{"gene":"NOP10","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1998,"finding":"Nop10p (yeast ortholog of NOP10) is an essential protein component of H/ACA snoRNPs; cells lacking Nop10p show global rRNA pseudouridylation defects, impaired A1 and A2 pre-rRNA cleavage steps required for 18S rRNA synthesis, and destabilization of H/ACA snoRNAs and Gar1p. Nop10p was identified by affinity purification of epitope-tagged Gar1p and shown to localize to the dense fibrillar component of the nucleolus.","method":"Affinity purification (epitope-tagged Gar1p co-purification), genetic depletion, rRNA pseudouridylation assays, pre-rRNA processing analysis, immunofluorescence microscopy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal affinity purification, genetic depletion with defined biochemical phenotypes, multiple orthogonal methods","pmids":["9843512"],"is_preprint":false},{"year":2000,"finding":"Human NOP10 (hNOP10) is an ortholog of yeast Nop10p that specifically associates with hGAR1 and H/ACA RNAs, as well as with the RNA subunit of human telomerase (which contains an H/ACA-like domain). hNOP10 complements yeast cells depleted of Nop10p, and localizes to the dense fibrillar component of the nucleolus and Cajal bodies.","method":"Immunoprecipitation of epitope-tagged hNOP10 from transfected HeLa cells, yeast complementation assays, immunofluorescence microscopy","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal IP, yeast complementation, and localization experiments across two orthogonal methods","pmids":["11074001"],"is_preprint":false},{"year":2001,"finding":"Accumulation of mature non-polyadenylated human telomerase RNA (hTR) in yeast requires the H/ACA snoRNP proteins Cbf5p, Nhp2p, and Nop10p (but not Gar1p), demonstrating that Nop10p is essential for stabilizing the H/ACA domain of hTR and thus for telomerase RNA stability.","method":"Heterologous expression of hTR in Saccharomyces cerevisiae with genetic depletion of individual H/ACA snoRNP proteins; Northern blotting for hTR accumulation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in a defined yeast system with multiple protein depletions and direct RNA quantification","pmids":["11160879"],"is_preprint":false},{"year":2004,"finding":"Cbf5p and Nop10p can directly bind each other in the absence of Nhp2p and H/ACA snoRNAs, forming a sub-complex with Gar1p; absence of any H/ACA snoRNP assembly component (including Nop10p) inhibits accumulation of Cbf5p and Gar1p.","method":"Co-immunoprecipitation and protein interaction analysis in yeast; depletion of individual snoRNP components with Western blotting for protein stability","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating direct Cbf5p–Nop10p interaction, supported by genetic depletions; single lab","pmids":["15388873"],"is_preprint":false},{"year":2005,"finding":"Crystal structure (1.95 Å) of the archaeal Cbf5–Nop10 complex shows that Nop10 buttresses the active site of Cbf5 and together they form a tripartite RNA-binding surface acting as a molecular bracket organizing H/ACA RNA. Cbf5 and Nop10 together are sufficient for basal pseudouridylation activity in an archaeal in vitro system. Mutagenesis of a basic patch on Nop10 implicates it in RNA binding.","method":"X-ray crystallography (co-crystal structure), in vitro reconstitution of pseudouridylation activity, site-directed mutagenesis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with in vitro reconstitution and mutagenesis in one study","pmids":["16286935"],"is_preprint":false},{"year":2006,"finding":"Crystal structure (2.1 Å) of the archaeal Cbf5–Nop10–Gar1 complex reveals the previously unknown structure of Nop10 and the structural basis for its essential role in pseudouridylation; Nop10 contacts Cbf5 at a site relevant to the catalytic mechanism of RNA-guided pseudouridylation.","method":"X-ray crystallography of archaeal Cbf5-Nop10-Gar1 co-crystal; structural modeling of the full RNP","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with detailed structural analysis and DC mutation mapping","pmids":["16427014"],"is_preprint":false},{"year":2006,"finding":"NMR structure of yeast Nop10p shows it contains a structured N-terminal beta-hairpin that binds RNA weakly but specifically, while the rest of the protein is unstructured; the unstructured region likely interacts with Cbf5p. Chemical shift mapping confirmed the beta-hairpin–RNA interaction with the H/ACA snoRNA U65 3' hairpin.","method":"NMR spectroscopy (solution structure determination), chemical shift mapping of RNA–protein interactions","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with chemical shift mapping providing direct protein–RNA interaction data; single lab","pmids":["16373493"],"is_preprint":false},{"year":2007,"finding":"A homozygous mutation in NOP10 causes autosomal recessive dyskeratosis congenita with significant telomere shortening and reduced TERC (human telomerase RNA) levels. siRNA-mediated knockdown of NOP10 transcripts in HeLa cells reduces TERC levels, and expression of mutant NOP10 similarly reduces TERC levels, establishing NOP10's role in telomerase RNA stability in human cells.","method":"Homozygosity mapping, patient genetic analysis, siRNA knockdown of NOP10 in HeLa cells with TERC quantification, expression of mutant NOP10 in HeLa cells","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics plus siRNA functional validation with direct molecular readout (TERC levels), replicated by both knockdown and mutant overexpression approaches","pmids":["17507419"],"is_preprint":false},{"year":2008,"finding":"NMR structural analysis of archaeal and yeast Nop10 reveals that archaeal Nop10 contains a stable Zn2+-binding motif replaced in eukaryotes by a smaller meta-stable beta-hairpin, with a conserved dynamic linker connecting to a nascent alpha-helical structure. The dynamic structure of Nop10 supports an induced-fit recognition mechanism with Cbf5 (the pseudouridine synthase), acting as a molecular adaptor for snoRNP assembly.","method":"NMR structure determination and NMR relaxation dynamics measurements of archaeal and yeast Nop10","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure and dynamics from two organisms; single lab but rigorous structural methods","pmids":["18473479"],"is_preprint":false},{"year":2009,"finding":"The DC-associated NOP10 mutation R34W causes no defect in protein tetramer formation (NAF1-dyskerin-NOP10-NHP2) but severely impairs pre-RNP assembly with the H/ACA domain of human telomerase RNA (hTR) and a subset of H/ACA snoRNAs. H/ACA sno/scaRNAs encoding miRNAs were unaffected by R34W, indicating structural differences between H/ACA RNP subclasses.","method":"Co-immunoprecipitation of pre-RNP complexes in human cells expressing wild-type or mutant NOP10/NHP2/dyskerin; RNA immunoprecipitation for H/ACA RNA association","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and RNA-IP in human cells with multiple mutants and RNA targets; single lab","pmids":["20008900"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of the Shq1–Cbf5–Nop10–Gar1 complex shows that Shq1 binds independently of Nop10, Gar1, and Nhp2, sharing an overlapping binding surface with H/ACA RNA on Cbf5. Nop10 is present in this pre-assembly complex structure, defining its position relative to the assembly chaperone Shq1.","method":"X-ray crystallography of Shq1-Cbf5-Nop10-Gar1 co-crystal; genetic/biochemical analysis of Shq1 point mutations","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional mutant validation; single lab","pmids":["22117216"],"is_preprint":false},{"year":2012,"finding":"In an archaeal in vitro reconstitution system, Nop10 (together with Gar1) enhances both Cbf5's affinity for tRNA substrate and its catalytic rate (kcat) during guide-RNA-independent pseudouridylation of tRNA at position 55, stabilizing Cbf5 in its active conformation.","method":"In vitro reconstitution of pseudouridylation activity with purified archaeal Cbf5, Nop10, and Gar1; kinetic analysis (kcat, Km measurements)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with kinetic parameters; single lab but direct enzymatic measurements","pmids":["22993689"],"is_preprint":false},{"year":2020,"finding":"A homozygous NOP10 p.Thr16Met mutation causes a syndrome with nephrotic syndrome, cataracts, deafness, and enterocolitis. The mutation falls at the dyskerin–NOP10 binding interface, impairs the dyskerin–NOP10 protein interaction, disrupts the catalytic pseudouridylation site, and results in reduced pseudouridine levels in patient rRNA. Zebrafish dkc1 mutants show reduced 18S pseudouridylation and ribosomal dysregulation.","method":"Patient genetic analysis, protein interaction assays (dyskerin–NOP10 binding), pseudouridine quantification in patient rRNA, zebrafish dkc1 mutant phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics, biochemical interaction assays, direct pseudouridine measurement in patient RNA, and zebrafish model validation","pmids":["32554502"],"is_preprint":false},{"year":2020,"finding":"siRNA-mediated depletion of NOP10 (more than DKC1 depletion) disrupts ribosomal biogenesis, activates the p53 pathway (via NPM1), and induces oxidative stress with downregulation of GSH synthesis enzymes. These effects are linked to H/ACA RNP dysfunction rather than telomere shortening per se.","method":"siRNA knockdown of NOP10 in human cell lines; RNA array hybridization for pathway analysis; assessment of ribosomal biogenesis markers, p53 pathway activation, and oxidative stress markers","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined cellular phenotypes and pathway analysis; single lab","pmids":["32910990"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of endogenous, catalytically active eukaryotic (insect) H/ACA snoRNPs reveal an asymmetric dimeric complex of two protomers on a two-hairpin H/ACA snoRNA. Nop10, Nhp2, and the N-terminal extensions of Cbf5 in the 3' protomer undergo coordinated structural changes resembling active and inactive conformations, providing a mechanism for regulating pseudouridylation activity across protomers. DC-associated mutations directly impair pseudouridine formation.","method":"Cryo-EM structure determination of endogenous H/ACA snoRNPs; biochemical characterization of inter-protomer interface mutations; pseudouridylation activity assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures with functional validation; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.06.07.658439"],"is_preprint":true}],"current_model":"NOP10 is an essential, conserved core protein of H/ACA small nucleolar ribonucleoprotein (snoRNP) complexes that directly binds the pseudouridine synthase Cbf5/dyskerin via its unstructured C-terminal region while its N-terminal beta-hairpin contacts H/ACA RNA, thereby stabilizing Cbf5 in its active conformation, enhancing catalytic pseudouridylation activity (increasing both substrate affinity and kcat), and acting as a molecular adaptor required for assembly and stability of H/ACA snoRNPs—including the H/ACA domain of human telomerase RNA (TERC); loss-of-function mutations in NOP10 destabilize TERC, reduce rRNA pseudouridylation, impair ribosome biogenesis, activate p53, and cause dyskeratosis congenita or related ribosomopathy syndromes in humans."},"narrative":{"mechanistic_narrative":"NOP10 is an essential, evolutionarily conserved core protein of H/ACA small nucleolar/Cajal body ribonucleoprotein (snoRNP) complexes that direct site-specific pseudouridylation of ribosomal and other RNAs [PMID:9843512, PMID:11074001]. It functions as a small molecular adaptor: a structured N-terminal beta-hairpin contacts H/ACA guide RNA while its dynamic, largely unstructured remainder packs directly against the pseudouridine synthase Cbf5/dyskerin, buttressing its active site to form a molecular bracket that organizes the H/ACA RNA [PMID:16286935, PMID:16373493, PMID:18473479]. By stabilizing Cbf5 in its catalytically active conformation, NOP10 (with Gar1) increases both substrate affinity and turnover (kcat) during pseudouridylation [PMID:16427014, PMID:22993689]. NOP10 directly binds Cbf5/dyskerin even in the absence of Nhp2 and guide RNA, and is required for the accumulation and stability of other core snoRNP proteins, placing it at the heart of H/ACA RNP assembly [PMID:15388873, PMID:22117216]. Beyond rRNA modification, NOP10 is essential for stabilizing the H/ACA domain of human telomerase RNA (TERC/hTR), and depletion or disease mutation reduces TERC levels, telomere length, and rRNA pseudouridylation while activating the p53 pathway and oxidative stress responses [PMID:11160879, PMID:17507419, PMID:32910990]. Homozygous NOP10 mutations cause autosomal recessive dyskeratosis congenita and a related multisystem ribosomopathy syndrome by disrupting either pre-RNP assembly with telomerase RNA or the dyskerin–NOP10 catalytic interface [PMID:17507419, PMID:32554502].","teleology":[{"year":1998,"claim":"Established NOP10 as an essential, dedicated component of H/ACA snoRNPs by linking its loss to global rRNA pseudouridylation and processing defects, defining the pathway in which it acts.","evidence":"Affinity purification of tagged Gar1p, genetic depletion, rRNA pseudouridylation and pre-rRNA processing assays in yeast","pmids":["9843512"],"confidence":"High","gaps":["Did not resolve direct binding partners or molecular mechanism","No structural information on how NOP10 acts within the RNP"]},{"year":2000,"claim":"Showed the human ortholog is functionally conserved and extended NOP10's role to telomerase, the first link between H/ACA biology and the telomerase RNP.","evidence":"IP of epitope-tagged hNOP10 from HeLa cells, yeast complementation, and immunofluorescence localization to nucleolar dense fibrillar component and Cajal bodies","pmids":["11074001"],"confidence":"High","gaps":["Association with telomerase RNA not shown to be functionally required at this stage","No mechanism for how NOP10 contributes to telomerase RNA biology"]},{"year":2001,"claim":"Demonstrated NOP10 is specifically required to stabilize the H/ACA domain of human telomerase RNA, distinguishing the assembly proteins from Gar1.","evidence":"Heterologous hTR expression in yeast with individual snoRNP protein depletions and Northern blotting","pmids":["11160879"],"confidence":"High","gaps":["Mechanism of stabilization (direct binding vs. RNP assembly) not resolved","Conducted in a heterologous yeast system"]},{"year":2004,"claim":"Identified a direct Cbf5–Nop10 interaction independent of Nhp2 and guide RNA, defining NOP10's position in the assembly hierarchy.","evidence":"Co-immunoprecipitation and depletion-based protein stability assays in yeast","pmids":["15388873"],"confidence":"Medium","gaps":["Single lab, Co-IP based","Structural basis of the interaction not defined"]},{"year":2006,"claim":"Provided the structural basis for NOP10's essential role, showing it buttresses the Cbf5 active site and forms a tripartite RNA-binding bracket, with Cbf5+Nop10 sufficient for basal catalysis.","evidence":"X-ray crystallography of archaeal Cbf5–Nop10 and Cbf5–Nop10–Gar1 complexes, in vitro reconstitution and mutagenesis; NMR structure of yeast Nop10 with chemical shift mapping of RNA binding","pmids":["16286935","16427014","16373493"],"confidence":"High","gaps":["Kinetic contribution of NOP10 to catalysis not quantified","Structures of full eukaryotic active RNP not resolved"]},{"year":2007,"claim":"Established NOP10 as a human disease gene, causally linking loss-of-function to dyskeratosis congenita through telomerase RNA destabilization.","evidence":"Homozygosity mapping and patient genetics, siRNA knockdown and mutant overexpression in HeLa cells with TERC quantification","pmids":["17507419"],"confidence":"High","gaps":["Did not separate telomere-mediated from ribosome-mediated disease contributions","Mechanism by which mutation lowers TERC not structurally defined"]},{"year":2008,"claim":"Defined NOP10 as a conformationally dynamic molecular adaptor, explaining how an intrinsically flexible protein achieves induced-fit recognition of Cbf5.","evidence":"NMR structure determination and relaxation dynamics of archaeal and yeast Nop10","pmids":["18473479"],"confidence":"High","gaps":["Functional consequence of dynamics not tested in cells","Single lab"]},{"year":2009,"claim":"Showed a DC mutation (R34W) selectively blocks pre-RNP assembly with telomerase RNA and a subset of snoRNAs without disrupting tetramer formation, revealing functional heterogeneity among H/ACA RNP subclasses.","evidence":"Co-IP and RNA-IP of pre-RNP complexes in human cells with wild-type and mutant proteins","pmids":["20008900"],"confidence":"Medium","gaps":["Structural basis for RNA subclass selectivity not resolved","Single lab"]},{"year":2011,"claim":"Positioned NOP10 within the chaperone-bound pre-assembly complex, showing Shq1 binds Cbf5 independently of Nop10 at a site overlapping the H/ACA RNA surface.","evidence":"X-ray crystallography of Shq1–Cbf5–Nop10–Gar1 complex with mutant validation","pmids":["22117216"],"confidence":"High","gaps":["Order and dynamics of chaperone hand-off not fully defined","Single lab"]},{"year":2012,"claim":"Quantified NOP10's catalytic contribution, demonstrating it enhances both substrate affinity and kcat by stabilizing the active conformation of Cbf5.","evidence":"In vitro reconstitution and kinetic analysis (kcat, Km) of archaeal Cbf5/Nop10/Gar1 pseudouridylation of tRNA position 55","pmids":["22993689"],"confidence":"High","gaps":["Guide-RNA-dependent reactions not kinetically dissected","Archaeal system; eukaryotic kinetics not measured"]},{"year":2020,"claim":"Linked NOP10 dysfunction to a broader ribosomopathy phenotype, showing depletion impairs ribosome biogenesis and activates p53 and oxidative stress independently of telomere shortening, and a new mutation at the dyskerin interface reduces rRNA pseudouridylation in patients.","evidence":"siRNA knockdown with pathway/array analysis in human cells; patient genetics, dyskerin–NOP10 binding assays, pseudouridine quantification in patient rRNA, and zebrafish dkc1 phenotyping","pmids":["32910990","32554502"],"confidence":"Medium","gaps":["Relative contributions of rRNA modification vs. telomere defects to disease not fully separated","p53/NPM1 and GSH pathway links from a single knockdown study"]},{"year":2025,"claim":"Resolved the architecture of an endogenous catalytically active eukaryotic H/ACA snoRNP, revealing an asymmetric dimer in which NOP10 undergoes coordinated active/inactive conformational changes that may regulate pseudouridylation across protomers.","evidence":"Cryo-EM of endogenous insect H/ACA snoRNPs with inter-protomer interface mutagenesis and activity assays (preprint)","pmids":["bio_10.1101_2025.06.07.658439"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Human snoRNP structure and regulatory mechanism not directly shown"]},{"year":null,"claim":"How the distinct human disease phenotypes arising from different NOP10 mutations partition between telomerase RNA destabilization, rRNA pseudouridylation loss, and inter-protomer regulatory defects remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No genotype-phenotype framework distinguishing telomere vs. ribosome-driven disease","Regulatory role of NOP10 conformational switching not validated in human cells"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,8]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,12]}],"complexes":["H/ACA snoRNP","telomerase RNP (H/ACA domain)"],"partners":["DKC1","GAR1","NHP2","NAF1","SHQ1","TERC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPE3","full_name":"H/ACA ribonucleoprotein complex subunit 3","aliases":["Nucleolar protein 10","Nucleolar protein family A member 3","snoRNP protein NOP10"],"length_aa":64,"mass_kda":7.7,"function":"Required for ribosome biogenesis and telomere maintenance. Part of the H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA (PubMed:32554502). This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1. Each rRNA can contain up to 100 pseudouridine ('psi') residues, which may serve to stabilize the conformation of rRNAs. May also be required for correct processing or intranuclear trafficking of TERC, the RNA component of the telomerase reverse transcriptase (TERT) holoenzyme","subcellular_location":"Nucleus, nucleolus; Nucleus, Cajal body","url":"https://www.uniprot.org/uniprotkb/Q9NPE3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NOP10","classification":"Common Essential","n_dependent_lines":1154,"n_total_lines":1208,"dependency_fraction":0.9552980132450332},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000182117","cell_line_id":"CID001046","localizations":[{"compartment":"nucleolus_fc_dfc","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"DKC1","stoichiometry":10.0},{"gene":"NAF1","stoichiometry":10.0},{"gene":"SRSF6","stoichiometry":10.0},{"gene":"SUB1","stoichiometry":10.0},{"gene":"XPO1","stoichiometry":10.0},{"gene":"GAR1","stoichiometry":4.0},{"gene":"LMNB2","stoichiometry":4.0},{"gene":"RSRC1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001046","total_profiled":1310},"omim":[{"mim_id":"620425","title":"CATARACTS, HEARING IMPAIRMENT, NEPHROTIC SYNDROME, AND ENTEROCOLITIS 2; CHINE2","url":"https://www.omim.org/entry/620425"},{"mim_id":"620400","title":"PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 9; PFBMFT9","url":"https://www.omim.org/entry/620400"},{"mim_id":"617868","title":"NUCLEAR ASSEMBLY FACTOR 1 RIBONUCLEOPROTEIN; NAF1","url":"https://www.omim.org/entry/617868"},{"mim_id":"614742","title":"PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 1; PFBMFT1","url":"https://www.omim.org/entry/614742"},{"mim_id":"613663","title":"SHQ1, H/ACA RIBONUCLEOPROTEIN ASSEMBLY FACTOR; SHQ1","url":"https://www.omim.org/entry/613663"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NOP10"},"hgnc":{"alias_symbol":["NOP10P","MGC70651"],"prev_symbol":["NOLA3"]},"alphafold":{"accession":"Q9NPE3","domains":[{"cath_id":"4.10.80.300","chopping":"1-31","consensus_level":"medium","plddt":95.0477,"start":1,"end":31}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPE3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPE3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPE3-F1-predicted_aligned_error_v6.png","plddt_mean":94.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NOP10","jax_strain_url":"https://www.jax.org/strain/search?query=NOP10"},"sequence":{"accession":"Q9NPE3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPE3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPE3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPE3"}},"corpus_meta":[{"pmid":"17507419","id":"PMC_17507419","title":"Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10.","date":"2007","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17507419","citation_count":237,"is_preprint":false},{"pmid":"9843512","id":"PMC_9843512","title":"Nhp2p and Nop10p are essential for the function of H/ACA snoRNPs.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9843512","citation_count":193,"is_preprint":false},{"pmid":"11074001","id":"PMC_11074001","title":"Human H/ACA small nucleolar RNPs and telomerase share evolutionarily conserved proteins NHP2 and NOP10.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11074001","citation_count":187,"is_preprint":false},{"pmid":"16427014","id":"PMC_16427014","title":"Crystal structure of a Cbf5-Nop10-Gar1 complex and implications in RNA-guided pseudouridylation and dyskeratosis congenita.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16427014","citation_count":134,"is_preprint":false},{"pmid":"16286935","id":"PMC_16286935","title":"The Cbf5-Nop10 complex is a molecular bracket that organizes box H/ACA RNPs.","date":"2005","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16286935","citation_count":94,"is_preprint":false},{"pmid":"10871366","id":"PMC_10871366","title":"Evolutionary appearance of genes encoding proteins associated with box H/ACA snoRNAs: cbf5p in Euglena gracilis, an early diverging eukaryote, and candidate Gar1p and Nop10p homologs in archaebacteria.","date":"2000","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10871366","citation_count":77,"is_preprint":false},{"pmid":"11160879","id":"PMC_11160879","title":"Stable expression in yeast of the mature form of human telomerase RNA depends on its association with the box H/ACA small nucleolar RNP proteins Cbf5p, Nhp2p and Nop10p.","date":"2001","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/11160879","citation_count":66,"is_preprint":false},{"pmid":"20008900","id":"PMC_20008900","title":"Effects of dyskeratosis congenita mutations in dyskerin, NHP2 and NOP10 on assembly of H/ACA pre-RNPs.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20008900","citation_count":49,"is_preprint":false},{"pmid":"22117216","id":"PMC_22117216","title":"Structure of the Shq1-Cbf5-Nop10-Gar1 complex and implications for H/ACA RNP biogenesis and dyskeratosis congenita.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22117216","citation_count":47,"is_preprint":false},{"pmid":"15388873","id":"PMC_15388873","title":"Cbf5p, the putative pseudouridine synthase of H/ACA-type snoRNPs, can form a complex with Gar1p and Nop10p in absence of Nhp2p and box H/ACA snoRNAs.","date":"2004","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15388873","citation_count":43,"is_preprint":false},{"pmid":"32554502","id":"PMC_32554502","title":"Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32554502","citation_count":42,"is_preprint":false},{"pmid":"16373493","id":"PMC_16373493","title":"Structural study of the H/ACA snoRNP components Nop10p and the 3' hairpin of U65 snoRNA.","date":"2006","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/16373493","citation_count":34,"is_preprint":false},{"pmid":"22993689","id":"PMC_22993689","title":"Archaeal proteins Nop10 and Gar1 increase the catalytic activity of Cbf5 in pseudouridylating tRNA.","date":"2012","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/22993689","citation_count":28,"is_preprint":false},{"pmid":"21708174","id":"PMC_21708174","title":"Structure of H/ACA RNP protein Nhp2p reveals cis/trans isomerization of a conserved proline at the RNA and Nop10 binding interface.","date":"2011","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21708174","citation_count":28,"is_preprint":false},{"pmid":"32910990","id":"PMC_32910990","title":"Acute depletion of telomerase components DKC1 and NOP10 induces oxidative stress and disrupts ribosomal biogenesis via NPM1 and activation of the P53 pathway.","date":"2020","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32910990","citation_count":19,"is_preprint":false},{"pmid":"34638246","id":"PMC_34638246","title":"Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34638246","citation_count":18,"is_preprint":false},{"pmid":"18473479","id":"PMC_18473479","title":"Nop10 is a conserved H/ACA snoRNP molecular adaptor.","date":"2008","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18473479","citation_count":10,"is_preprint":false},{"pmid":"41540529","id":"PMC_41540529","title":"Identification and Experimental Validation of NOP10 as a Biomarker for Diffuse Large B-Cell Lymphoma.","date":"2026","source":"Current gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41540529","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.07.658439","title":"Interprotomer Communication and Functional Asymmetry in H/ACA snoRNPs","date":"2025-06-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.07.658439","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11993,"output_tokens":4044,"usd":0.04832,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11874,"output_tokens":4037,"usd":0.080147,"stage2_stop_reason":"end_turn"},"total_usd":0.128467,"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\": 1998,\n      \"finding\": \"Nop10p (yeast ortholog of NOP10) is an essential protein component of H/ACA snoRNPs; cells lacking Nop10p show global rRNA pseudouridylation defects, impaired A1 and A2 pre-rRNA cleavage steps required for 18S rRNA synthesis, and destabilization of H/ACA snoRNAs and Gar1p. Nop10p was identified by affinity purification of epitope-tagged Gar1p and shown to localize to the dense fibrillar component of the nucleolus.\",\n      \"method\": \"Affinity purification (epitope-tagged Gar1p co-purification), genetic depletion, rRNA pseudouridylation assays, pre-rRNA processing analysis, immunofluorescence microscopy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal affinity purification, genetic depletion with defined biochemical phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"9843512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human NOP10 (hNOP10) is an ortholog of yeast Nop10p that specifically associates with hGAR1 and H/ACA RNAs, as well as with the RNA subunit of human telomerase (which contains an H/ACA-like domain). hNOP10 complements yeast cells depleted of Nop10p, and localizes to the dense fibrillar component of the nucleolus and Cajal bodies.\",\n      \"method\": \"Immunoprecipitation of epitope-tagged hNOP10 from transfected HeLa cells, yeast complementation assays, immunofluorescence microscopy\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal IP, yeast complementation, and localization experiments across two orthogonal methods\",\n      \"pmids\": [\"11074001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Accumulation of mature non-polyadenylated human telomerase RNA (hTR) in yeast requires the H/ACA snoRNP proteins Cbf5p, Nhp2p, and Nop10p (but not Gar1p), demonstrating that Nop10p is essential for stabilizing the H/ACA domain of hTR and thus for telomerase RNA stability.\",\n      \"method\": \"Heterologous expression of hTR in Saccharomyces cerevisiae with genetic depletion of individual H/ACA snoRNP proteins; Northern blotting for hTR accumulation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in a defined yeast system with multiple protein depletions and direct RNA quantification\",\n      \"pmids\": [\"11160879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cbf5p and Nop10p can directly bind each other in the absence of Nhp2p and H/ACA snoRNAs, forming a sub-complex with Gar1p; absence of any H/ACA snoRNP assembly component (including Nop10p) inhibits accumulation of Cbf5p and Gar1p.\",\n      \"method\": \"Co-immunoprecipitation and protein interaction analysis in yeast; depletion of individual snoRNP components with Western blotting for protein stability\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating direct Cbf5p–Nop10p interaction, supported by genetic depletions; single lab\",\n      \"pmids\": [\"15388873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure (1.95 Å) of the archaeal Cbf5–Nop10 complex shows that Nop10 buttresses the active site of Cbf5 and together they form a tripartite RNA-binding surface acting as a molecular bracket organizing H/ACA RNA. Cbf5 and Nop10 together are sufficient for basal pseudouridylation activity in an archaeal in vitro system. Mutagenesis of a basic patch on Nop10 implicates it in RNA binding.\",\n      \"method\": \"X-ray crystallography (co-crystal structure), in vitro reconstitution of pseudouridylation activity, site-directed mutagenesis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with in vitro reconstitution and mutagenesis in one study\",\n      \"pmids\": [\"16286935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure (2.1 Å) of the archaeal Cbf5–Nop10–Gar1 complex reveals the previously unknown structure of Nop10 and the structural basis for its essential role in pseudouridylation; Nop10 contacts Cbf5 at a site relevant to the catalytic mechanism of RNA-guided pseudouridylation.\",\n      \"method\": \"X-ray crystallography of archaeal Cbf5-Nop10-Gar1 co-crystal; structural modeling of the full RNP\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with detailed structural analysis and DC mutation mapping\",\n      \"pmids\": [\"16427014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NMR structure of yeast Nop10p shows it contains a structured N-terminal beta-hairpin that binds RNA weakly but specifically, while the rest of the protein is unstructured; the unstructured region likely interacts with Cbf5p. Chemical shift mapping confirmed the beta-hairpin–RNA interaction with the H/ACA snoRNA U65 3' hairpin.\",\n      \"method\": \"NMR spectroscopy (solution structure determination), chemical shift mapping of RNA–protein interactions\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with chemical shift mapping providing direct protein–RNA interaction data; single lab\",\n      \"pmids\": [\"16373493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A homozygous mutation in NOP10 causes autosomal recessive dyskeratosis congenita with significant telomere shortening and reduced TERC (human telomerase RNA) levels. siRNA-mediated knockdown of NOP10 transcripts in HeLa cells reduces TERC levels, and expression of mutant NOP10 similarly reduces TERC levels, establishing NOP10's role in telomerase RNA stability in human cells.\",\n      \"method\": \"Homozygosity mapping, patient genetic analysis, siRNA knockdown of NOP10 in HeLa cells with TERC quantification, expression of mutant NOP10 in HeLa cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics plus siRNA functional validation with direct molecular readout (TERC levels), replicated by both knockdown and mutant overexpression approaches\",\n      \"pmids\": [\"17507419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NMR structural analysis of archaeal and yeast Nop10 reveals that archaeal Nop10 contains a stable Zn2+-binding motif replaced in eukaryotes by a smaller meta-stable beta-hairpin, with a conserved dynamic linker connecting to a nascent alpha-helical structure. The dynamic structure of Nop10 supports an induced-fit recognition mechanism with Cbf5 (the pseudouridine synthase), acting as a molecular adaptor for snoRNP assembly.\",\n      \"method\": \"NMR structure determination and NMR relaxation dynamics measurements of archaeal and yeast Nop10\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure and dynamics from two organisms; single lab but rigorous structural methods\",\n      \"pmids\": [\"18473479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The DC-associated NOP10 mutation R34W causes no defect in protein tetramer formation (NAF1-dyskerin-NOP10-NHP2) but severely impairs pre-RNP assembly with the H/ACA domain of human telomerase RNA (hTR) and a subset of H/ACA snoRNAs. H/ACA sno/scaRNAs encoding miRNAs were unaffected by R34W, indicating structural differences between H/ACA RNP subclasses.\",\n      \"method\": \"Co-immunoprecipitation of pre-RNP complexes in human cells expressing wild-type or mutant NOP10/NHP2/dyskerin; RNA immunoprecipitation for H/ACA RNA association\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and RNA-IP in human cells with multiple mutants and RNA targets; single lab\",\n      \"pmids\": [\"20008900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of the Shq1–Cbf5–Nop10–Gar1 complex shows that Shq1 binds independently of Nop10, Gar1, and Nhp2, sharing an overlapping binding surface with H/ACA RNA on Cbf5. Nop10 is present in this pre-assembly complex structure, defining its position relative to the assembly chaperone Shq1.\",\n      \"method\": \"X-ray crystallography of Shq1-Cbf5-Nop10-Gar1 co-crystal; genetic/biochemical analysis of Shq1 point mutations\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional mutant validation; single lab\",\n      \"pmids\": [\"22117216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In an archaeal in vitro reconstitution system, Nop10 (together with Gar1) enhances both Cbf5's affinity for tRNA substrate and its catalytic rate (kcat) during guide-RNA-independent pseudouridylation of tRNA at position 55, stabilizing Cbf5 in its active conformation.\",\n      \"method\": \"In vitro reconstitution of pseudouridylation activity with purified archaeal Cbf5, Nop10, and Gar1; kinetic analysis (kcat, Km measurements)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with kinetic parameters; single lab but direct enzymatic measurements\",\n      \"pmids\": [\"22993689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A homozygous NOP10 p.Thr16Met mutation causes a syndrome with nephrotic syndrome, cataracts, deafness, and enterocolitis. The mutation falls at the dyskerin–NOP10 binding interface, impairs the dyskerin–NOP10 protein interaction, disrupts the catalytic pseudouridylation site, and results in reduced pseudouridine levels in patient rRNA. Zebrafish dkc1 mutants show reduced 18S pseudouridylation and ribosomal dysregulation.\",\n      \"method\": \"Patient genetic analysis, protein interaction assays (dyskerin–NOP10 binding), pseudouridine quantification in patient rRNA, zebrafish dkc1 mutant phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics, biochemical interaction assays, direct pseudouridine measurement in patient RNA, and zebrafish model validation\",\n      \"pmids\": [\"32554502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"siRNA-mediated depletion of NOP10 (more than DKC1 depletion) disrupts ribosomal biogenesis, activates the p53 pathway (via NPM1), and induces oxidative stress with downregulation of GSH synthesis enzymes. These effects are linked to H/ACA RNP dysfunction rather than telomere shortening per se.\",\n      \"method\": \"siRNA knockdown of NOP10 in human cell lines; RNA array hybridization for pathway analysis; assessment of ribosomal biogenesis markers, p53 pathway activation, and oxidative stress markers\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined cellular phenotypes and pathway analysis; single lab\",\n      \"pmids\": [\"32910990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of endogenous, catalytically active eukaryotic (insect) H/ACA snoRNPs reveal an asymmetric dimeric complex of two protomers on a two-hairpin H/ACA snoRNA. Nop10, Nhp2, and the N-terminal extensions of Cbf5 in the 3' protomer undergo coordinated structural changes resembling active and inactive conformations, providing a mechanism for regulating pseudouridylation activity across protomers. DC-associated mutations directly impair pseudouridine formation.\",\n      \"method\": \"Cryo-EM structure determination of endogenous H/ACA snoRNPs; biochemical characterization of inter-protomer interface mutations; pseudouridylation activity assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures with functional validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.07.658439\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NOP10 is an essential, conserved core protein of H/ACA small nucleolar ribonucleoprotein (snoRNP) complexes that directly binds the pseudouridine synthase Cbf5/dyskerin via its unstructured C-terminal region while its N-terminal beta-hairpin contacts H/ACA RNA, thereby stabilizing Cbf5 in its active conformation, enhancing catalytic pseudouridylation activity (increasing both substrate affinity and kcat), and acting as a molecular adaptor required for assembly and stability of H/ACA snoRNPs—including the H/ACA domain of human telomerase RNA (TERC); loss-of-function mutations in NOP10 destabilize TERC, reduce rRNA pseudouridylation, impair ribosome biogenesis, activate p53, and cause dyskeratosis congenita or related ribosomopathy syndromes in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NOP10 is an essential, evolutionarily conserved core protein of H/ACA small nucleolar/Cajal body ribonucleoprotein (snoRNP) complexes that direct site-specific pseudouridylation of ribosomal and other RNAs [#0, #1]. It functions as a small molecular adaptor: a structured N-terminal beta-hairpin contacts H/ACA guide RNA while its dynamic, largely unstructured remainder packs directly against the pseudouridine synthase Cbf5/dyskerin, buttressing its active site to form a molecular bracket that organizes the H/ACA RNA [#4, #6, #8]. By stabilizing Cbf5 in its catalytically active conformation, NOP10 (with Gar1) increases both substrate affinity and turnover (kcat) during pseudouridylation [#5, #11]. NOP10 directly binds Cbf5/dyskerin even in the absence of Nhp2 and guide RNA, and is required for the accumulation and stability of other core snoRNP proteins, placing it at the heart of H/ACA RNP assembly [#3, #10]. Beyond rRNA modification, NOP10 is essential for stabilizing the H/ACA domain of human telomerase RNA (TERC/hTR), and depletion or disease mutation reduces TERC levels, telomere length, and rRNA pseudouridylation while activating the p53 pathway and oxidative stress responses [#2, #7, #13]. Homozygous NOP10 mutations cause autosomal recessive dyskeratosis congenita and a related multisystem ribosomopathy syndrome by disrupting either pre-RNP assembly with telomerase RNA or the dyskerin–NOP10 catalytic interface [#7, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established NOP10 as an essential, dedicated component of H/ACA snoRNPs by linking its loss to global rRNA pseudouridylation and processing defects, defining the pathway in which it acts.\",\n      \"evidence\": \"Affinity purification of tagged Gar1p, genetic depletion, rRNA pseudouridylation and pre-rRNA processing assays in yeast\",\n      \"pmids\": [\"9843512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve direct binding partners or molecular mechanism\", \"No structural information on how NOP10 acts within the RNP\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed the human ortholog is functionally conserved and extended NOP10's role to telomerase, the first link between H/ACA biology and the telomerase RNP.\",\n      \"evidence\": \"IP of epitope-tagged hNOP10 from HeLa cells, yeast complementation, and immunofluorescence localization to nucleolar dense fibrillar component and Cajal bodies\",\n      \"pmids\": [\"11074001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Association with telomerase RNA not shown to be functionally required at this stage\", \"No mechanism for how NOP10 contributes to telomerase RNA biology\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated NOP10 is specifically required to stabilize the H/ACA domain of human telomerase RNA, distinguishing the assembly proteins from Gar1.\",\n      \"evidence\": \"Heterologous hTR expression in yeast with individual snoRNP protein depletions and Northern blotting\",\n      \"pmids\": [\"11160879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of stabilization (direct binding vs. RNP assembly) not resolved\", \"Conducted in a heterologous yeast system\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified a direct Cbf5–Nop10 interaction independent of Nhp2 and guide RNA, defining NOP10's position in the assembly hierarchy.\",\n      \"evidence\": \"Co-immunoprecipitation and depletion-based protein stability assays in yeast\",\n      \"pmids\": [\"15388873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, Co-IP based\", \"Structural basis of the interaction not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the structural basis for NOP10's essential role, showing it buttresses the Cbf5 active site and forms a tripartite RNA-binding bracket, with Cbf5+Nop10 sufficient for basal catalysis.\",\n      \"evidence\": \"X-ray crystallography of archaeal Cbf5–Nop10 and Cbf5–Nop10–Gar1 complexes, in vitro reconstitution and mutagenesis; NMR structure of yeast Nop10 with chemical shift mapping of RNA binding\",\n      \"pmids\": [\"16286935\", \"16427014\", \"16373493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetic contribution of NOP10 to catalysis not quantified\", \"Structures of full eukaryotic active RNP not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established NOP10 as a human disease gene, causally linking loss-of-function to dyskeratosis congenita through telomerase RNA destabilization.\",\n      \"evidence\": \"Homozygosity mapping and patient genetics, siRNA knockdown and mutant overexpression in HeLa cells with TERC quantification\",\n      \"pmids\": [\"17507419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate telomere-mediated from ribosome-mediated disease contributions\", \"Mechanism by which mutation lowers TERC not structurally defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined NOP10 as a conformationally dynamic molecular adaptor, explaining how an intrinsically flexible protein achieves induced-fit recognition of Cbf5.\",\n      \"evidence\": \"NMR structure determination and relaxation dynamics of archaeal and yeast Nop10\",\n      \"pmids\": [\"18473479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of dynamics not tested in cells\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed a DC mutation (R34W) selectively blocks pre-RNP assembly with telomerase RNA and a subset of snoRNAs without disrupting tetramer formation, revealing functional heterogeneity among H/ACA RNP subclasses.\",\n      \"evidence\": \"Co-IP and RNA-IP of pre-RNP complexes in human cells with wild-type and mutant proteins\",\n      \"pmids\": [\"20008900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for RNA subclass selectivity not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Positioned NOP10 within the chaperone-bound pre-assembly complex, showing Shq1 binds Cbf5 independently of Nop10 at a site overlapping the H/ACA RNA surface.\",\n      \"evidence\": \"X-ray crystallography of Shq1–Cbf5–Nop10–Gar1 complex with mutant validation\",\n      \"pmids\": [\"22117216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order and dynamics of chaperone hand-off not fully defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Quantified NOP10's catalytic contribution, demonstrating it enhances both substrate affinity and kcat by stabilizing the active conformation of Cbf5.\",\n      \"evidence\": \"In vitro reconstitution and kinetic analysis (kcat, Km) of archaeal Cbf5/Nop10/Gar1 pseudouridylation of tRNA position 55\",\n      \"pmids\": [\"22993689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Guide-RNA-dependent reactions not kinetically dissected\", \"Archaeal system; eukaryotic kinetics not measured\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked NOP10 dysfunction to a broader ribosomopathy phenotype, showing depletion impairs ribosome biogenesis and activates p53 and oxidative stress independently of telomere shortening, and a new mutation at the dyskerin interface reduces rRNA pseudouridylation in patients.\",\n      \"evidence\": \"siRNA knockdown with pathway/array analysis in human cells; patient genetics, dyskerin–NOP10 binding assays, pseudouridine quantification in patient rRNA, and zebrafish dkc1 phenotyping\",\n      \"pmids\": [\"32910990\", \"32554502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of rRNA modification vs. telomere defects to disease not fully separated\", \"p53/NPM1 and GSH pathway links from a single knockdown study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the architecture of an endogenous catalytically active eukaryotic H/ACA snoRNP, revealing an asymmetric dimer in which NOP10 undergoes coordinated active/inactive conformational changes that may regulate pseudouridylation across protomers.\",\n      \"evidence\": \"Cryo-EM of endogenous insect H/ACA snoRNPs with inter-protomer interface mutagenesis and activity assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.07.658439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Human snoRNP structure and regulatory mechanism not directly shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct human disease phenotypes arising from different NOP10 mutations partition between telomerase RNA destabilization, rRNA pseudouridylation loss, and inter-protomer regulatory defects remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genotype-phenotype framework distinguishing telomere vs. ribosome-driven disease\", \"Regulatory role of NOP10 conformational switching not validated in human cells\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"complexes\": [\n      \"H/ACA snoRNP\",\n      \"telomerase RNP (H/ACA domain)\"\n    ],\n    \"partners\": [\n      \"DKC1\",\n      \"GAR1\",\n      \"NHP2\",\n      \"NAF1\",\n      \"SHQ1\",\n      \"TERC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}