conjunctival Melanosis, and Eye Asymmetry due to a de novo AHDC1 Gene Variant - A Case Report and a Brief Review of the Literature.","date":"2023","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/38357260","citation_count":7,"is_preprint":false},{"pmid":"31223043","id":"PMC_31223043","title":"Formulation and evaluation of letrozole-loaded spray dried liposomes with PEs for topical application.","date":"2019","source":"Journal of liposome research","url":"https://pubmed.ncbi.nlm.nih.gov/31223043","citation_count":7,"is_preprint":false},{"pmid":"16343865","id":"PMC_16343865","title":"Improved protein-adsorption-resistant property of PES/SPC blend membrane by adjustment of coagulation bath composition.","date":"2005","source":"Colloids and surfaces. B, Biointerfaces","url":"https://pubmed.ncbi.nlm.nih.gov/16343865","citation_count":7,"is_preprint":false},{"pmid":"18241355","id":"PMC_18241355","title":"The effectiveness of pulsed electrical stimulation (E-PES) in the management of osteoarthritis of the knee: a protocol for a randomised controlled trial.","date":"2008","source":"BMC musculoskeletal disorders","url":"https://pubmed.ncbi.nlm.nih.gov/18241355","citation_count":7,"is_preprint":false},{"pmid":"39209183","id":"PMC_39209183","title":"Emerging role of PES1 in disease: A promising therapeutic target?","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/39209183","citation_count":6,"is_preprint":false},{"pmid":"2665922","id":"PMC_2665922","title":"The developmental anatomy of pes valgo planus.","date":"1989","source":"Clinics in podiatric medicine and surgery","url":"https://pubmed.ncbi.nlm.nih.gov/2665922","citation_count":6,"is_preprint":false},{"pmid":"36252532","id":"PMC_36252532","title":"A high-protein retained PES hemodialysis membrane with tannic acid as a multifunctional modifier.","date":"2022","source":"Colloids and surfaces. B, Biointerfaces","url":"https://pubmed.ncbi.nlm.nih.gov/36252532","citation_count":6,"is_preprint":false},{"pmid":"35756195","id":"PMC_35756195","title":"Phytochemistry, biological activities and in silico molecular docking studies of Oxalis pes-caprae L. compounds against SARS-CoV-2.","date":"2022","source":"Journal of King Saud University. Science","url":"https://pubmed.ncbi.nlm.nih.gov/35756195","citation_count":6,"is_preprint":false},{"pmid":"32388231","id":"PMC_32388231","title":"Probing protein rejection behavior of blended PES-based flat-sheet ultrafiltration membranes: A density functional theory (DFT) study.","date":"2020","source":"Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy","url":"https://pubmed.ncbi.nlm.nih.gov/32388231","citation_count":6,"is_preprint":false},{"pmid":"34830469","id":"PMC_34830469","title":"In Leishmania major, the Homolog of the Oncogene PES1 May Play a Critical Role in Parasite Infectivity.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34830469","citation_count":5,"is_preprint":false},{"pmid":"39187102","id":"PMC_39187102","title":"Targeting host inducible-heat shock protein 70 with PES-Cl is a promising antiviral strategy against SARS-CoV-2 infection and pathogenesis.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39187102","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47899,"output_tokens":5578,"usd":0.113684,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14119,"output_tokens":4205,"usd":0.08786,"stage2_stop_reason":"end_turn"},"total_usd":0.201544,"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\": 2004,\n      \"finding\": \"Pes1 (mouse homolog of zebrafish Pescadillo/yeast Nop7p) physically interacts with the nucleolar protein Bop1; both proteins direct common pre-rRNA processing steps (maturation of 28S and 5.8S rRNAs); interaction with Bop1 is essential for efficient incorporation of Pes1 into nucleolar preribosomal complexes; Pes1 mutants defective for Bop1 interaction lose the ability to affect rRNA maturation and cell cycle arrest.\",\n      \"method\": \"Transposon-derived dominant mutants, co-immunoprecipitation, rRNA processing assays, cell cycle analysis, sucrose gradient fractionation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional mutant analysis plus rRNA processing assays in a single focused study; foundational mechanistic paper replicated by subsequent work\",\n      \"pmids\": [\"15225545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Pes1 and Bop1 form a stable trimeric complex with a novel WD40 repeat protein, WDR12 (PeBoW complex). Endogenous WDR12 is required for processing of 32S precursor rRNA and cell proliferation. A dominant-negative WDR12 mutant blocks rRNA processing and induces p53 accumulation in a p19ARF-independent manner in proliferating but not quiescent cells.\",\n      \"method\": \"Co-immunoprecipitation, conditional dominant-negative expression, rRNA processing assays, p53/p19ARF genetic analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying trimeric complex, functional rRNA and cell-cycle assays, multiple orthogonal methods, replicated by subsequent studies\",\n      \"pmids\": [\"16043514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Dominant-negative Pes1 deletion mutants (N- and C-terminal truncations) incorporate into the PeBoW complex, block processing of 36S/32S precursors to mature 28S rRNA, inhibit cell proliferation, and induce high p53 levels in proliferating but not resting cells. The dominant-negative effect requires proper incorporation into the PeBoW complex.\",\n      \"method\": \"Deletion mutant expression, co-immunoprecipitation with Bop1/WDR12, nucleolar localization by immunofluorescence, rRNA processing assays, p53 western blot\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple deletion mutants, Co-IP, rRNA assays, p53 measurements; mechanistically confirms PeBoW complex requirement\",\n      \"pmids\": [\"16738141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Recombinant expression of Pes1, Bop1, and WDR12 is sufficient for PeBoW complex formation. Bop1 is the integral/central component: knockdown of Bop1 abolishes co-purification of Pes1 with WDR12; transport of Bop1 from cytoplasm to nucleolus is Pes1-dependent, while Pes1 migrates to the nucleolus and associates with preribosomal particles independently of Bop1. Overexpression of Bop1 (but not WDR12 or Pes1 alone) inhibits cell proliferation and rRNA processing.\",\n      \"method\": \"Recombinant complex reconstitution, siRNA knockdown, immunofluorescence, cell fractionation, sucrose gradient centrifugation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution of trimeric complex, knockdown epistasis, multiple orthogonal localization and functional assays\",\n      \"pmids\": [\"17353269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The BRCT domain of mammalian Pes1 is required for nucleolar localization and rRNA processing. Deletion of the BRCT domain or point mutations of conserved residues cause diffuse nucleoplasmic distribution, failure to rescue rRNA processing in Pes1-knockdown cells, reduced protein stability, and loss of incorporation into the PeBoW complex.\",\n      \"method\": \"siRNA-based knock-down/knock-in system, Pes1 truncation and point mutants, immunofluorescence, rRNA processing assays, co-immunoprecipitation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis combined with knockdown-rescue, Co-IP, localization, and rRNA functional assays in one study\",\n      \"pmids\": [\"17189298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Murine Pes1 encodes a nuclear protein containing a BRCT domain; recombinant Pes1 expressed in HepG2 cells localizes to the nucleus.\",\n      \"method\": \"Genomic cloning, sequence analysis, recombinant protein expression, subcellular localization by microscopy\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment, single lab, single method for localization; sequence analysis for domain identification\",\n      \"pmids\": [\"11112348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In yeast, the Nop7 subcomplex (Nop7/Erb1/Ytm1, orthologs of Pes1/Bop1/WDR12) is present in four consecutive 66S preribosomes; Ytm1 binds directly to Erb1 and is present in a heterotrimeric subcomplex with Erb1 and Nop7 both within and independently of preribosomes; Nop7 and Erb1 assemble into preribosomes prior to Ytm1; mutations in WD40 motifs of Ytm1 disrupt binding to Erb1, destabilize the heterotrimer, and delay pre-rRNA processing and nuclear export.\",\n      \"method\": \"Affinity purification, co-immunoprecipitation, pre-rRNA processing assays, nuclear export assays, WD40 mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast ortholog study with reciprocal Co-IP, mutant analysis, rRNA processing, and export assays; multiple orthogonal methods in a focused study\",\n      \"pmids\": [\"16287855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In yeast, Ytm1, Erb1, and Nop7 (orthologs of WDR12, Bop1, Pes1) assemble into preribosomes interdependently; specific domains within each protein are necessary for interaction and sufficient for preribosome recruitment; dominant-negative truncations of each protein impair growth and ribosome biogenesis.\",\n      \"method\": \"Domain truncation analysis, co-immunoprecipitation, dominant-negative overexpression, ribosome biogenesis assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic domain mapping with Co-IP, dominant-negative genetics, and functional ribosome assays in yeast ortholog system\",\n      \"pmids\": [\"18448671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Light chain 1 of microtubule-associated protein 1B (Mtap1b-LC1) interacts with the BRCT domain of Pes1; overexpression of Mtap1b-LC1 relocalizes Pes1 from the nucleus/nucleolus to the cytoplasm, reduces nuclear Pes1 levels, and inhibits cell proliferation—phenocopying Pes1 depletion.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, deletion analysis, immunofluorescence, cell proliferation assay, shRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, domain mapping, and localization with functional consequence; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17308336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nucleolar protein B23 (nucleophosmin) physically interacts with PES1; knockdown of B23 by RNAi increases nucleoplasmic distribution of PES1, indicating B23 is involved in the nucleolar localization of PES1.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, in vitro pulldown domain mapping, immunofluorescence colocalization, siRNA knockdown\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — endogenous Co-IP plus pulldown plus knockdown localization effect; single lab, two orthogonal methods\",\n      \"pmids\": [\"20011973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PES1 differentially regulates ERα and ERβ: it enhances ERα transcriptional activity while inhibiting ERβ transcriptional activity; increases ERα protein stability and decreases ERβ protein stability via the ubiquitin-proteasome pathway mediated by CHIP (carboxyl terminus of Hsc70-interacting protein); PES1 transforms normal mammary epithelial cells and is required for estrogen-induced breast tumor growth in nude mice.\",\n      \"method\": \"Transcriptional reporter assays, co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, knockdown/overexpression, cell transformation assay, xenograft tumor model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assays, Co-IP, ubiquitination, proteasome inhibition, in vivo tumor model) in a single focused study\",\n      \"pmids\": [\"22820289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PES1 is SUMOylated by SUMO-1, SUMO-2, and SUMO-3; the major SUMOylation site is K517 in the C-terminal Glu-rich domain; SUMOylation is stimulated by estrogen; SUMOylation stabilizes PES1 by inhibiting its ubiquitination; SUMOylated PES1 enhances ERα stability and ERα-mediated transcription, increases S-phase fraction, and promotes breast cancer cell proliferation.\",\n      \"method\": \"SUMOylation assays, site-directed mutagenesis (K517R), ubiquitination assays, estrogen treatment, reporter assays, cell cycle analysis, xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SUMOylation site mutagenesis confirmed by multiple assays (SUMO, ubiquitin, transcription, proliferation); single lab but orthogonal methods\",\n      \"pmids\": [\"27409667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PES1 forms a complex with telomerase reverse transcriptase (TERT) and telomerase RNA (TR) through direct interaction with TERT; PES1 facilitates telomerase assembly by promoting direct interaction between TERT and TR without affecting their expression levels; PES1 does not interact with previously reported telomerase components Reptin, Pontin, p23, or Hsp90; depletion of PES1 reduces telomerase activity, leads to telomere shortening, and induces cellular senescence.\",\n      \"method\": \"Co-immunoprecipitation, direct interaction assays, telomerase activity assays (TRAP), telomere length measurement, cellular senescence assays, PES1 knockdown\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction demonstrated by Co-IP and pulldown, functional TRAP assays, telomere length, senescence phenotype; multiple orthogonal methods; includes explicit negative results for Reptin/Pontin/p23/Hsp90\",\n      \"pmids\": [\"31106266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"c-Jun (but not JunB, JunD, c-Fos, or dominant-negative c-Jun) directly activates PES1 promoter transcription; the c-Jun binding sequence was mapped to the -274/-264 region of the PES1 promoter; JNK kinase is upstream of c-Jun in controlling PES1 expression; PES1 silencing in colon cancer cells reduces proliferation and causes G1 arrest.\",\n      \"method\": \"Luciferase reporter assays, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), siRNA knockdown, xenograft model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, EMSA, and reporter assays provide three orthogonal methods to define the c-Jun binding site; single lab\",\n      \"pmids\": [\"22860098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PES1 is transcriptionally regulated by bromodomain-containing protein BRD4; PES1 knockdown decreases glycolysis (altering GLUT1, PKM2, ENO1, FBP1, PCK1 expression) in hepatocellular carcinoma cells; PES1 is partially responsible for the antitumor effect of BET inhibitors.\",\n      \"method\": \"BRD4 knockdown/inhibitor experiments, PES1 knockdown, glycolysis gene expression analysis, BET inhibitor treatment\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transcriptional regulation by BRD4 and glycolytic pathway placement shown by knockdown; single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"30172011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PES1 interacts with BRD4 to enhance c-Myc expression; elevated c-Myc is the primary cause of cancer cell resistance to BET inhibitors; CDK5 inhibitors destabilize PES1 and overcome resistance to BET inhibitors in pancreatic cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (PES1-BRD4 interaction), western blotting, CDK5 inhibitor treatment, BET inhibitor resistance assays, xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for PES1-BRD4 interaction, CDK5 inhibitor functional assays; single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"31718704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NOP7 (PES1) is a binding partner of β-catenin; NOP7 strengthens interaction between β-catenin and TCF4, leading to activation of β-catenin/TCF signaling in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, β-catenin/TCF reporter assay, cell growth and migration assays\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus reporter assay; single lab, limited mechanistic depth\",\n      \"pmids\": [\"30319277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNHG17 (lncRNA) impedes PES1 degradation by inhibiting Trim23-mediated ubiquitination of PES1, thereby stabilizing PES1 protein in colorectal cancer cells.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assays, SNHG17 knockdown/overexpression\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitination assay plus RNA pulldown/RIP identifies Trim23 as the E3 ligase and SNHG17 as its inhibitor; single lab\",\n      \"pmids\": [\"34782005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PES1 interacts with ILF3 and interferes with the interaction between ILF3 and IL15 mRNA, impairing ILF3-mediated stabilization of IL15 mRNA and thereby reducing IL15 protein level; this suppresses CD8+ T cell infiltration in esophageal squamous cell carcinoma.\",\n      \"method\": \"Mass spectrometry (interactome), co-immunoprecipitation, proximity ligation assay, RNA immunoprecipitation, IL15 mRNA stability assays, RNA sequencing, PES1 knockdown in vitro and in vivo\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP and PLA; RNA binding mechanism via RIP; multiple methods but single lab\",\n      \"pmids\": [\"36959575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PES1 ablation in colorectal cancer cells increases steady-state and etoposide-induced γ-H2AX levels, delays resolution of γ-H2AX after DNA damage removal, decreases DNA repair capacity by comet assay, and diminishes steady-state and DNA-damage-induced nuclear RAD51 levels, indicating a role for PES1 in the DNA damage response and chemoresistance.\",\n      \"method\": \"PES1 siRNA knockdown, γ-H2AX western blot and immunofluorescence, comet assay, RAD51 nuclear localization by fractionation, drug sensitivity assays, rescue by exogenous PES1 re-expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal DNA damage assays with knockdown-rescue; single lab\",\n      \"pmids\": [\"23333390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In neuroblastoma cells, PES1 localizes to the dense fibrillar component of the nucleolus (not the granular component); treatment with the DNA-damaging agent camptothecin causes dramatic redistribution of PES1 to diffuse nucleoplasmic localization.\",\n      \"method\": \"Immunofluorescence with nucleolar compartment markers, camptothecin treatment, confocal microscopy\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with subnucleolar resolution and stimulus-dependent redistribution; single lab, single method\",\n      \"pmids\": [\"25557119\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PES1 (Pescadillo) is a nucleolar protein that functions as a core subunit of the trimeric PeBoW complex (with Bop1/WDR12), where it is required—via its BRCT domain—for nucleolar localization and processing of 32S/36S pre-rRNA precursors into mature 28S and 5.8S rRNAs and assembly of the 60S ribosomal subunit; beyond ribosome biogenesis, PES1 directly binds TERT to facilitate telomerase assembly and activity, differentially stabilizes ERα (promoting) and ERβ (inhibiting) through CHIP-mediated ubiquitin-proteasome regulation, is itself stabilized by SUMO modification at K517 which reciprocally suppresses its ubiquitination, is transcriptionally activated by c-Jun/JNK and by BRD4, interacts with BRD4 to sustain c-Myc expression, binds β-catenin/TCF4 to activate Wnt signaling, and modulates the DNA damage response by supporting nuclear RAD51 accumulation, collectively placing PES1 at the intersection of ribosome biogenesis, telomere maintenance, estrogen signaling, oncogenic transcription, and DNA repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PES1 (Pescadillo) is a nucleolar protein that functions as a core subunit of the trimeric PeBoW complex with Bop1 and WDR12, where it directs maturation of 36S/32S pre-rRNA precursors into mature 28S and 5.8S rRNAs and supports 60S subunit assembly and cell proliferation [#0, #1, #2, #3]. Its BRCT domain is required for nucleolar localization, protein stability, and incorporation into the PeBoW complex; loss of this domain produces diffuse nucleoplasmic distribution and failure to rescue rRNA processing [#4]. PES1 occupies the dense fibrillar component of the nucleolus and redistributes to the nucleoplasm upon DNA damage [#20], and its nucleolar retention depends on partners including B23/nucleophosmin and is antagonized by Mtap1b-LC1, which sequesters PES1 to the cytoplasm [#8, #9]. Studies of the yeast Nop7/Erb1/Ytm1 subcomplex establish that these orthologs assemble interdependently into consecutive 66S preribosomes through defined interaction domains [#6, #7]. Beyond ribosome biogenesis, PES1 directly binds TERT to promote telomerase assembly with telomerase RNA, sustaining telomerase activity and preventing telomere shortening and senescence [#12]. PES1 also acts as an oncogenic effector: it differentially controls estrogen receptor signaling by stabilizing ERα and destabilizing ERβ through CHIP-mediated ubiquitin-proteasome regulation, and is itself stabilized by SUMOylation at K517 which suppresses its ubiquitination [#10, #11]. PES1 transcription is driven by JNK/c-Jun and by BRD4, and PES1 interacts with BRD4 to sustain c-Myc expression and BET-inhibitor resistance [#13, #14, #15]. Additional roles include binding β-catenin to strengthen β-catenin/TCF4 signaling [#16] and supporting nuclear RAD51 accumulation and DNA repair capacity [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that mammalian Pes1 acts in pre-rRNA processing by physically partnering with Bop1, defining a functional unit for 28S/5.8S rRNA maturation.\",\n      \"evidence\": \"Reciprocal Co-IP, dominant mutant and rRNA processing assays in mouse cells\",\n      \"pmids\": [\"15225545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Third subunit and full complex composition not yet defined\", \"No structural basis for the Pes1-Bop1 interaction\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the complex composition by showing Pes1/Bop1 form a stable trimer with WDR12 (PeBoW) required for 32S processing and proliferation, linking ribosome biogenesis to p53-dependent cell-cycle control.\",\n      \"evidence\": \"Co-IP, dominant-negative WDR12 expression, rRNA and p53/p19ARF genetic analysis\",\n      \"pmids\": [\"16043514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How rRNA processing failure signals to p53 not defined\", \"Subunit assembly order not yet mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined that Pes1's dominant-negative activity and rRNA processing function require correct PeBoW incorporation, and that the BRCT domain governs nucleolar localization and stability.\",\n      \"evidence\": \"Deletion and point mutants, Co-IP, immunofluorescence, knockdown-rescue rRNA assays\",\n      \"pmids\": [\"16738141\", \"17189298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"BRCT ligand/binding partner not identified\", \"Structural model of PeBoW assembly absent\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Reconstituted the PeBoW complex and established assembly hierarchy, showing Bop1 is central and its nucleolar transport is Pes1-dependent while Pes1 localizes independently.\",\n      \"evidence\": \"Recombinant reconstitution, siRNA epistasis, fractionation, sucrose gradients\",\n      \"pmids\": [\"17353269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic activity of the complex not defined\", \"How the complex is released from mature ribosomes unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Yeast ortholog studies clarified that Nop7/Erb1/Ytm1 assemble interdependently into consecutive 66S preribosomes via discrete interaction domains, providing the conserved mechanistic framework for PeBoW.\",\n      \"evidence\": \"Affinity purification, Co-IP, domain truncation, dominant-negative genetics, export and rRNA assays in yeast\",\n      \"pmids\": [\"16287855\", \"18448671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mapping of human domain requirements to yeast not fully tested\", \"Mechanism of preribosome release not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified B23/nucleophosmin and Mtap1b-LC1 as regulators of PES1 subcellular distribution, showing nucleolar retention is actively controlled.\",\n      \"evidence\": \"Endogenous Co-IP, pulldown domain mapping, yeast two-hybrid, knockdown and localization assays\",\n      \"pmids\": [\"20011973\", \"17308336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these interactions affect rRNA processing not tested\", \"Single-lab findings without reciprocal validation across studies\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended PES1 beyond the nucleolus into estrogen signaling and transcriptional control, showing it differentially stabilizes ERα/ERβ via CHIP and is induced by JNK/c-Jun, placing it in oncogenic pathways.\",\n      \"evidence\": \"Reporter, Co-IP, ubiquitination, proteasome inhibition, xenograft, ChIP and EMSA\",\n      \"pmids\": [\"22820289\", \"22860098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a nucleolar protein engages cytoplasmic/nuclear receptor turnover unclear\", \"Direct vs indirect role in CHIP recruitment not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed PES1 is itself stabilized by SUMOylation at K517, which suppresses ubiquitination and reinforces ERα-driven proliferation, defining a post-translational control loop.\",\n      \"evidence\": \"SUMOylation assays, K517R mutagenesis, ubiquitination assays, estrogen treatment, cell cycle and xenograft\",\n      \"pmids\": [\"27409667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase for PES1 not identified\", \"Crosstalk with PeBoW function not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a telomere-maintenance function: PES1 directly binds TERT and promotes telomerase assembly with TR, distinct from known telomerase chaperones.\",\n      \"evidence\": \"Co-IP, direct interaction assays, TRAP, telomere length and senescence assays with explicit negative controls\",\n      \"pmids\": [\"31106266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PES1-TERT contact unknown\", \"Whether nucleolar PeBoW role is separable from telomerase role untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected PES1 to BRD4-driven oncogenic transcription, showing PES1-BRD4 interaction sustains c-Myc and BET-inhibitor resistance, with CDK5 inhibition destabilizing PES1.\",\n      \"evidence\": \"Co-IP, BRD4/CDK5 inhibitor experiments, glycolysis gene profiling, BET resistance assays, xenograft\",\n      \"pmids\": [\"30172011\", \"31718704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which PES1 enhances c-Myc transcription not defined\", \"Single-lab findings of limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the ubiquitin-proteasome control of PES1, identifying Trim23 as its E3 ligase whose action is blocked by lncRNA SNHG17.\",\n      \"evidence\": \"RNA pull-down, RIP, Co-IP, ubiquitination assays, SNHG17 manipulation\",\n      \"pmids\": [\"34782005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trim23 ubiquitination site on PES1 not mapped\", \"Relationship to SUMO-mediated stabilization untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded PES1 into immune evasion by showing it binds ILF3 to disrupt IL15 mRNA stabilization, reducing CD8+ T cell infiltration.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, PLA, RIP, mRNA stability and RNA-seq, knockdown in vitro and in vivo\",\n      \"pmids\": [\"36959575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PES1 directly binds RNA or only ILF3 unclear\", \"Single-lab finding without reciprocal validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PES1's core nucleolar ribosome-biogenesis function mechanistically connects to its diverse extranucleolar oncogenic roles (telomerase, ER signaling, BRD4/c-Myc, Wnt, DNA repair, immune evasion) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking nucleolar and extranucleolar pools of PES1\", \"No structural data for non-PeBoW interactions\", \"Stimulus-dependent partitioning between functions uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 12, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 3, 4, 9, 20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 4]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2, 3, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 2, 13]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"complexes\": [\n      \"PeBoW complex (PES1/Bop1/WDR12)\",\n      \"Nop7 subcomplex (Nop7/Erb1/Ytm1, yeast)\",\n      \"telomerase (PES1/TERT/TR)\"\n    ],\n    \"partners\": [\n      \"BOP1\",\n      \"WDR12\",\n      \"TERT\",\n      \"BRD4\",\n      \"CTNNB1\",\n      \"ILF3\",\n      \"NPM1\",\n      \"MAP1B\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}