{"gene":"NOL10","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2016,"finding":"NOL10 forms a salt-stable trimeric complex (ANN complex) with AATF/Che-1 and NGDN in the nucleolus; the WD40 repeats of NOL10 are required for complex formation. All three members show mutual dependence for protein stability, and the complex is required for 18S rRNA maturation and nucleolar cleavage steps in the 5'ETS and ITS1 regions of pre-rRNA, supporting 40S ribosomal subunit biogenesis.","method":"Immunoprecipitation, protein interaction domain mapping, siRNA depletion, rRNA processing analysis (Northern blot/pulse-chase), nucleolar localization by microscopy","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping mutagenesis, functional depletion with specific rRNA processing readout, multiple orthogonal methods in a single rigorous study","pmids":["27599843"],"is_preprint":false},{"year":2023,"finding":"PQBP5/NOL10 is an intrinsically disordered protein that constitutes the skeletal granule meshwork of the granular component of the nucleolus. Unlike other nucleolar proteins, it remains in the nucleolus under osmotic stress and functions as an anchor for reassembly of dispersed nucleolar proteins. Its biophysical properties (assessed by droplet and thermal shift assays) remain stable under stress. Sequestration by polyglutamine disease proteins depletes functional PQBP5/NOL10, causing pathological nucleolar deformity or disappearance.","method":"High-speed atomic force microscopy (HS-AFM), super-resolution microscopy, correlative light and electron microscopy (CLEM), droplet assay, thermal shift assay, live-cell imaging under osmotic stress, in vitro and in vivo polyglutamine sequestration","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal structural and biophysical methods (HS-AFM, CLEM, super-resolution), functional rescue/depletion assays, replicated across in vitro and in vivo models","pmids":["36599853"],"is_preprint":false},{"year":2014,"finding":"GFP-NOL10 localizes to the granular component region of nucleoli and exhibits very low mobility in living cells, consistent with tight association with large protein complexes; when rRNA transcription is suppressed, its mobility increases but remains slow, suggesting it acts as a scaffold or core component within SSU processome-related complexes.","method":"GFP fusion live-cell imaging, FRAP in HeLa cells, pharmacological inhibition of rRNA transcription","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization and dynamics experiment with functional inference, single lab but consistent with broader complex data","pmids":["24754225"],"is_preprint":false},{"year":2025,"finding":"A homozygous NOL10 variant (p.Asn228His) within the WD-repeat domain causes nucleoplasmic mislocalization of NOL10 and loss of interaction with AATF and NGDN. Patient fibroblasts show specific impairment of 40S subunit maturation, reduced 40S, 80S, and polysome content, G0/G1 arrest, and increased cell death, establishing that NOL10 WD-repeat integrity is required for its nucleolar localization, partner binding, and 40S ribosome biogenesis function.","method":"Exome sequencing, structural modeling (ΔΔG), immunofluorescence (mislocalization), co-immunoprecipitation (loss of AATF/NGDN interaction), polysome profiling, cell cycle analysis, cell death assay in patient fibroblasts","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, polysome profiling, and localization in patient-derived cells with functional readouts; single lab, single case","pmids":["41093997"],"is_preprint":false},{"year":2025,"finding":"NOL10 interacts with 24 amino acids within the DDX10 moiety of the NUP98::DDX10 fusion protein. NOL10 acts cooperatively with NUP98::DDX10 to regulate the serine biosynthesis pathway and stabilize ATF4 mRNA. Loss of Nol10 in a mouse model impairs NUP98::DDX10 leukemia progression and improves survival, identifying NOL10 as a critical dependency of this leukemia.","method":"Co-immunoprecipitation (interaction mapping with 24 aa DDX10 domain), mouse leukemia model (Nol10 knockout/loss-of-function), metabolic pathway analysis (serine biosynthesis), ATF4 mRNA stability assay","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction mapping, in vivo mouse model with survival readout, mRNA stability assay; single lab, multiple methods","pmids":["40263434"],"is_preprint":false},{"year":2025,"finding":"The risk allele A of SNP rs4519489 at the 2p25 locus exhibits enhanced binding to USF1 transcription factor, resulting in elevated NOL10 expression. NOL10 in turn regulates cell cycle pathways to promote prostate cancer progression, establishing a rs4519489–USF1–NOL10 regulatory axis.","method":"High-throughput SNPs-seq, unbiased proteomics (allele-specific protein capture), NOL10 knockdown/overexpression with cell cycle pathway analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — allele-specific proteomics capture identifies USF1 binding, functional knockdown with cell cycle readout; single lab, two orthogonal methods","pmids":["41062477"],"is_preprint":false},{"year":2025,"finding":"In fission yeast quiescence, the NOL10 ortholog Enp2/NOL10 forms a complex with the non-coding RNA RiboCop and RNase H1; this complex is triggered by improper pre-rRNA processing (Dicer mutants) and mediates rDNA repeat silencing via Sir2, RENT, and H3K9 methylation, revealing a role for Enp2/NOL10 in a nucleolar stress surveillance pathway.","method":"Co-immunoprecipitation (RiboCop-Enp2/NOL10-RNase H1 complex), ChIP (Dicer at rDNA), genetic mutant analysis, ncRNA identification","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, fission yeast ortholog, single lab, complex identification without full mechanistic reconstitution","pmids":["41000809"],"is_preprint":true}],"current_model":"NOL10 (PQBP5) is a nucleolar WD40-repeat intrinsically disordered protein that forms a stable trimeric ANN complex with AATF and NGDN to support 40S ribosomal subunit biogenesis via pre-rRNA processing at the 5'ETS and ITS1 sites; it also constitutes the granular component scaffold of the nucleolus, acting as a structural anchor that retains nucleolar integrity under osmotic stress, and its WD40 domain integrity is required for nucleolar localization and partner interactions, while it additionally interacts with oncogenic fusion proteins (NUP98::DDX10) to regulate serine biosynthesis and ATF4 mRNA stability in leukemia."},"narrative":{"mechanistic_narrative":"NOL10 (PQBP5) is a nucleolar WD40-repeat protein central to 40S ribosomal subunit biogenesis and to the structural integrity of the nucleolus [PMID:27599843, PMID:36599853]. It assembles into a salt-stable trimeric \"ANN\" complex with AATF/Che-1 and NGDN, with its WD40 repeats mediating complex formation and all three subunits showing mutual dependence for stability; this complex drives 18S rRNA maturation through pre-rRNA cleavage at the 5'ETS and ITS1 sites [PMID:27599843]. As an intrinsically disordered protein, NOL10 constitutes the skeletal granule meshwork of the granular component of the nucleolus, remaining nucleolar under osmotic stress and serving as an anchor for reassembly of dispersed nucleolar proteins; its sequestration by polyglutamine disease proteins depletes functional NOL10 and produces nucleolar deformity [PMID:36599853]. Consistent with this scaffolding role, NOL10 localizes to the granular component and exhibits very low mobility indicative of tight association with large processome-related complexes [PMID:24754225]. WD-repeat integrity is essential for these functions: a homozygous p.Asn228His variant causes nucleoplasmic mislocalization, loss of AATF/NGDN binding, impaired 40S maturation, reduced polysome content, and G0/G1 arrest with increased cell death, defining NOL10 as the basis of a human ribosomopathy [PMID:41093997]. NOL10 expression is regulated through a 2p25 risk allele that enhances USF1 binding to promote cell-cycle progression in prostate cancer [PMID:41062477], and it is a dependency of NUP98::DDX10 leukemia, binding the DDX10 moiety to regulate serine biosynthesis and ATF4 mRNA stability [PMID:40263434].","teleology":[{"year":2014,"claim":"Before its complex partners were known, it was unclear whether NOL10 was a transient or core nucleolar factor; live-cell dynamics established it as a low-mobility scaffold of large processome-related complexes.","evidence":"GFP-NOL10 FRAP and pharmacological rRNA transcription inhibition in HeLa cells","pmids":["24754225"],"confidence":"Medium","gaps":["Did not identify the protein partners conferring low mobility","No direct rRNA processing readout"]},{"year":2016,"claim":"Established the molecular partnership and biochemical function of NOL10 by defining the ANN complex and its requirement for pre-rRNA processing, answering how NOL10 contributes to 40S biogenesis.","evidence":"Reciprocal Co-IP, WD40 domain-mapping mutagenesis, siRNA depletion with Northern/pulse-chase rRNA processing analysis","pmids":["27599843"],"confidence":"High","gaps":["Atomic structure of the trimeric complex not resolved","Order of assembly onto pre-rRNA undefined"]},{"year":2023,"claim":"Resolved why NOL10 behaves as a stable scaffold rather than a phase-separating component, identifying it as the intrinsically disordered granular-component meshwork that anchors nucleolar reassembly and whose sequestration drives polyQ disease pathology.","evidence":"HS-AFM, super-resolution, CLEM, droplet and thermal shift assays, osmotic stress imaging, and in vitro/in vivo polyglutamine sequestration","pmids":["36599853"],"confidence":"High","gaps":["How the meshwork interfaces with the ANN ribosome-biogenesis function not integrated","Mechanism of stress-resistant retention at molecular level unresolved"]},{"year":2025,"claim":"Linked NOL10 to human disease by showing a WD-repeat point mutation abolishes localization, partner binding, and 40S maturation, establishing WD-domain integrity as the determinant of NOL10 function in patients.","evidence":"Exome sequencing, ΔΔG modeling, immunofluorescence, Co-IP, polysome profiling, cell cycle and death assays in patient fibroblasts","pmids":["41093997"],"confidence":"Medium","gaps":["Single case","Spectrum of clinical phenotypes and additional alleles unknown"]},{"year":2025,"claim":"Extended NOL10 beyond housekeeping ribosome biogenesis into oncogenic dependency, showing it cooperates with the NUP98::DDX10 fusion to control serine biosynthesis and ATF4 mRNA stability in leukemia.","evidence":"Co-IP interaction mapping to a 24-aa DDX10 region, Nol10 loss-of-function mouse leukemia model with survival readout, metabolic and ATF4 mRNA stability assays","pmids":["40263434"],"confidence":"Medium","gaps":["Single lab","Mechanism by which NOL10 stabilizes ATF4 mRNA undefined"]},{"year":2025,"claim":"Identified a transcriptional regulatory axis controlling NOL10 levels, connecting a GWAS risk allele to USF1-driven NOL10 expression and prostate cancer cell-cycle progression.","evidence":"SNPs-seq, allele-specific proteomic capture, NOL10 knockdown/overexpression with cell cycle pathway analysis","pmids":["41062477"],"confidence":"Medium","gaps":["Direct cell-cycle effectors downstream of NOL10 not defined","Single lab"]},{"year":2025,"claim":"Suggested a conserved nucleolar stress-surveillance role via the fission yeast ortholog Enp2/NOL10 in rDNA silencing.","evidence":"Co-IP of RiboCop-Enp2-RNase H1 complex, ChIP, and genetic mutant analysis in fission yeast (preprint)","pmids":["41000809"],"confidence":"Low","gaps":["Preprint, yeast ortholog only","Complex not reconstituted and human relevance unestablished"]},{"year":null,"claim":"How NOL10's structural scaffolding role in the granular component is mechanistically coupled to its ANN-complex pre-rRNA processing activity, and how this dual function is co-opted across distinct cancers, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of NOL10 within both the meshwork and the processome","Substrate selectivity of pre-rRNA cleavage undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,5]}],"complexes":["ANN complex (NOL10-AATF-NGDN)"],"partners":["AATF","NGDN","USF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BSC4","full_name":"Nucleolar protein 10","aliases":[],"length_aa":688,"mass_kda":80.3,"function":"","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9BSC4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NOL10","classification":"Common Essential","n_dependent_lines":1202,"n_total_lines":1208,"dependency_fraction":0.9950331125827815},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000115761","cell_line_id":"CID001112","localizations":[{"compartment":"nucleolus_gc","grade":3}],"interactors":[{"gene":"ZNF644","stoichiometry":10.0},{"gene":"SRI","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001112","total_profiled":1310},"omim":[{"mim_id":"616197","title":"NUCLEOLAR PROTEIN 10; NOL10","url":"https://www.omim.org/entry/616197"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NOL10"},"hgnc":{"alias_symbol":["FLJ14075"],"prev_symbol":["PQBP5"]},"alphafold":{"accession":"Q9BSC4","domains":[{"cath_id":"2.130.10.10","chopping":"1-362","consensus_level":"medium","plddt":88.7197,"start":1,"end":362},{"cath_id":"-","chopping":"372-415","consensus_level":"high","plddt":84.5545,"start":372,"end":415}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BSC4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BSC4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BSC4-F1-predicted_aligned_error_v6.png","plddt_mean":77.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NOL10","jax_strain_url":"https://www.jax.org/strain/search?query=NOL10"},"sequence":{"accession":"Q9BSC4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BSC4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BSC4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BSC4"}},"corpus_meta":[{"pmid":"30693177","id":"PMC_30693177","title":"Circular RNA circNOL10 Inhibits Lung Cancer Development by Promoting SCLM1-Mediated Transcriptional Regulation of the Humanin Polypeptide Family.","date":"2018","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/30693177","citation_count":87,"is_preprint":false},{"pmid":"35035657","id":"PMC_35035657","title":"Methylation Pattern Mediated by m6A Regulator and Tumor Microenvironment Invasion in Lung Adenocarcinoma.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/35035657","citation_count":30,"is_preprint":false},{"pmid":"27599843","id":"PMC_27599843","title":"Human AATF/Che-1 forms a nucleolar protein complex with NGDN and NOL10 required for 40S ribosomal subunit synthesis.","date":"2016","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/27599843","citation_count":23,"is_preprint":false},{"pmid":"36599853","id":"PMC_36599853","title":"PQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36599853","citation_count":20,"is_preprint":false},{"pmid":"34729247","id":"PMC_34729247","title":"circ-NOL10 regulated by MTDH/CASC3 inhibits breast cancer progression and metastasis via multiple miRNAs and PDCD4.","date":"2021","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/34729247","citation_count":19,"is_preprint":false},{"pmid":"24754225","id":"PMC_24754225","title":"Dynamics of WD-repeat containing proteins in SSU processome components.","date":"2014","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/24754225","citation_count":17,"is_preprint":false},{"pmid":"37587156","id":"PMC_37587156","title":"Expression status of circ-SMARCA5, circ-NOL10, circ-LDLRAD3, and circ-RHOT1 in patients with colorectal cancer.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37587156","citation_count":10,"is_preprint":false},{"pmid":"30666567","id":"PMC_30666567","title":"Exome sequencing in genomic regions related to racing performance of Quarter Horses.","date":"2019","source":"Journal of applied genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30666567","citation_count":9,"is_preprint":false},{"pmid":"41093997","id":"PMC_41093997","title":"NOL10 variant disrupts ribosome biogenesis and underlies hippocampal sclerosis.","date":"2025","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41093997","citation_count":5,"is_preprint":false},{"pmid":"32953199","id":"PMC_32953199","title":"Integrative omics analysis identifies macrophage migration inhibitory factor signaling pathways underlying human hepatic fibrogenesis and fibrosis.","date":"2019","source":"Journal of bio-X research","url":"https://pubmed.ncbi.nlm.nih.gov/32953199","citation_count":5,"is_preprint":false},{"pmid":"40263434","id":"PMC_40263434","title":"Loss of NOL10 leads to impaired disease progression of NUP98::DDX10 leukemia.","date":"2025","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/40263434","citation_count":3,"is_preprint":false},{"pmid":"41062477","id":"PMC_41062477","title":"Combined SNPs sequencing and allele specific proteomics capture reveal functional causality underpinning the 2p25 prostate cancer susceptibility locus.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41062477","citation_count":3,"is_preprint":false},{"pmid":"38645058","id":"PMC_38645058","title":"Combined SNPs sequencing and allele specific proteomics capture reveal functional causality underpinning the 2p25 prostate cancer susceptibility locus.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/38645058","citation_count":2,"is_preprint":false},{"pmid":"39126896","id":"PMC_39126896","title":"PQBP3/NOL7 is an intrinsically disordered protein.","date":"2024","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/39126896","citation_count":0,"is_preprint":false},{"pmid":"41763606","id":"PMC_41763606","title":"Diagnostic Utility of Expression Imbalance in the Idylla GeneFusion Assay for Non-Small-Cell Lung Cancer.","date":"2026","source":"The Journal of molecular diagnostics : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/41763606","citation_count":0,"is_preprint":false},{"pmid":"41000809","id":"PMC_41000809","title":"RiboCop surveils pre-rRNA processing by Dicer in cellular quiescence.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41000809","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9933,"output_tokens":2117,"usd":0.030777,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9135,"output_tokens":2762,"usd":0.057362,"stage2_stop_reason":"end_turn"},"total_usd":0.088139,"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\": 2016,\n      \"finding\": \"NOL10 forms a salt-stable trimeric complex (ANN complex) with AATF/Che-1 and NGDN in the nucleolus; the WD40 repeats of NOL10 are required for complex formation. All three members show mutual dependence for protein stability, and the complex is required for 18S rRNA maturation and nucleolar cleavage steps in the 5'ETS and ITS1 regions of pre-rRNA, supporting 40S ribosomal subunit biogenesis.\",\n      \"method\": \"Immunoprecipitation, protein interaction domain mapping, siRNA depletion, rRNA processing analysis (Northern blot/pulse-chase), nucleolar localization by microscopy\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping mutagenesis, functional depletion with specific rRNA processing readout, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"27599843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PQBP5/NOL10 is an intrinsically disordered protein that constitutes the skeletal granule meshwork of the granular component of the nucleolus. Unlike other nucleolar proteins, it remains in the nucleolus under osmotic stress and functions as an anchor for reassembly of dispersed nucleolar proteins. Its biophysical properties (assessed by droplet and thermal shift assays) remain stable under stress. Sequestration by polyglutamine disease proteins depletes functional PQBP5/NOL10, causing pathological nucleolar deformity or disappearance.\",\n      \"method\": \"High-speed atomic force microscopy (HS-AFM), super-resolution microscopy, correlative light and electron microscopy (CLEM), droplet assay, thermal shift assay, live-cell imaging under osmotic stress, in vitro and in vivo polyglutamine sequestration\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal structural and biophysical methods (HS-AFM, CLEM, super-resolution), functional rescue/depletion assays, replicated across in vitro and in vivo models\",\n      \"pmids\": [\"36599853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GFP-NOL10 localizes to the granular component region of nucleoli and exhibits very low mobility in living cells, consistent with tight association with large protein complexes; when rRNA transcription is suppressed, its mobility increases but remains slow, suggesting it acts as a scaffold or core component within SSU processome-related complexes.\",\n      \"method\": \"GFP fusion live-cell imaging, FRAP in HeLa cells, pharmacological inhibition of rRNA transcription\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization and dynamics experiment with functional inference, single lab but consistent with broader complex data\",\n      \"pmids\": [\"24754225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A homozygous NOL10 variant (p.Asn228His) within the WD-repeat domain causes nucleoplasmic mislocalization of NOL10 and loss of interaction with AATF and NGDN. Patient fibroblasts show specific impairment of 40S subunit maturation, reduced 40S, 80S, and polysome content, G0/G1 arrest, and increased cell death, establishing that NOL10 WD-repeat integrity is required for its nucleolar localization, partner binding, and 40S ribosome biogenesis function.\",\n      \"method\": \"Exome sequencing, structural modeling (ΔΔG), immunofluorescence (mislocalization), co-immunoprecipitation (loss of AATF/NGDN interaction), polysome profiling, cell cycle analysis, cell death assay in patient fibroblasts\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, polysome profiling, and localization in patient-derived cells with functional readouts; single lab, single case\",\n      \"pmids\": [\"41093997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NOL10 interacts with 24 amino acids within the DDX10 moiety of the NUP98::DDX10 fusion protein. NOL10 acts cooperatively with NUP98::DDX10 to regulate the serine biosynthesis pathway and stabilize ATF4 mRNA. Loss of Nol10 in a mouse model impairs NUP98::DDX10 leukemia progression and improves survival, identifying NOL10 as a critical dependency of this leukemia.\",\n      \"method\": \"Co-immunoprecipitation (interaction mapping with 24 aa DDX10 domain), mouse leukemia model (Nol10 knockout/loss-of-function), metabolic pathway analysis (serine biosynthesis), ATF4 mRNA stability assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction mapping, in vivo mouse model with survival readout, mRNA stability assay; single lab, multiple methods\",\n      \"pmids\": [\"40263434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The risk allele A of SNP rs4519489 at the 2p25 locus exhibits enhanced binding to USF1 transcription factor, resulting in elevated NOL10 expression. NOL10 in turn regulates cell cycle pathways to promote prostate cancer progression, establishing a rs4519489–USF1–NOL10 regulatory axis.\",\n      \"method\": \"High-throughput SNPs-seq, unbiased proteomics (allele-specific protein capture), NOL10 knockdown/overexpression with cell cycle pathway analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — allele-specific proteomics capture identifies USF1 binding, functional knockdown with cell cycle readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"41062477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In fission yeast quiescence, the NOL10 ortholog Enp2/NOL10 forms a complex with the non-coding RNA RiboCop and RNase H1; this complex is triggered by improper pre-rRNA processing (Dicer mutants) and mediates rDNA repeat silencing via Sir2, RENT, and H3K9 methylation, revealing a role for Enp2/NOL10 in a nucleolar stress surveillance pathway.\",\n      \"method\": \"Co-immunoprecipitation (RiboCop-Enp2/NOL10-RNase H1 complex), ChIP (Dicer at rDNA), genetic mutant analysis, ncRNA identification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, fission yeast ortholog, single lab, complex identification without full mechanistic reconstitution\",\n      \"pmids\": [\"41000809\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NOL10 (PQBP5) is a nucleolar WD40-repeat intrinsically disordered protein that forms a stable trimeric ANN complex with AATF and NGDN to support 40S ribosomal subunit biogenesis via pre-rRNA processing at the 5'ETS and ITS1 sites; it also constitutes the granular component scaffold of the nucleolus, acting as a structural anchor that retains nucleolar integrity under osmotic stress, and its WD40 domain integrity is required for nucleolar localization and partner interactions, while it additionally interacts with oncogenic fusion proteins (NUP98::DDX10) to regulate serine biosynthesis and ATF4 mRNA stability in leukemia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NOL10 (PQBP5) is a nucleolar WD40-repeat protein central to 40S ribosomal subunit biogenesis and to the structural integrity of the nucleolus [#0, #1]. It assembles into a salt-stable trimeric \\\"ANN\\\" complex with AATF/Che-1 and NGDN, with its WD40 repeats mediating complex formation and all three subunits showing mutual dependence for stability; this complex drives 18S rRNA maturation through pre-rRNA cleavage at the 5'ETS and ITS1 sites [#0]. As an intrinsically disordered protein, NOL10 constitutes the skeletal granule meshwork of the granular component of the nucleolus, remaining nucleolar under osmotic stress and serving as an anchor for reassembly of dispersed nucleolar proteins; its sequestration by polyglutamine disease proteins depletes functional NOL10 and produces nucleolar deformity [#1]. Consistent with this scaffolding role, NOL10 localizes to the granular component and exhibits very low mobility indicative of tight association with large processome-related complexes [#2]. WD-repeat integrity is essential for these functions: a homozygous p.Asn228His variant causes nucleoplasmic mislocalization, loss of AATF/NGDN binding, impaired 40S maturation, reduced polysome content, and G0/G1 arrest with increased cell death, defining NOL10 as the basis of a human ribosomopathy [#3]. NOL10 expression is regulated through a 2p25 risk allele that enhances USF1 binding to promote cell-cycle progression in prostate cancer [#5], and it is a dependency of NUP98::DDX10 leukemia, binding the DDX10 moiety to regulate serine biosynthesis and ATF4 mRNA stability [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Before its complex partners were known, it was unclear whether NOL10 was a transient or core nucleolar factor; live-cell dynamics established it as a low-mobility scaffold of large processome-related complexes.\",\n      \"evidence\": \"GFP-NOL10 FRAP and pharmacological rRNA transcription inhibition in HeLa cells\",\n      \"pmids\": [\"24754225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the protein partners conferring low mobility\", \"No direct rRNA processing readout\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the molecular partnership and biochemical function of NOL10 by defining the ANN complex and its requirement for pre-rRNA processing, answering how NOL10 contributes to 40S biogenesis.\",\n      \"evidence\": \"Reciprocal Co-IP, WD40 domain-mapping mutagenesis, siRNA depletion with Northern/pulse-chase rRNA processing analysis\",\n      \"pmids\": [\"27599843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the trimeric complex not resolved\", \"Order of assembly onto pre-rRNA undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved why NOL10 behaves as a stable scaffold rather than a phase-separating component, identifying it as the intrinsically disordered granular-component meshwork that anchors nucleolar reassembly and whose sequestration drives polyQ disease pathology.\",\n      \"evidence\": \"HS-AFM, super-resolution, CLEM, droplet and thermal shift assays, osmotic stress imaging, and in vitro/in vivo polyglutamine sequestration\",\n      \"pmids\": [\"36599853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the meshwork interfaces with the ANN ribosome-biogenesis function not integrated\", \"Mechanism of stress-resistant retention at molecular level unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked NOL10 to human disease by showing a WD-repeat point mutation abolishes localization, partner binding, and 40S maturation, establishing WD-domain integrity as the determinant of NOL10 function in patients.\",\n      \"evidence\": \"Exome sequencing, ΔΔG modeling, immunofluorescence, Co-IP, polysome profiling, cell cycle and death assays in patient fibroblasts\",\n      \"pmids\": [\"41093997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case\", \"Spectrum of clinical phenotypes and additional alleles unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended NOL10 beyond housekeeping ribosome biogenesis into oncogenic dependency, showing it cooperates with the NUP98::DDX10 fusion to control serine biosynthesis and ATF4 mRNA stability in leukemia.\",\n      \"evidence\": \"Co-IP interaction mapping to a 24-aa DDX10 region, Nol10 loss-of-function mouse leukemia model with survival readout, metabolic and ATF4 mRNA stability assays\",\n      \"pmids\": [\"40263434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which NOL10 stabilizes ATF4 mRNA undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a transcriptional regulatory axis controlling NOL10 levels, connecting a GWAS risk allele to USF1-driven NOL10 expression and prostate cancer cell-cycle progression.\",\n      \"evidence\": \"SNPs-seq, allele-specific proteomic capture, NOL10 knockdown/overexpression with cell cycle pathway analysis\",\n      \"pmids\": [\"41062477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cell-cycle effectors downstream of NOL10 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Suggested a conserved nucleolar stress-surveillance role via the fission yeast ortholog Enp2/NOL10 in rDNA silencing.\",\n      \"evidence\": \"Co-IP of RiboCop-Enp2-RNase H1 complex, ChIP, and genetic mutant analysis in fission yeast (preprint)\",\n      \"pmids\": [\"41000809\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, yeast ortholog only\", \"Complex not reconstituted and human relevance unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NOL10's structural scaffolding role in the granular component is mechanistically coupled to its ANN-complex pre-rRNA processing activity, and how this dual function is co-opted across distinct cancers, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of NOL10 within both the meshwork and the processome\", \"Substrate selectivity of pre-rRNA cleavage undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\"ANN complex (NOL10-AATF-NGDN)\"],\n    \"partners\": [\"AATF\", \"NGDN\", \"USF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}