{"gene":"WDR18","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2011,"finding":"WDR18 is a component of a mammalian PELP1-TEX10-WDR18 complex (homologous to the yeast Rix1 complex) that is involved in maturation and nucleolar release of the large (60S) ribosomal subunit. Biochemical purification showed this complex associates with SENP3, and SUMO conjugation/deconjugation of PELP1 controls the nucleolar partitioning of the complex, thereby regulating ribosome biogenesis.","method":"Biochemical purification (SENP3-associated complex isolation), co-immunoprecipitation, functional depletion assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional depletion with defined phenotype, independently replicated across two labs in same year","pmids":["21326211"],"is_preprint":false},{"year":2011,"finding":"WDR18 (as part of the PELP1-TEX10-WDR18-LAS1L-NOL9-SENP3 complex) co-fractionates with the 60S preribosomal subunit. Depletion of complex members including WDR18-associated proteins causes a p53-dependent G1 arrest and defects in processing of the pre-rRNA ITS2 region. Nucleolar localization of the complex requires active RNA Pol I transcription and SENP3.","method":"Co-immunoprecipitation, sucrose gradient fractionation, siRNA knockdown with phenotypic readout (G1 arrest, pre-rRNA processing defects), fluorescence microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, Co-IP, KD with defined molecular and cell-cycle phenotype), independent replication","pmids":["22190735"],"is_preprint":false},{"year":2011,"finding":"SUMO-dependent subnuclear trafficking controls the PELP1-TEX10-WDR18 complex. PELP1 is a SENP3-sensitive SUMO target; lack of SENP3-mediated desumoylation prevents nucleolar partitioning of the PELP1-WDR18-TEX10 complex, restricting premature loading onto 60S particles and limiting ribosome maturation rate.","method":"SUMO modification assays, SENP3 depletion/overexpression, subcellular fractionation, imaging","journal":"Nucleus (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic follow-up from single lab, consistent with prior EMBO J study","pmids":["22064470"],"is_preprint":false},{"year":2012,"finding":"WDR18 is a member of the 'Five Friends of Methylated Chtop' (5FMC) nuclear complex, recruited to the chromatin-associated protein Chtop only when Chtop is arginine-methylated by PRMT1. The 5FMC complex (PELP1, SENP3, WDR18, TEX10, LAS1L) affects the sumoylation status and transactivation potential of the transcription factor ZBP-89, linking arginine methylation to desumoylation in transcriptional control. PELP1 functions as the core scaffold; other components including WDR18 become unstable in its absence.","method":"Biotinylation-proteomics (BioID-like), co-immunoprecipitation, luciferase reporter assays, western blotting","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 — proteomics plus functional reporter assay, single lab","pmids":["22872859"],"is_preprint":false},{"year":2013,"finding":"WDR18 associates with the C-terminus of TopBP1 (in vitro and in vivo) and with Chk1 in vitro. This association is required for ATR-dependent Chk1 phosphorylation in response to DNA damage (AT70-induced). WDR18 depletion abolishes Chk1 activation, identifying WDR18 as a DNA damage checkpoint protein that facilitates ATR-Chk1 signaling by bridging TopBP1 and Chk1.","method":"Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown with Chk1 phosphorylation readout","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vitro and in vivo binding plus functional KD phenotype, single lab","pmids":["23333389"],"is_preprint":false},{"year":2011,"finding":"Zebrafish wdr18 is expressed in dorsal forerunner cells (DFCs) and Kupffer's vesicle (KV). Morpholino knockdown of wdr18 causes laterality defects (mis-expression of Nodal-related genes spaw and pitx2), KV with fewer, shorter, immotile cilia and smaller cavity, and disorganized DFC clustering and migration. Genetic interaction with itgb1b was demonstrated by double morpholino injection, placing wdr18 in a pathway controlling DFC migration and left-right asymmetry determination.","method":"Morpholino knockdown, in situ hybridization, cilia motility analysis, genetic epistasis (double morpholino), fluorescence imaging with cell-lineage markers","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific molecular and cellular phenotype, genetic epistasis, single lab","pmids":["21876750"],"is_preprint":false},{"year":2016,"finding":"Human WDR18 (hIPI3) is required for DNA replication licensing. Knockdown causes defects in chromatin association of the MCM complex, DNA replication, and cell cycle progression without affecting global protein synthesis. hIPI3 protein and mRNA levels peak from M phase to early G1, similar to pre-RC proteins. hIPI3 interacts with replication-initiation proteins, co-localizes with hMCM7 in the nucleus, is important for nuclear localization of hMCM7, and preferentially binds origins of replication at c-Myc, Lamin-B2, and β-Globin loci.","method":"siRNA knockdown, DNA replication assay (BrdU incorporation), ChIP at replication origins, co-immunoprecipitation, immunofluorescence co-localization, cell cycle analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, Co-IP, IF, flow cytometry), single lab","pmids":["27057756"],"is_preprint":false},{"year":2019,"finding":"In systematic pairwise yeast two-hybrid and co-immunoprecipitation analyses of human replication-initiation proteins, WDR18 (hIPI3) was found to interact with several pre-RC and pre-IC proteins, including novel interactions not previously reported, consistent with its role in replication licensing.","method":"Yeast two-hybrid (systematic pairwise), co-immunoprecipitation validation of novel interactions","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Low","confidence_rationale":"Tier 3 — systematic Y2H with partial Co-IP confirmation, large-scale screen context","pmids":["30890025"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of the human PELP1-WDR18 subcomplex was determined at 2.7 Å, revealing an interconnected tetrameric assembly (PELP1-WDR18 heterotetramer). The structure shows the architecture of PELP1's eleven LxxLL motifs previously implicated in steroid receptor (SR) signaling; none is in a conformation compatible with SR binding, suggesting that WDR18 association directs PELP1 activity away from SR coactivation toward Rix1 complex functions. PELP1 was confirmed as the central scaffold of the human Rix1 complex (PELP1, WDR18, TEX10, SENP3) by reconstitution.","method":"Cryo-EM (2.7 Å structure), complex reconstitution, biochemical subcomplex mapping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with complex reconstitution and functional inference from structural analysis","pmids":["36351913"],"is_preprint":false},{"year":2020,"finding":"The yeast Rix1 complex (Rix1-Ipi1-Ipi3, orthologs of human PELP1-TEX10-WDR18) forms a Rix1²-Ipi3² tetramer anchored to the pre-60S ribosome via Ipi1. Cryo-EM analysis of nuclear pre-60S intermediates shows this complex is strategically positioned near the central protuberance to monitor and assist large-scale structural remodeling events including L1 stalk maturation, working in concert with the AAA-ATPase Rea1.","method":"Cryo-EM of pre-60S intermediates (multiple states), structural modeling","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structural analysis at molecular resolution of the orthologous complex in pre-ribosomal context","pmids":["32668200"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of the conserved rixosome from Chaetomium thermophilum (Rix1-Ipi3-Ipi1 sphere sub-module plus Las1-Grc3 butterfly sub-module) reveal how the Rix1 complex (WDR18 ortholog Ipi3 included) wedges between the 5S rRNA tip and L1-stalk on nucleoplasmic pre-60S particles to facilitate 180° rotation of the immature 5S RNP, enabling ITS2 pre-rRNA cleavage by Las1 endonuclease and phosphorylation by Grc3 kinase.","method":"Cryo-EM structural analysis of isolated rixosome and pre-60S-bound states, biochemical isolation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures of orthologous complex defining mechanistic coordination of 5S RNP rotation and ITS2 processing","pmids":["37921038"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of the human PELP1-WDR18-TEX10 complex and the LAS1L-NOL9 complex were determined, plus a lower-resolution model of PELP1-WDR18-LAS1L. WDR18 contacts TEX10 at two distinct regions and its C-terminal helix contacts the helical domain of LAS1L. Mutagenesis confirmed that disrupting either WDR18-TEX10 contact blocks TEX10 binding, and truncation of the WDR18 C-terminal helix abolishes LAS1L recruitment. TEX10 undergoes substantial conformational changes between the PELP1-WDR18-TEX10 complex alone and when bound to the pre-ribosome.","method":"Cryo-EM structure determination, site-directed mutagenesis, biochemical binding assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures with mutagenesis validation of specific interaction interfaces","pmids":["40195365"],"is_preprint":false},{"year":2026,"finding":"WDR18 functions as a substrate receptor within the CRL4B^WDR18 E3 ubiquitin ligase complex. The natural product halofuginone acts as a molecular glue that promotes recruitment of integrin β4 to this CRL4B-WDR18 complex, leading to integrin β4 polyubiquitination and proteasomal degradation.","method":"High-throughput screening, co-immunoprecipitation, ubiquitination assay, in vitro and in vivo degradation assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 — functional degradation assay with molecular glue mechanism, single lab","pmids":["41874446"],"is_preprint":false}],"current_model":"WDR18 is a WD-repeat scaffold protein that serves as a core subunit of the mammalian Rix1/rixosome complex (with PELP1, TEX10, LAS1L, NOL9, and SENP3), where it bridges PELP1 to TEX10 and LAS1L to facilitate 60S ribosomal subunit biogenesis and ITS2 pre-rRNA processing; its nucleolar localization is regulated by SUMO-controlled partitioning of PELP1; it also participates in DNA damage checkpoint signaling by associating with TopBP1 and Chk1 to promote ATR-dependent Chk1 phosphorylation, plays a role in DNA replication licensing via MCM complex chromatin loading, and can function as an E3 ubiquitin ligase substrate receptor within a CRL4B complex."},"narrative":{"teleology":[{"year":2011,"claim":"Identification of WDR18 as a subunit of the mammalian Rix1-equivalent complex (PELP1–TEX10–WDR18–LAS1L–NOL9–SENP3) established its primary role in 60S ribosomal subunit biogenesis and ITS2 pre-rRNA processing, answering what the human ortholog of yeast Ipi3 does and how SUMO-dependent nucleolar partitioning regulates complex activity.","evidence":"Biochemical purification, reciprocal Co-IP, sucrose gradient fractionation, siRNA knockdown with pre-rRNA processing and G1-arrest phenotypes, SUMO modification assays across two independent labs","pmids":["21326211","22190735","22064470"],"confidence":"High","gaps":["Structural basis of how WDR18 contacts other rixosome subunits was unknown","Whether WDR18 has functions outside ribosome biogenesis was not addressed","Direct role of WDR18 versus other subunits in ITS2 cleavage was unresolved"]},{"year":2012,"claim":"Discovery that the same PELP1–WDR18–TEX10–LAS1L–SENP3 module is recruited to arginine-methylated Chtop as the '5FMC' complex revealed a second context—transcriptional regulation via desumoylation of the transcription factor ZBP-89—linking ribosome biogenesis components to chromatin-associated signaling.","evidence":"Biotinylation-proteomics, Co-IP, luciferase reporter assays for transactivation","pmids":["22872859"],"confidence":"Medium","gaps":["Whether WDR18 has a specific role in 5FMC beyond structural scaffolding is unknown","Functional significance of 5FMC-mediated desumoylation for endogenous gene regulation was not tested genome-wide"]},{"year":2013,"claim":"Demonstration that WDR18 binds TopBP1 and Chk1 and is required for ATR-dependent Chk1 phosphorylation established a ribosome-biogenesis-independent role in the DNA damage checkpoint, answering whether WDR18 participates in genome integrity pathways.","evidence":"In vitro and in vivo Co-IP with TopBP1 and Chk1, siRNA knockdown with Chk1 phosphorylation readout after AT70-induced damage","pmids":["23333389"],"confidence":"Medium","gaps":["Single-lab finding; independent replication is lacking","Mechanism of bridging between TopBP1 and Chk1 (direct or complex-mediated) is undefined","Whether rixosome subunits co-participate in checkpoint signaling was not tested"]},{"year":2016,"claim":"Evidence that WDR18 promotes MCM complex chromatin loading at replication origins and that its depletion impairs DNA replication licensing broadened its nuclear functions to the initiation of DNA replication.","evidence":"siRNA knockdown, BrdU incorporation, ChIP at c-Myc/Lamin-B2/β-Globin origins, Co-IP with replication-initiation proteins, immunofluorescence co-localization with MCM7","pmids":["27057756"],"confidence":"Medium","gaps":["Single-lab study; replication licensing role not independently confirmed","Whether WDR18 acts at origins as part of the rixosome or independently is unknown","Biochemical mechanism linking a WD-repeat protein to pre-RC assembly is not defined"]},{"year":2020,"claim":"Cryo-EM of yeast pre-60S intermediates revealed that the Rix1 complex (Ipi3/WDR18 ortholog included) forms a Rix1²–Ipi3² tetramer positioned near the central protuberance to monitor L1-stalk maturation in concert with Rea1, establishing the structural logic of WDR18's role in ribosome remodeling.","evidence":"Cryo-EM of multiple pre-60S states in S. cerevisiae","pmids":["32668200"],"confidence":"High","gaps":["Human-specific structural features of WDR18 in pre-60S context were not resolved","Functional contribution of WDR18/Ipi3 versus Rix1/PELP1 within the tetramer was not dissected"]},{"year":2022,"claim":"Determination of the 2.7 Å cryo-EM structure of the human PELP1–WDR18 heterotetramer revealed the atomic architecture of the core rixosome scaffold and showed that WDR18 association occludes PELP1's LxxLL motifs, structurally explaining how rixosome assembly diverts PELP1 from steroid receptor coactivation.","evidence":"Cryo-EM at 2.7 Å, complex reconstitution, biochemical subcomplex mapping","pmids":["36351913"],"confidence":"High","gaps":["How TEX10 and LAS1L attach to the PELP1–WDR18 core was not structurally resolved","Whether PELP1 switches between SR-coactivation and rixosome pools in vivo was not tested"]},{"year":2023,"claim":"Cryo-EM of the Chaetomium thermophilum rixosome on pre-60S particles showed how the Rix1 sub-module (including WDR18 ortholog) wedges between 5S rRNA and the L1 stalk to enable the 180° 5S RNP rotation required for ITS2 cleavage by Las1, providing the mechanistic basis for rixosome-coupled pre-rRNA processing.","evidence":"Cryo-EM of isolated rixosome and pre-60S-bound states from C. thermophilum","pmids":["37921038"],"confidence":"High","gaps":["Whether the human rixosome engages the pre-60S in an identical geometry was not confirmed","Regulatory inputs controlling rixosome docking timing are unresolved"]},{"year":2025,"claim":"High-resolution structures of human PELP1–WDR18–TEX10 and PELP1–WDR18–LAS1L defined the precise interfaces by which WDR18 bridges the sphere and butterfly sub-modules: two WDR18 regions contact TEX10 and a C-terminal helix contacts LAS1L, answering how the full rixosome is assembled.","evidence":"Cryo-EM of human subcomplexes, site-directed mutagenesis disrupting each contact, biochemical binding assays","pmids":["40195365"],"confidence":"High","gaps":["Complete structure of the fully assembled human rixosome on a pre-60S particle is still lacking","Conformational change of TEX10 upon ribosome engagement needs mechanistic explanation"]},{"year":2026,"claim":"Discovery that WDR18 functions as a substrate receptor in the CRL4B E3 ubiquitin ligase complex and that halofuginone acts as a molecular glue to recruit integrin β4 for degradation revealed an unexpected ubiquitin-ligase adaptor function for WDR18 outside ribosome biogenesis.","evidence":"High-throughput screening, Co-IP, ubiquitination assay, in vitro and in vivo degradation assays","pmids":["41874446"],"confidence":"Medium","gaps":["Endogenous substrates of CRL4B-WDR18 in the absence of molecular glue are unknown","Whether CRL4B-WDR18 activity intersects with ribosome biogenesis or checkpoint functions is unexplored","Single-lab finding; independent replication is awaited"]},{"year":null,"claim":"Key unresolved questions include: the identity of physiological CRL4B-WDR18 substrates, a complete cryo-EM structure of the human rixosome on the pre-60S particle, and whether WDR18's checkpoint and replication-licensing functions operate through the rixosome or represent independent moonlighting activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No endogenous CRL4B-WDR18 substrates identified","Full human rixosome-on-pre-60S structure not yet determined","Mechanistic relationship between ribosome biogenesis and DNA replication/checkpoint roles is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,8,9,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,12]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,9,10,11]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[12]}],"complexes":["Rix1/rixosome (PELP1-WDR18-TEX10-LAS1L-NOL9-SENP3)","5FMC (Five Friends of Methylated Chtop)","CRL4B-WDR18 E3 ubiquitin ligase"],"partners":["PELP1","TEX10","LAS1L","NOL9","SENP3","TOPBP1","CHEK1","MCM7"],"other_free_text":[]},"mechanistic_narrative":"WDR18 is a WD-repeat scaffold protein that functions as a core subunit of the mammalian rixosome (PELP1–WDR18–TEX10–LAS1L–NOL9–SENP3), the complex responsible for 60S ribosomal subunit maturation and ITS2 pre-rRNA processing. Within this complex, WDR18 forms a heterotetrameric assembly with PELP1, bridges TEX10 via two distinct contact sites, and recruits LAS1L through its C-terminal helix, thereby coupling the Rix1 sphere sub-module to the Las1–Grc3/NOL9 endonuclease–kinase sub-module that executes ITS2 cleavage during 5S RNP rotation on pre-60S particles [PMID:36351913, PMID:40195365, PMID:37921038]. Beyond ribosome biogenesis, WDR18 participates in DNA damage checkpoint signaling by associating with TopBP1 and Chk1 to facilitate ATR-dependent Chk1 phosphorylation [PMID:23333389], contributes to DNA replication licensing by promoting MCM complex chromatin loading at replication origins [PMID:27057756], and can serve as a substrate receptor in the CRL4B E3 ubiquitin ligase complex, where the molecular glue halofuginone redirects it to recruit integrin β4 for proteasomal degradation [PMID:41874446]."},"prefetch_data":{"uniprot":{"accession":"Q9BV38","full_name":"WD repeat-containing protein 18","aliases":[],"length_aa":432,"mass_kda":47.4,"function":"Functions as a component of the Five Friends of Methylated CHTOP (5FMC) complex; the 5FMC complex is recruited to ZNF148 by methylated CHTOP, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes (PubMed:22872859). Component of the PELP1 complex involved in the nucleolar steps of 28S rRNA maturation and the subsequent nucleoplasmic transit of the pre-60S ribosomal subunit (PubMed:21326211). May play a role during development (By similarity)","subcellular_location":"Nucleus, nucleolus; Nucleus, nucleoplasm; Cytoplasm; Dynein axonemal particle","url":"https://www.uniprot.org/uniprotkb/Q9BV38/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR18","classification":"Common Essential","n_dependent_lines":1174,"n_total_lines":1208,"dependency_fraction":0.9718543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"SRP68","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR18","total_profiled":1310},"omim":[{"mim_id":"620291","title":"WD REPEAT-CONTAINING PROTEIN 18; WDR18","url":"https://www.omim.org/entry/620291"},{"mim_id":"616717","title":"TESTIS-EXPRESSED GENE 10; TEX10","url":"https://www.omim.org/entry/616717"},{"mim_id":"609455","title":"PROLINE-, GLUTAMIC ACID-, AND LEUCINE-RICH PROTEIN 1; PELP1","url":"https://www.omim.org/entry/609455"},{"mim_id":"607760","title":"DNA TOPOISOMERASE II-BINDING PROTEIN 1; TOPBP1","url":"https://www.omim.org/entry/607760"},{"mim_id":"603078","title":"CHECKPOINT KINASE 1; CHEK1","url":"https://www.omim.org/entry/603078"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR18"},"hgnc":{"alias_symbol":["Ipi3"],"prev_symbol":[]},"alphafold":{"accession":"Q9BV38","domains":[{"cath_id":"2.130.10.10","chopping":"7-326","consensus_level":"high","plddt":91.9082,"start":7,"end":326}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BV38","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BV38-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BV38-F1-predicted_aligned_error_v6.png","plddt_mean":85.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR18","jax_strain_url":"https://www.jax.org/strain/search?query=WDR18"},"sequence":{"accession":"Q9BV38","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BV38.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BV38/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BV38"}},"corpus_meta":[{"pmid":"29106665","id":"PMC_29106665","title":"Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143.","date":"2018","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29106665","citation_count":392,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21326211","id":"PMC_21326211","title":"The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21326211","citation_count":109,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22190735","id":"PMC_22190735","title":"LAS1L interacts with the mammalian Rix1 complex to regulate ribosome biogenesis.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22190735","citation_count":89,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15528184","id":"PMC_15528184","title":"Rea1, a dynein-related nuclear AAA-ATPase, is involved in late rRNA processing and nuclear export of 60 S subunits.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15528184","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22064470","id":"PMC_22064470","title":"SUMO routes ribosome maturation.","date":"2011","source":"Nucleus (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22064470","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22872859","id":"PMC_22872859","title":"Five friends of methylated chromatin target of protein-arginine-methyltransferase[prmt]-1 (chtop), a complex linking arginine methylation to desumoylation.","date":"2012","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/22872859","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16876152","id":"PMC_16876152","title":"Alterations in ribosome biogenesis cause specific defects in C. elegans hermaphrodite gonadogenesis.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16876152","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38608691","id":"PMC_38608691","title":"Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1-2, open-label, multicohort trial.","date":"2024","source":"The Lancet. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38608691","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32668200","id":"PMC_32668200","title":"Construction of the Central Protuberance and L1 Stalk during 60S Subunit Biogenesis.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/32668200","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7565780","id":"PMC_7565780","title":"Genetic enhancement of RNA-processing defects by a dominant mutation in B52, the Drosophila gene for an SR protein splicing factor.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7565780","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15722182","id":"PMC_15722182","title":"Cloning and expression of the human NMDA receptor subunit NR3B in the adult human hippocampus.","date":"2004","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/15722182","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31691159","id":"PMC_31691159","title":"A positive feedback loop involving the LINC00346/β-catenin/MYC axis promotes hepatocellular carcinoma development.","date":"2019","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/31691159","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7828820","id":"PMC_7828820","title":"Suppressor U1 snRNAs in Drosophila.","date":"1994","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7828820","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36351913","id":"PMC_36351913","title":"Cryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36351913","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23333389","id":"PMC_23333389","title":"WD40-repeat protein WDR18 collaborates with TopBP1 to facilitate DNA damage checkpoint signaling.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23333389","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21876750","id":"PMC_21876750","title":"Wdr18 is required for Kupffer's vesicle formation and regulation of body asymmetry in zebrafish.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21876750","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19350421","id":"PMC_19350421","title":"Diffuse large B-cell lymphoma: experience from a tertiary care center in North India.","date":"2009","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19350421","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35659704","id":"PMC_35659704","title":"Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males.","date":"2022","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35659704","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37174027","id":"PMC_37174027","title":"Granulomatous and Sarcoid-like Immune-Related Adverse Events following CTLA4 and PD1 Blockade Adjuvant Therapy of Melanoma: A Combined Analysis of ECOG-ACRIN E1609 and SWOG S1404 Phase III Trials and a Literature Review.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37174027","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27057756","id":"PMC_27057756","title":"A Role of hIPI3 in DNA Replication Licensing in Human Cells.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27057756","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30890025","id":"PMC_30890025","title":"The interaction networks of the budding yeast and human DNA replication-initiation proteins.","date":"2019","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/30890025","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37921038","id":"PMC_37921038","title":"Structural insights into coordinating 5S RNP rotation with ITS2 pre-RNA processing during ribosome formation.","date":"2023","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/37921038","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39719505","id":"PMC_39719505","title":"An atlas of the shared genetic architecture between atopic and gastrointestinal diseases.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/39719505","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40195365","id":"PMC_40195365","title":"Molecular insights into the overall architecture of human rixosome.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40195365","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40677927","id":"PMC_40677927","title":"Whole Genome Sequencing of \"Mutation-Negative\" Individuals With Cornelia de Lange Syndrome.","date":"2025","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/40677927","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37398360","id":"PMC_37398360","title":"Response to high dose ipilimumab plus temozolomide after progression on standard or low dose ipilimumab in advanced melanoma: a retrospective analysis.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37398360","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40136348","id":"PMC_40136348","title":"Dramatic Responses to High-Dose Ipilimumab Plus Temozolomide After Progression on Standard- or Low-Dose Ipilimumab in Advanced Melanoma.","date":"2025","source":"Current oncology (Toronto, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/40136348","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40723429","id":"PMC_40723429","title":"Molecular Mechanism of Body Color Change in the Ecological Seedling Breeding Model of Apostichopus japonicus.","date":"2025","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40723429","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41874446","id":"PMC_41874446","title":"Halofuginone is a Molecular Glue Degrader of Integrin β4.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41874446","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22658674","id":"PMC_22658674","title":"Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22658674","citation_count":1718,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16169070","id":"PMC_16169070","title":"A human protein-protein interaction network: a resource for annotating the proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19615732","id":"PMC_19615732","title":"Defining the human deubiquitinating enzyme interaction landscape.","date":"2009","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19615732","citation_count":1282,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15635413","id":"PMC_15635413","title":"Nucleolar proteome dynamics.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15635413","citation_count":934,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11790298","id":"PMC_11790298","title":"Directed proteomic analysis of the human nucleolus.","date":"2002","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/11790298","citation_count":780,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28302793","id":"PMC_28302793","title":"Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28302793","citation_count":533,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20360068","id":"PMC_20360068","title":"Systematic analysis of human protein complexes identifies chromosome segregation proteins.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20360068","citation_count":421,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21145461","id":"PMC_21145461","title":"Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21145461","citation_count":318,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15057824","id":"PMC_15057824","title":"The DNA sequence and biology of human chromosome 19.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15057824","citation_count":271,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26949251","id":"PMC_26949251","title":"The cell proliferation antigen Ki-67 organises heterochromatin.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26949251","citation_count":265,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21900206","id":"PMC_21900206","title":"A directed protein interaction network for investigating intracellular signal transduction.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21900206","citation_count":258,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23602568","id":"PMC_23602568","title":"The protein interaction landscape of the human CMGC kinase group.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23602568","citation_count":174,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25544563","id":"PMC_25544563","title":"Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25544563","citation_count":173,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32807901","id":"PMC_32807901","title":"UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32807901","citation_count":168,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30804502","id":"PMC_30804502","title":"H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30804502","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30833792","id":"PMC_30833792","title":"A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30833792","citation_count":159,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32416067","id":"PMC_32416067","title":"Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/32416067","citation_count":159,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31995728","id":"PMC_31995728","title":"AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31995728","citation_count":152,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21549307","id":"PMC_21549307","title":"Maintenance of silent chromatin through replication requires SWI/SNF-like chromatin remodeler SMARCAD1.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21549307","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16776,"output_tokens":3159,"usd":0.048856},"stage2":{"model":"claude-opus-4-6","input_tokens":6535,"output_tokens":3375,"usd":0.175575},"total_usd":0.470678,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":28295,"output_tokens":3730,"usd":0.070417},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7364,"output_tokens":3216,"usd":0.17583}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"WDR18 is a component of a mammalian SENP3-associated complex comprising PELP1, TEX10, and WDR18, which is involved in maturation and nucleolar release of the large (60S) ribosomal subunit; SUMO conjugation/deconjugation of PELP1 controls the nucleolar partitioning of this complex.\",\n      \"method\": \"Biochemical purification, co-immunoprecipitation, functional depletion assays, subcellular localization imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, biochemical purification, functional depletion with defined cellular phenotype, replicated across two papers from the same group\",\n      \"pmids\": [\"21326211\", \"22064470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"WDR18 (as part of the LAS1L-PELP1-TEX10-WDR18-NOL9-SENP3 complex, the mammalian Rix1 complex) co-fractionates with the 60S preribosomal subunit, and depletion of WDR18-associated proteins causes defects in pre-rRNA ITS2 processing and p53-dependent G1 arrest; nucleolar localization of the complex requires active RNA Pol I transcription and SENP3.\",\n      \"method\": \"Co-immunoprecipitation, sucrose gradient fractionation, siRNA knockdown with pre-rRNA processing assays and cell cycle analysis, immunofluorescence localization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, defined cellular and molecular phenotypes, independently corroborated\",\n      \"pmids\": [\"22190735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WDR18 is a component of the Five Friends of Methylated Chtop (5FMC) nuclear complex, which also includes PELP1, SENP3, TEX10, and LAS1L; PELP1 serves as the core scaffold and WDR18 becomes unstable in its absence; recruitment of 5FMC to transcription factor Zbp-89 affects its sumoylation and transactivation, linking arginine methylation to desumoylation in transcriptional control.\",\n      \"method\": \"Biotinylation-proteomics (BioID-like), co-immunoprecipitation, siRNA knockdown, luciferase transcriptional assay\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS interactome plus functional co-IP and reporter assay, single lab\",\n      \"pmids\": [\"22872859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WDR18 associates with the C-terminus of TopBP1 in vitro and in vivo, and also binds Chk1; WDR18 is required for ATR-dependent Chk1 phosphorylation in response to DNA damage, functioning together with TopBP1 to promote DNA damage checkpoint signaling.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo), siRNA knockdown with Chk1 phosphorylation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding shown in vitro and in vivo, functional KD with defined phosphorylation readout; single lab\",\n      \"pmids\": [\"23333389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Zebrafish wdr18 is expressed in dorsal forerunner cells (DFCs) and Kupffer's vesicle (KV), and morpholino knockdown disrupts DFC clustering/migration, results in fewer and shorter immotile cilia in the KV, and causes laterality defects; wdr18 genetically interacts with itgb1b in L-R asymmetry determination.\",\n      \"method\": \"Morpholino knockdown, in situ hybridization, cilia imaging, genetic epistasis (double morphant)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct knockdown with specific morphological/molecular readouts and genetic interaction, single lab\",\n      \"pmids\": [\"21876750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human WDR18 (hIPI3) is required for DNA replication licensing: knockdown causes defects in chromatin association of the MCM complex, DNA replication, cell cycle progression, and cell proliferation; hIPI3 protein levels peak from M phase to early G1, co-localizes with hMCM7 in the nucleus and is important for nuclear localization of hMCM7, and preferentially binds origins of replication (c-Myc, Lamin-B2, β-Globin loci).\",\n      \"method\": \"siRNA knockdown, BrdU incorporation assay, chromatin fractionation, co-immunoprecipitation, ChIP, immunofluorescence, cell cycle analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing DNA replication licensing role, single lab\",\n      \"pmids\": [\"27057756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pairwise yeast two-hybrid and co-immunoprecipitation analyses confirmed that human WDR18 (hIPI3) interacts with multiple DNA replication initiation proteins including ORC subunits, MCM subunits, and pre-RC/pre-IC components, expanding its known protein interaction network in replication licensing.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — systematic Y2H confirmed by co-IP for selected interactions, single lab\",\n      \"pmids\": [\"30890025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure at 2.7 Å of the human PELP1 Rix1 domain–WDR18 subcomplex reveals an interconnected tetrameric assembly; WDR18 forms the core scaffold with PELP1, and the structure shows that PELP1's eleven LxxLL motifs are in conformations incompatible with steroid receptor binding, suggesting WDR18 association directs PELP1 activity away from steroid receptor coactivation toward ribosome biogenesis.\",\n      \"method\": \"Cryo-EM structure determination (2.7 Å), biochemical reconstitution of mammalian Rix1 complex, mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure plus biochemical reconstitution and functional interpretation via mutagenesis\",\n      \"pmids\": [\"36351913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The yeast Rix1 complex (Rix1-Ipi1-Ipi3, orthologous to human PELP1-TEX10-WDR18) forms a Rix1²-Ipi3² tetramer anchored to pre-60S particles via Ipi1 and, together with the AAA ATPase Rea1, catalyzes large-scale structural transitions in 60S ribosome maturation including development of the L1 stalk and central protuberance.\",\n      \"method\": \"Cryo-EM of pre-60S intermediates, structural analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM at molecular resolution of yeast ortholog complex in its native pre-ribosomal context\",\n      \"pmids\": [\"32668200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The rixosome (including the Rix1-Ipi3-Ipi1 sphere sub-module orthologous to PELP1-WDR18-TEX10) uses Sda1 as a landing platform on nucleoplasmic pre-60S particles; wedging between the 5S rRNA tip and L1-stalk facilitates the 180° rotation of the immature 5S RNP, and positions the Las1 endonuclease/Grc3 kinase sub-module to cleave and 5'-phosphorylate ITS2 pre-rRNA.\",\n      \"method\": \"Cryo-EM structural analysis of rixosome from Chaetomium thermophilum bound to pre-60S\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structural determination of intact rixosome in pre-ribosomal context, mechanistic interpretation supported by structure\",\n      \"pmids\": [\"37921038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of human PELP1-WDR18-TEX10 and LAS1L-NOL9 complexes, plus a lower-resolution model of PELP1-WDR18-LAS1L, reveal that WDR18 contacts TEX10 via two regions and its C-terminal helix contacts the helical domain of LAS1L; mutagenesis of WDR18-TEX10 contact regions blocks TEX10 binding, and truncation of WDR18's C-terminal helix abolishes LAS1L binding.\",\n      \"method\": \"Cryo-EM structure determination, site-directed mutagenesis, co-immunoprecipitation binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures combined with functional mutagenesis validating specific protein-protein contacts\",\n      \"pmids\": [\"40195365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"WDR18 is a component of the CRL4B-WDR18 E3 ubiquitin ligase complex; the natural product halofuginone acts as a molecular glue degrader that uses this complex to promote ubiquitin-dependent degradation of integrin β4 (ITGB4).\",\n      \"method\": \"High-throughput screening, protein degradation assays in vitro and in vivo, complex identification\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional degradation assay with complex identification, single lab, mechanism proposed but detailed biochemical reconstitution not fully described in abstract\",\n      \"pmids\": [\"41874446\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR18 is a WD-repeat scaffold protein that functions as a core structural component of the mammalian Rix1/rixosome complex (with PELP1, TEX10, LAS1L, NOL9, and SENP3), where its C-terminal helix recruits LAS1L endonuclease activity and two contact regions anchor TEX10, together driving 60S ribosomal subunit maturation by facilitating ITS2 pre-rRNA cleavage and 5S RNP rotation; additionally, WDR18 participates in DNA damage checkpoint signaling by interacting with TopBP1 and Chk1 to promote ATR-dependent Chk1 phosphorylation, contributes to DNA replication licensing by supporting MCM complex chromatin loading, and serves as a substrate receptor in a CRL4B E3 ubiquitin ligase complex.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"WDR18 is a component of a mammalian PELP1-TEX10-WDR18 complex (homologous to the yeast Rix1 complex) that is involved in maturation and nucleolar release of the large (60S) ribosomal subunit. Biochemical purification showed this complex associates with SENP3, and SUMO conjugation/deconjugation of PELP1 controls the nucleolar partitioning of the complex, thereby regulating ribosome biogenesis.\",\n      \"method\": \"Biochemical purification (SENP3-associated complex isolation), co-immunoprecipitation, functional depletion assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional depletion with defined phenotype, independently replicated across two labs in same year\",\n      \"pmids\": [\"21326211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"WDR18 (as part of the PELP1-TEX10-WDR18-LAS1L-NOL9-SENP3 complex) co-fractionates with the 60S preribosomal subunit. Depletion of complex members including WDR18-associated proteins causes a p53-dependent G1 arrest and defects in processing of the pre-rRNA ITS2 region. Nucleolar localization of the complex requires active RNA Pol I transcription and SENP3.\",\n      \"method\": \"Co-immunoprecipitation, sucrose gradient fractionation, siRNA knockdown with phenotypic readout (G1 arrest, pre-rRNA processing defects), fluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, Co-IP, KD with defined molecular and cell-cycle phenotype), independent replication\",\n      \"pmids\": [\"22190735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SUMO-dependent subnuclear trafficking controls the PELP1-TEX10-WDR18 complex. PELP1 is a SENP3-sensitive SUMO target; lack of SENP3-mediated desumoylation prevents nucleolar partitioning of the PELP1-WDR18-TEX10 complex, restricting premature loading onto 60S particles and limiting ribosome maturation rate.\",\n      \"method\": \"SUMO modification assays, SENP3 depletion/overexpression, subcellular fractionation, imaging\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic follow-up from single lab, consistent with prior EMBO J study\",\n      \"pmids\": [\"22064470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WDR18 is a member of the 'Five Friends of Methylated Chtop' (5FMC) nuclear complex, recruited to the chromatin-associated protein Chtop only when Chtop is arginine-methylated by PRMT1. The 5FMC complex (PELP1, SENP3, WDR18, TEX10, LAS1L) affects the sumoylation status and transactivation potential of the transcription factor ZBP-89, linking arginine methylation to desumoylation in transcriptional control. PELP1 functions as the core scaffold; other components including WDR18 become unstable in its absence.\",\n      \"method\": \"Biotinylation-proteomics (BioID-like), co-immunoprecipitation, luciferase reporter assays, western blotting\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics plus functional reporter assay, single lab\",\n      \"pmids\": [\"22872859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WDR18 associates with the C-terminus of TopBP1 (in vitro and in vivo) and with Chk1 in vitro. This association is required for ATR-dependent Chk1 phosphorylation in response to DNA damage (AT70-induced). WDR18 depletion abolishes Chk1 activation, identifying WDR18 as a DNA damage checkpoint protein that facilitates ATR-Chk1 signaling by bridging TopBP1 and Chk1.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown with Chk1 phosphorylation readout\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vitro and in vivo binding plus functional KD phenotype, single lab\",\n      \"pmids\": [\"23333389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Zebrafish wdr18 is expressed in dorsal forerunner cells (DFCs) and Kupffer's vesicle (KV). Morpholino knockdown of wdr18 causes laterality defects (mis-expression of Nodal-related genes spaw and pitx2), KV with fewer, shorter, immotile cilia and smaller cavity, and disorganized DFC clustering and migration. Genetic interaction with itgb1b was demonstrated by double morpholino injection, placing wdr18 in a pathway controlling DFC migration and left-right asymmetry determination.\",\n      \"method\": \"Morpholino knockdown, in situ hybridization, cilia motility analysis, genetic epistasis (double morpholino), fluorescence imaging with cell-lineage markers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific molecular and cellular phenotype, genetic epistasis, single lab\",\n      \"pmids\": [\"21876750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human WDR18 (hIPI3) is required for DNA replication licensing. Knockdown causes defects in chromatin association of the MCM complex, DNA replication, and cell cycle progression without affecting global protein synthesis. hIPI3 protein and mRNA levels peak from M phase to early G1, similar to pre-RC proteins. hIPI3 interacts with replication-initiation proteins, co-localizes with hMCM7 in the nucleus, is important for nuclear localization of hMCM7, and preferentially binds origins of replication at c-Myc, Lamin-B2, and β-Globin loci.\",\n      \"method\": \"siRNA knockdown, DNA replication assay (BrdU incorporation), ChIP at replication origins, co-immunoprecipitation, immunofluorescence co-localization, cell cycle analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, Co-IP, IF, flow cytometry), single lab\",\n      \"pmids\": [\"27057756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In systematic pairwise yeast two-hybrid and co-immunoprecipitation analyses of human replication-initiation proteins, WDR18 (hIPI3) was found to interact with several pre-RC and pre-IC proteins, including novel interactions not previously reported, consistent with its role in replication licensing.\",\n      \"method\": \"Yeast two-hybrid (systematic pairwise), co-immunoprecipitation validation of novel interactions\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — systematic Y2H with partial Co-IP confirmation, large-scale screen context\",\n      \"pmids\": [\"30890025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of the human PELP1-WDR18 subcomplex was determined at 2.7 Å, revealing an interconnected tetrameric assembly (PELP1-WDR18 heterotetramer). The structure shows the architecture of PELP1's eleven LxxLL motifs previously implicated in steroid receptor (SR) signaling; none is in a conformation compatible with SR binding, suggesting that WDR18 association directs PELP1 activity away from SR coactivation toward Rix1 complex functions. PELP1 was confirmed as the central scaffold of the human Rix1 complex (PELP1, WDR18, TEX10, SENP3) by reconstitution.\",\n      \"method\": \"Cryo-EM (2.7 Å structure), complex reconstitution, biochemical subcomplex mapping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with complex reconstitution and functional inference from structural analysis\",\n      \"pmids\": [\"36351913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The yeast Rix1 complex (Rix1-Ipi1-Ipi3, orthologs of human PELP1-TEX10-WDR18) forms a Rix1²-Ipi3² tetramer anchored to the pre-60S ribosome via Ipi1. Cryo-EM analysis of nuclear pre-60S intermediates shows this complex is strategically positioned near the central protuberance to monitor and assist large-scale structural remodeling events including L1 stalk maturation, working in concert with the AAA-ATPase Rea1.\",\n      \"method\": \"Cryo-EM of pre-60S intermediates (multiple states), structural modeling\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structural analysis at molecular resolution of the orthologous complex in pre-ribosomal context\",\n      \"pmids\": [\"32668200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of the conserved rixosome from Chaetomium thermophilum (Rix1-Ipi3-Ipi1 sphere sub-module plus Las1-Grc3 butterfly sub-module) reveal how the Rix1 complex (WDR18 ortholog Ipi3 included) wedges between the 5S rRNA tip and L1-stalk on nucleoplasmic pre-60S particles to facilitate 180° rotation of the immature 5S RNP, enabling ITS2 pre-rRNA cleavage by Las1 endonuclease and phosphorylation by Grc3 kinase.\",\n      \"method\": \"Cryo-EM structural analysis of isolated rixosome and pre-60S-bound states, biochemical isolation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures of orthologous complex defining mechanistic coordination of 5S RNP rotation and ITS2 processing\",\n      \"pmids\": [\"37921038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of the human PELP1-WDR18-TEX10 complex and the LAS1L-NOL9 complex were determined, plus a lower-resolution model of PELP1-WDR18-LAS1L. WDR18 contacts TEX10 at two distinct regions and its C-terminal helix contacts the helical domain of LAS1L. Mutagenesis confirmed that disrupting either WDR18-TEX10 contact blocks TEX10 binding, and truncation of the WDR18 C-terminal helix abolishes LAS1L recruitment. TEX10 undergoes substantial conformational changes between the PELP1-WDR18-TEX10 complex alone and when bound to the pre-ribosome.\",\n      \"method\": \"Cryo-EM structure determination, site-directed mutagenesis, biochemical binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures with mutagenesis validation of specific interaction interfaces\",\n      \"pmids\": [\"40195365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"WDR18 functions as a substrate receptor within the CRL4B^WDR18 E3 ubiquitin ligase complex. The natural product halofuginone acts as a molecular glue that promotes recruitment of integrin β4 to this CRL4B-WDR18 complex, leading to integrin β4 polyubiquitination and proteasomal degradation.\",\n      \"method\": \"High-throughput screening, co-immunoprecipitation, ubiquitination assay, in vitro and in vivo degradation assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional degradation assay with molecular glue mechanism, single lab\",\n      \"pmids\": [\"41874446\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR18 is a WD-repeat scaffold protein that serves as a core subunit of the mammalian Rix1/rixosome complex (with PELP1, TEX10, LAS1L, NOL9, and SENP3), where it bridges PELP1 to TEX10 and LAS1L to facilitate 60S ribosomal subunit biogenesis and ITS2 pre-rRNA processing; its nucleolar localization is regulated by SUMO-controlled partitioning of PELP1; it also participates in DNA damage checkpoint signaling by associating with TopBP1 and Chk1 to promote ATR-dependent Chk1 phosphorylation, plays a role in DNA replication licensing via MCM complex chromatin loading, and can function as an E3 ubiquitin ligase substrate receptor within a CRL4B complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"WDR18 is a WD-repeat scaffold protein that functions at the intersection of ribosome biogenesis, DNA damage checkpoint signaling, and DNA replication licensing. As a core subunit of the mammalian rixosome (PELP1–WDR18–TEX10–LAS1L–NOL9–SENP3), WDR18 forms an interconnected tetramer with PELP1, recruits TEX10 via two contact regions, and bridges LAS1L endonuclease through its C-terminal helix, thereby enabling ITS2 pre-rRNA cleavage and 5S RNP rotation during 60S ribosomal subunit maturation [PMID:22190735, PMID:36351913, PMID:40195365, PMID:37921038]. Independent of ribosome biogenesis, WDR18 interacts with TopBP1 and Chk1 to promote ATR-dependent Chk1 phosphorylation in DNA damage checkpoint signaling [PMID:23333389], supports DNA replication licensing by facilitating MCM complex chromatin loading and binding replication origins [PMID:27057756], and serves as a substrate receptor in the CRL4B E3 ubiquitin ligase complex [PMID:41874446].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that WDR18 is a stable subunit of a SENP3-associated complex (with PELP1, TEX10, LAS1L, NOL9) that co-fractionates with the pre-60S ribosomal subunit and is required for ITS2 pre-rRNA processing answered the fundamental question of WDR18's primary molecular context and linked it to large ribosomal subunit biogenesis.\",\n      \"evidence\": \"Biochemical purification, co-IP, sucrose gradient fractionation, siRNA knockdown with pre-rRNA processing assays and cell cycle analysis in mammalian cells\",\n      \"pmids\": [\"21326211\", \"22064470\", \"22190735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contribution of WDR18 versus other subunits to ITS2 cleavage not resolved\", \"No structural information on WDR18 within the complex\", \"Mechanism by which SUMO/SENP3 regulates complex assembly unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Zebrafish knockdown revealed a developmental role for wdr18 in dorsal forerunner cell clustering, Kupffer's vesicle ciliogenesis, and left-right asymmetry, broadening WDR18 function beyond ribosome biogenesis to organ patterning.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with cilia imaging and genetic epistasis with itgb1b\",\n      \"pmids\": [\"21876750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino artifacts not ruled out by genetic mutant\", \"Whether the cilia/laterality phenotype is secondary to ribosome biogenesis defects not tested\", \"Mammalian cilia role not examined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of the 5FMC complex showed that PELP1 is the core scaffold stabilizing WDR18, and that the complex can be recruited to transcription factors to modulate sumoylation, raising the possibility that WDR18 participates in transcriptional regulation beyond ribosome biogenesis.\",\n      \"evidence\": \"BioID-like proteomics, co-IP, siRNA knockdown, luciferase reporter assay in mammalian cells\",\n      \"pmids\": [\"22872859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional role assessed with a single reporter; genome-wide effects unknown\", \"Whether WDR18 directly contacts Zbp-89 or acts indirectly through PELP1 unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that WDR18 binds TopBP1 and Chk1 and is required for ATR-dependent Chk1 phosphorylation established a discrete checkpoint-signaling function for WDR18 independent of its ribosome biogenesis role.\",\n      \"evidence\": \"In vitro and in vivo co-IP, siRNA knockdown with Chk1 phosphorylation readout in mammalian cells\",\n      \"pmids\": [\"23333389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not independently confirmed by a second group\", \"Whether TopBP1 binding is direct or bridged by another factor not resolved with purified proteins\", \"Relationship between ribosome biogenesis and checkpoint functions of WDR18 not delineated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that WDR18 protein levels peak in M/G1, co-localizes with MCM7, binds replication origins, and is required for MCM chromatin loading established a role in DNA replication licensing, temporally and functionally distinct from its ribosome biogenesis activity.\",\n      \"evidence\": \"siRNA knockdown, BrdU incorporation, chromatin fractionation, ChIP, co-IP, immunofluorescence in human cells\",\n      \"pmids\": [\"27057756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding; independent replication lacking\", \"Whether WDR18 directly contacts ORC/MCM subunits or acts through a bridging factor not determined\", \"No separation-of-function mutant distinguishing replication licensing from ribosome biogenesis\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Systematic yeast two-hybrid mapping extended WDR18's interaction network to multiple ORC and MCM subunits and pre-RC/pre-IC components, reinforcing the replication licensing model.\",\n      \"evidence\": \"Yeast two-hybrid screen confirmed by co-IP for selected interactions\",\n      \"pmids\": [\"30890025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Y2H interactions not validated by endogenous co-IP in all cases\", \"Functional significance of individual interactions not tested\", \"Potential for indirect bridging not excluded\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cryo-EM of yeast pre-60S particles revealed that the Rix1–Ipi3 (PELP1–WDR18) tetramer anchors to the pre-ribosome via Ipi1 (TEX10) and, together with Rea1, catalyzes large-scale structural rearrangements including L1 stalk development and central protuberance formation, providing the first structural view of WDR18's ortholog in its functional context.\",\n      \"evidence\": \"Cryo-EM of S. cerevisiae pre-60S intermediates\",\n      \"pmids\": [\"32668200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast structure; human rixosome conformation on pre-60S not resolved\", \"Specific contacts between Ipi3 and rRNA/ribosomal proteins not fully mapped\", \"Mechanism of Rea1 coordination with rixosome not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A 2.7 Å cryo-EM structure of the human PELP1 Rix1 domain–WDR18 subcomplex showed an interconnected tetrameric assembly and demonstrated that PELP1's LxxLL motifs adopt conformations incompatible with steroid receptor binding, establishing that WDR18 association structurally redirects PELP1 toward ribosome biogenesis.\",\n      \"evidence\": \"Cryo-EM structure determination with biochemical reconstitution and mutagenesis of human proteins\",\n      \"pmids\": [\"36351913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure lacks TEX10 and LAS1L; full human rixosome architecture not resolved\", \"Functional consequence of disrupting the PELP1–WDR18 tetramer on ribosome biogenesis in cells not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-EM of the Chaetomium thermophilum rixosome on pre-60S particles showed how the Rix1–Ipi3 sphere wedges between 5S rRNA and the L1 stalk to drive 5S RNP rotation and positions LAS1 for ITS2 cleavage, mechanistically explaining the rixosome's catalytic role.\",\n      \"evidence\": \"Cryo-EM of fungal rixosome bound to pre-60S particles\",\n      \"pmids\": [\"37921038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human rixosome on pre-60S not yet visualized\", \"Whether human complex uses identical landing platform (Sda1 ortholog) unconfirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"High-resolution cryo-EM structures of human PELP1–WDR18–TEX10 and PELP1–WDR18–LAS1L, combined with mutagenesis, mapped two WDR18 contact regions for TEX10 and identified WDR18's C-terminal helix as essential for LAS1L recruitment, defining WDR18 as the central hub connecting the rixosome's scaffold and catalytic modules.\",\n      \"evidence\": \"Cryo-EM of human subcomplexes, site-directed mutagenesis with co-IP binding assays\",\n      \"pmids\": [\"40195365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full hexameric human rixosome structure (with NOL9 and SENP3) not yet solved\", \"Functional impact of WDR18 contact-site mutations on ITS2 processing in cells not reported\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of WDR18 as the substrate receptor in a CRL4B E3 ubiquitin ligase complex that mediates halofuginone-induced degradation of integrin β4 uncovered a ubiquitin-ligase adaptor function for WDR18 outside the rixosome.\",\n      \"evidence\": \"High-throughput screening, protein degradation assays in vitro and in vivo, complex identification\",\n      \"pmids\": [\"41874446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous substrates of CRL4B-WDR18 beyond the molecular-glue context unknown\", \"Whether CRL4B-WDR18 operates constitutively or is induced under specific conditions not determined\", \"Structural basis of WDR18-DDB1/CUL4B interaction not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include how WDR18's ribosome biogenesis, DNA replication licensing, checkpoint, and ubiquitin ligase functions are coordinated or partitioned in cells, whether separation-of-function mutants can delineate these activities, and how the complete human rixosome engages pre-60S particles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No separation-of-function mutants distinguishing rixosome vs. replication vs. checkpoint roles\", \"Full human rixosome on pre-60S not visualized by cryo-EM\", \"Endogenous CRL4B-WDR18 substrates not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 7, 10, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [7, 8, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 9, 10]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"complexes\": [\n      \"Rixosome (PELP1-WDR18-TEX10-LAS1L-NOL9-SENP3)\",\n      \"CRL4B-WDR18 E3 ubiquitin ligase\"\n    ],\n    \"partners\": [\n      \"PELP1\",\n      \"TEX10\",\n      \"LAS1L\",\n      \"NOL9\",\n      \"SENP3\",\n      \"TOPBP1\",\n      \"CHEK1\",\n      \"MCM7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"WDR18 is a WD-repeat scaffold protein that functions as a core subunit of the mammalian rixosome (PELP1–WDR18–TEX10–LAS1L–NOL9–SENP3), the complex responsible for 60S ribosomal subunit maturation and ITS2 pre-rRNA processing. Within this complex, WDR18 forms a heterotetrameric assembly with PELP1, bridges TEX10 via two distinct contact sites, and recruits LAS1L through its C-terminal helix, thereby coupling the Rix1 sphere sub-module to the Las1–Grc3/NOL9 endonuclease–kinase sub-module that executes ITS2 cleavage during 5S RNP rotation on pre-60S particles [PMID:36351913, PMID:40195365, PMID:37921038]. Beyond ribosome biogenesis, WDR18 participates in DNA damage checkpoint signaling by associating with TopBP1 and Chk1 to facilitate ATR-dependent Chk1 phosphorylation [PMID:23333389], contributes to DNA replication licensing by promoting MCM complex chromatin loading at replication origins [PMID:27057756], and can serve as a substrate receptor in the CRL4B E3 ubiquitin ligase complex, where the molecular glue halofuginone redirects it to recruit integrin β4 for proteasomal degradation [PMID:41874446].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of WDR18 as a subunit of the mammalian Rix1-equivalent complex (PELP1–TEX10–WDR18–LAS1L–NOL9–SENP3) established its primary role in 60S ribosomal subunit biogenesis and ITS2 pre-rRNA processing, answering what the human ortholog of yeast Ipi3 does and how SUMO-dependent nucleolar partitioning regulates complex activity.\",\n      \"evidence\": \"Biochemical purification, reciprocal Co-IP, sucrose gradient fractionation, siRNA knockdown with pre-rRNA processing and G1-arrest phenotypes, SUMO modification assays across two independent labs\",\n      \"pmids\": [\"21326211\", \"22190735\", \"22064470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of how WDR18 contacts other rixosome subunits was unknown\",\n        \"Whether WDR18 has functions outside ribosome biogenesis was not addressed\",\n        \"Direct role of WDR18 versus other subunits in ITS2 cleavage was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that the same PELP1–WDR18–TEX10–LAS1L–SENP3 module is recruited to arginine-methylated Chtop as the '5FMC' complex revealed a second context—transcriptional regulation via desumoylation of the transcription factor ZBP-89—linking ribosome biogenesis components to chromatin-associated signaling.\",\n      \"evidence\": \"Biotinylation-proteomics, Co-IP, luciferase reporter assays for transactivation\",\n      \"pmids\": [\"22872859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether WDR18 has a specific role in 5FMC beyond structural scaffolding is unknown\",\n        \"Functional significance of 5FMC-mediated desumoylation for endogenous gene regulation was not tested genome-wide\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that WDR18 binds TopBP1 and Chk1 and is required for ATR-dependent Chk1 phosphorylation established a ribosome-biogenesis-independent role in the DNA damage checkpoint, answering whether WDR18 participates in genome integrity pathways.\",\n      \"evidence\": \"In vitro and in vivo Co-IP with TopBP1 and Chk1, siRNA knockdown with Chk1 phosphorylation readout after AT70-induced damage\",\n      \"pmids\": [\"23333389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; independent replication is lacking\",\n        \"Mechanism of bridging between TopBP1 and Chk1 (direct or complex-mediated) is undefined\",\n        \"Whether rixosome subunits co-participate in checkpoint signaling was not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Evidence that WDR18 promotes MCM complex chromatin loading at replication origins and that its depletion impairs DNA replication licensing broadened its nuclear functions to the initiation of DNA replication.\",\n      \"evidence\": \"siRNA knockdown, BrdU incorporation, ChIP at c-Myc/Lamin-B2/β-Globin origins, Co-IP with replication-initiation proteins, immunofluorescence co-localization with MCM7\",\n      \"pmids\": [\"27057756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; replication licensing role not independently confirmed\",\n        \"Whether WDR18 acts at origins as part of the rixosome or independently is unknown\",\n        \"Biochemical mechanism linking a WD-repeat protein to pre-RC assembly is not defined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cryo-EM of yeast pre-60S intermediates revealed that the Rix1 complex (Ipi3/WDR18 ortholog included) forms a Rix1²–Ipi3² tetramer positioned near the central protuberance to monitor L1-stalk maturation in concert with Rea1, establishing the structural logic of WDR18's role in ribosome remodeling.\",\n      \"evidence\": \"Cryo-EM of multiple pre-60S states in S. cerevisiae\",\n      \"pmids\": [\"32668200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Human-specific structural features of WDR18 in pre-60S context were not resolved\",\n        \"Functional contribution of WDR18/Ipi3 versus Rix1/PELP1 within the tetramer was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Determination of the 2.7 Å cryo-EM structure of the human PELP1–WDR18 heterotetramer revealed the atomic architecture of the core rixosome scaffold and showed that WDR18 association occludes PELP1's LxxLL motifs, structurally explaining how rixosome assembly diverts PELP1 from steroid receptor coactivation.\",\n      \"evidence\": \"Cryo-EM at 2.7 Å, complex reconstitution, biochemical subcomplex mapping\",\n      \"pmids\": [\"36351913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How TEX10 and LAS1L attach to the PELP1–WDR18 core was not structurally resolved\",\n        \"Whether PELP1 switches between SR-coactivation and rixosome pools in vivo was not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-EM of the Chaetomium thermophilum rixosome on pre-60S particles showed how the Rix1 sub-module (including WDR18 ortholog) wedges between 5S rRNA and the L1 stalk to enable the 180° 5S RNP rotation required for ITS2 cleavage by Las1, providing the mechanistic basis for rixosome-coupled pre-rRNA processing.\",\n      \"evidence\": \"Cryo-EM of isolated rixosome and pre-60S-bound states from C. thermophilum\",\n      \"pmids\": [\"37921038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the human rixosome engages the pre-60S in an identical geometry was not confirmed\",\n        \"Regulatory inputs controlling rixosome docking timing are unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"High-resolution structures of human PELP1–WDR18–TEX10 and PELP1–WDR18–LAS1L defined the precise interfaces by which WDR18 bridges the sphere and butterfly sub-modules: two WDR18 regions contact TEX10 and a C-terminal helix contacts LAS1L, answering how the full rixosome is assembled.\",\n      \"evidence\": \"Cryo-EM of human subcomplexes, site-directed mutagenesis disrupting each contact, biochemical binding assays\",\n      \"pmids\": [\"40195365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Complete structure of the fully assembled human rixosome on a pre-60S particle is still lacking\",\n        \"Conformational change of TEX10 upon ribosome engagement needs mechanistic explanation\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Discovery that WDR18 functions as a substrate receptor in the CRL4B E3 ubiquitin ligase complex and that halofuginone acts as a molecular glue to recruit integrin β4 for degradation revealed an unexpected ubiquitin-ligase adaptor function for WDR18 outside ribosome biogenesis.\",\n      \"evidence\": \"High-throughput screening, Co-IP, ubiquitination assay, in vitro and in vivo degradation assays\",\n      \"pmids\": [\"41874446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous substrates of CRL4B-WDR18 in the absence of molecular glue are unknown\",\n        \"Whether CRL4B-WDR18 activity intersects with ribosome biogenesis or checkpoint functions is unexplored\",\n        \"Single-lab finding; independent replication is awaited\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the identity of physiological CRL4B-WDR18 substrates, a complete cryo-EM structure of the human rixosome on the pre-60S particle, and whether WDR18's checkpoint and replication-licensing functions operate through the rixosome or represent independent moonlighting activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No endogenous CRL4B-WDR18 substrates identified\",\n        \"Full human rixosome-on-pre-60S structure not yet determined\",\n        \"Mechanistic relationship between ribosome biogenesis and DNA replication/checkpoint roles is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 8, 9, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"Rix1/rixosome (PELP1-WDR18-TEX10-LAS1L-NOL9-SENP3)\",\n      \"5FMC (Five Friends of Methylated Chtop)\",\n      \"CRL4B-WDR18 E3 ubiquitin ligase\"\n    ],\n    \"partners\": [\n      \"PELP1\",\n      \"TEX10\",\n      \"LAS1L\",\n      \"NOL9\",\n      \"SENP3\",\n      \"TOPBP1\",\n      \"CHEK1\",\n      \"MCM7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}