{"gene":"NOB1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2004,"finding":"The PIN domain of yeast Nob1p (Nob1) is required for D-site cleavage of 20S pre-rRNA to produce mature 18S rRNA; a homology model of the PIN domain revealed structural mimicry of Mg2+-dependent exonucleases, and a point mutation predicted to abolish enzymatic activity abolished 20S pre-rRNA cleavage in vivo.","method":"Homology modeling, site-directed mutagenesis, in vivo pre-rRNA processing assay","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis with direct in vivo functional readout, foundational mechanistic paper","pmids":["15388878"],"is_preprint":false},{"year":2009,"finding":"Recombinant yeast Nob1 specifically cleaves RNA substrates containing site D (the 3'-end of 18S rRNA) in vitro; Nob1 forms a tetramer, binds directly to pre-rRNA analogs centered around the single-stranded cleavage site D via its PIN domain, and Nob1-dependent protections of pre-rRNA in vitro and in vivo locate its active site at the 3'-end of 18S rRNA.","method":"In vitro cleavage assay with recombinant protein, RNA binding/footprinting, analytical ultracentrifugation (tetramer determination), in vivo RNA protection","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple orthogonal methods (binding, cleavage, footprinting)","pmids":["19706509"],"is_preprint":false},{"year":2009,"finding":"In vivo cleavage of yeast pre-rRNA at site D requires functional interaction between Nob1 (PIN domain endonuclease) and the DEAH-box RNA helicase Prp43 and its cofactor Pfa1; increased dosage of wild-type Nob1 (but not catalytic-site mutant) suppresses accumulation of 20S pre-rRNA caused by loss of Ltv1 combined with Prp43/Pfa1 mutation, placing Nob1's catalytic activity downstream of Prp43/Pfa1 in the pre-40S maturation pathway.","method":"Genetic epistasis (suppressor dosage assay), in vitro endonuclease assay with PIN domain mutants, pre-rRNA Northern blotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1+2 — genetic epistasis combined with in vitro catalytic assay and PIN domain mutagenesis","pmids":["19801658"],"is_preprint":false},{"year":2011,"finding":"The archaeal (Pyrococcus horikoshii) Nob1 ortholog cleaves RNA substrates containing the D-site of pre-rRNA in a manganese-dependent manner; NMR structure revealed a PIN domain linked by a flexible linker to a zinc ribbon domain; PIN domain residues mediate substrate binding while the zinc ribbon domain alone binds helix 40 of the small subunit rRNA, serving as an anchor on the nascent subunit.","method":"NMR structure determination, in vitro RNA cleavage assay, domain deletion/mutagenesis, RNA binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with functional validation by mutagenesis and in vitro assays in a single study","pmids":["22156373"],"is_preprint":false},{"year":2002,"finding":"Yeast Nob1p forms a complex with the 19S regulatory particle (RP) of the 26S proteasome and with Pno1p; Nob1p acts as a chaperone to join the 20S proteasome with the 19S RP in the nucleus and facilitates maturation of the 20S proteasome and degradation of Ump1p; Nob1p is subsequently internalized into the 26S proteasome and degraded to complete 26S proteasome biogenesis.","method":"Genetic analysis (temperature-sensitive mutants), overexpression suppression assay, co-immunoprecipitation, glycerol gradient fractionation, immunofluorescence localization","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, fractionation, genetic suppression, and localization with multiple orthogonal methods","pmids":["12502737"],"is_preprint":false},{"year":2000,"finding":"Yeast Nob1p interacts with Nin1p/Rpn12, a subunit of the 19S regulatory particle of the 26S proteasome, as identified by two-hybrid screening; Nob1p co-immunoprecipitates with the ATPase Rpt1 and is found exclusively in proteasomal fractions by glycerol gradient centrifugation; Nob1p is degraded by the 26S proteasome during transition to stationary phase.","method":"Two-hybrid screen, co-immunoprecipitation, glycerol gradient centrifugation fractionation","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and fractionation, single lab","pmids":["10675611"],"is_preprint":false},{"year":2005,"finding":"The human NOB1 protein contains a PIN domain and a zinc ribbon domain; when expressed in mammalian culture cells, NOB1 protein is mainly localized in the nucleus.","method":"cDNA cloning, domain analysis, subcellular localization by fluorescence/fractionation in transfected cells, Western blot","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization experiment in mammalian cells, single method","pmids":["16172919"],"is_preprint":false},{"year":2025,"finding":"Human NOB1 and PNO1 have different subcellular localizations within cells; proximity labeling (TurboID) identified 1044 proximal proteins for NOB1, predominantly enriched in ribosome assembly, rRNA processing, and translation; co-IP validated interactions of NOB1 with translation-related proteins EIF4B and EIF4G2.","method":"TurboID proximity labeling, mass spectrometry, co-immunoprecipitation, immunofluorescence","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — proximity proteomics validated by Co-IP, single study","pmids":["40157618"],"is_preprint":false},{"year":2013,"finding":"NOB1 silencing in human glioma cell lines (U251, U87-MG) by shRNA lentivirus suppresses cell proliferation, colony formation, and migration, and induces G0/G1 cell cycle arrest and apoptosis, establishing a role for NOB1 in glioma cell growth and migration.","method":"Lentiviral shRNA knockdown, MTT/colony formation assay, flow cytometry, Transwell migration assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with multiple defined cellular phenotypes, single lab","pmids":["23911301"],"is_preprint":false},{"year":2016,"finding":"NOB1 silencing in laryngeal cancer cells inhibits proliferation, induces apoptosis and cell cycle arrest, and reduces migration/invasion by downregulating MMP-2 and MMP-9; mechanistic studies show the JNK signaling pathway is involved in NOB1's oncogenic functions.","method":"siRNA knockdown, Western blot, MTT, flow cytometry, Transwell assay, pathway inhibitor analysis","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — KD with multiple phenotypic readouts plus pathway identification, single lab","pmids":["27035645"],"is_preprint":false},{"year":2014,"finding":"Downregulation of NOB1 in papillary thyroid carcinoma cells (TPC-1) via RNAi activates p38 MAPK phosphorylation, inhibits cell proliferation, migration and invasion, induces apoptosis, and enhances radiosensitivity in vitro and in vivo.","method":"Adenovirus-mediated shRNA knockdown, Western blot, clonogenic survival assay, xenograft mouse model","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — KD with in vitro and in vivo validation plus signaling pathway identification, single lab","pmids":["25231838"],"is_preprint":false},{"year":2018,"finding":"Eukaryotic translation elongation factor 1A1 (eEF1A1) positively regulates NOB1 expression at both mRNA and protein levels, thereby promoting invasion and migration of hepatocellular carcinoma (HCC) cells; overexpression of NOB1 rescues invasion/migration in eEF1A1-knockdown cells, and NOB1 knockdown in eEF1A1-overexpressing cells reverses the enhanced invasion/migration.","method":"qRT-PCR, Western blot, shRNA knockdown, overexpression rescue, Transwell and RTCA assays","journal":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","confidence":"Medium","confidence_rationale":"Tier 3 — epistasis by rescue experiment with multiple orthogonal functional assays, single lab","pmids":["30377124"],"is_preprint":false},{"year":2020,"finding":"NOB1 silencing in colorectal cancer cells (SW480, LoVo) suppresses proliferation and colony formation, increases apoptosis, and elevates phosphorylation of JNK, ERK, and p38, implicating the JNK signaling pathway in NOB1-regulated cancer cell survival.","method":"siRNA knockdown, MTT, colony formation, flow cytometry, Western blot for pathway kinases","journal":"Journal of investigative surgery","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single method per endpoint, pathway assignment by phospho-Western only","pmids":["31906747"],"is_preprint":false},{"year":2015,"finding":"NOB1 knockdown in ovarian cancer cells upregulates DR5 expression and activates the MAPK pathway, contributing to increased sensitivity to TRAIL-induced apoptosis; combinatorial NOB1 shRNA + TRAIL synergistically suppresses tumor growth in vivo.","method":"Lentiviral shRNA knockdown, caspase activity assay, flow cytometry, Western blot, xenograft model","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, pathway inference from Western blot, limited mechanistic depth","pmids":["26617713"],"is_preprint":false}],"current_model":"NOB1 is a conserved PIN-domain endonuclease that catalyzes the final cleavage of 20S pre-rRNA at site D to generate the mature 3'-end of 18S rRNA during cytoplasmic maturation of the pre-40S ribosomal subunit; its PIN domain carries the catalytic active site (Mn2+-dependent), its zinc ribbon domain anchors it to helix 40 of the small subunit rRNA, and its activity is coordinated with the DEAH-box helicase Prp43 and cofactor Pfa1. In yeast, NOB1 also associates with the 19S regulatory particle and functions as a chaperone in 26S proteasome assembly before being degraded. In human cancer cells, NOB1 overexpression promotes proliferation and survival through pathways including MAPK/JNK and PI3K/AKT, and is regulated post-transcriptionally by multiple miRNAs targeting its 3'-UTR."},"narrative":{"teleology":[{"year":2000,"claim":"Identifying Nob1 as a proteasome-associated protein established its initial functional context: Nob1 physically interacts with the 19S regulatory particle subunit Rpn12 and co-fractionates with proteasomal complexes, and is itself a proteasome substrate.","evidence":"Two-hybrid screen, co-immunoprecipitation with Rpt1, glycerol gradient fractionation in yeast","pmids":["10675611"],"confidence":"Medium","gaps":["No reciprocal Co-IP at this stage","Mechanism of Nob1 degradation by proteasome not defined","Relationship to ribosome biogenesis unknown"]},{"year":2002,"claim":"Demonstrating that Nob1 acts as a chaperone for 26S proteasome assembly — facilitating 19S–20S joining and being degraded upon completion — resolved its mechanistic role in proteasome biogenesis distinct from its later-discovered rRNA processing function.","evidence":"Temperature-sensitive mutants, overexpression suppression, reciprocal Co-IP, glycerol gradient fractionation, immunofluorescence in yeast","pmids":["12502737"],"confidence":"High","gaps":["Whether this proteasome chaperone role is conserved in metazoans is unknown","Structural basis of 19S–20S bridging by Nob1 not resolved"]},{"year":2004,"claim":"Linking Nob1's PIN domain to D-site cleavage of 20S pre-rRNA revealed its second and now primary known function — as the endonuclease that generates the mature 3'-end of 18S rRNA.","evidence":"Homology modeling of PIN domain, active-site point mutagenesis, in vivo pre-rRNA processing assay in yeast","pmids":["15388878"],"confidence":"High","gaps":["No in vitro cleavage demonstrated yet","Domain architecture beyond PIN not characterized","Cofactor requirements unknown"]},{"year":2009,"claim":"Reconstitution of D-site cleavage in vitro with recombinant Nob1, combined with RNA footprinting, proved Nob1 is the direct endonuclease and mapped its binding site to the single-stranded region at the 3'-end of 18S rRNA; genetic epistasis simultaneously placed Nob1 catalytic activity downstream of the helicase Prp43/Pfa1 in the pre-40S maturation pathway.","evidence":"In vitro cleavage with recombinant yeast Nob1, RNA footprinting, analytical ultracentrifugation; genetic suppressor dosage assays with Prp43/Pfa1/Ltv1 mutants","pmids":["19706509","19801658"],"confidence":"High","gaps":["Oligomeric state in vivo (tetramer vs. monomer on pre-40S) unresolved","How Prp43 helicase activity licenses Nob1 cleavage mechanistically unclear","Metal ion identity for yeast Nob1 not defined"]},{"year":2011,"claim":"The NMR structure of archaeal Nob1 revealed a two-domain architecture — PIN domain plus zinc ribbon domain — and showed that the zinc ribbon anchors Nob1 to helix 40 of small subunit rRNA while the PIN domain performs Mn²⁺-dependent cleavage, explaining how the enzyme is positioned on the pre-40S particle.","evidence":"NMR structure determination of Pyrococcus horikoshii Nob1, in vitro RNA cleavage assays with manganese, domain deletion and mutagenesis, RNA binding assays","pmids":["22156373"],"confidence":"High","gaps":["No high-resolution structure of eukaryotic Nob1 on the pre-40S particle at this time","How cleavage timing is regulated structurally remains open"]},{"year":2005,"claim":"Cloning and localization of human NOB1 confirmed conservation of the PIN and zinc ribbon domains and established its predominantly nuclear localization in mammalian cells.","evidence":"cDNA cloning, domain analysis, fluorescence localization and fractionation in transfected mammalian cells","pmids":["16172919"],"confidence":"Medium","gaps":["Functional conservation of endonuclease activity not tested in human cells","Nuclear vs. cytoplasmic distribution during ribosome maturation not resolved"]},{"year":2013,"claim":"Functional loss-of-function studies in human cancer cells first established that NOB1 is required for proliferation, colony formation, and migration, and that its depletion induces cell cycle arrest and apoptosis — extending its relevance beyond ribosome biogenesis to cancer cell biology.","evidence":"Lentiviral shRNA knockdown in glioma lines U251/U87-MG, MTT, colony formation, flow cytometry, Transwell assay","pmids":["23911301"],"confidence":"Medium","gaps":["Whether proliferative effects are secondary to ribosome biogenesis defects or represent independent functions is unclear","Downstream signaling pathways not identified in this study"]},{"year":2014,"claim":"Multiple cancer-type knockdown studies converged on MAPK pathway modulation (p38, JNK, ERK) as a downstream consequence of NOB1 depletion, providing a signaling framework for its pro-survival role.","evidence":"shRNA/siRNA knockdown in thyroid carcinoma, laryngeal cancer, and colorectal cancer cells; phospho-Western blot for MAPK pathway components; xenograft models","pmids":["25231838","27035645","31906747"],"confidence":"Medium","gaps":["Causal chain from NOB1 loss to MAPK activation not defined — could be indirect via ribosome stress","No rescue with catalytic-dead NOB1 to distinguish endonuclease-dependent vs. -independent effects","Studies are from single labs per cancer type"]},{"year":2025,"claim":"Proximity proteomics of human NOB1 revealed its interactome is overwhelmingly enriched in ribosome assembly and translation factors, with validated interactions with EIF4B and EIF4G2, expanding its functional network beyond pre-rRNA processing.","evidence":"TurboID proximity labeling, mass spectrometry, co-immunoprecipitation in human cells","pmids":["40157618"],"confidence":"Medium","gaps":["Proximity interactions need validation as direct physical contacts","Functional significance of EIF4B/EIF4G2 association for translation regulation not tested","Whether these interactions depend on Nob1 endonuclease activity is unknown"]},{"year":null,"claim":"Key open questions include: (1) whether the cancer-proliferative phenotype of NOB1 depletion is entirely secondary to ribosome biogenesis defects or involves endonuclease-independent functions; (2) the structural basis of human NOB1 positioning on the pre-40S particle; and (3) the mechanistic link between NOB1 and translation initiation factor interactions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No catalytic-dead rescue experiment in human cancer models","No cryo-EM or crystal structure of human NOB1 on pre-40S","Functional role of NOB1–EIF4B/EIF4G2 interaction uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,5]}],"complexes":["pre-40S ribosomal subunit","26S proteasome (transient chaperone)"],"partners":["PNO1","PRP43","PFA1","RPN12","RPT1","EIF4B","EIF4G2","EEF1A1"],"other_free_text":[]},"mechanistic_narrative":"NOB1 is a conserved PIN-domain endonuclease essential for the final step of small ribosomal subunit biogenesis, catalyzing cleavage of 20S pre-rRNA at site D to generate the mature 3'-end of 18S rRNA. Its PIN domain carries the Mn²⁺-dependent catalytic active site and mediates substrate binding at the single-stranded cleavage site, while a zinc ribbon domain anchors the enzyme to helix 40 of small subunit rRNA, as demonstrated by NMR structure and mutagenesis of the archaeal ortholog [PMID:15388878, PMID:19706509, PMID:22156373]. In yeast, Nob1 catalytic activity at site D is coordinated with the DEAH-box helicase Prp43 and its cofactor Pfa1 through a genetically defined epistatic pathway [PMID:19801658], and Nob1 separately functions as a chaperone in 26S proteasome assembly by facilitating joining of the 19S regulatory particle with the 20S core, after which it is internalized and degraded [PMID:12502737]. In human cells, NOB1 proximity interactors are enriched in ribosome assembly and translation factors including EIF4B and EIF4G2 [PMID:40157618], and NOB1 silencing in multiple cancer cell types suppresses proliferation, induces apoptosis, and modulates MAPK/JNK signaling [PMID:23911301, PMID:27035645]."},"prefetch_data":{"uniprot":{"accession":"Q9ULX3","full_name":"RNA-binding protein NOB1","aliases":["Phosphorylation regulatory protein HP-10","Protein ART-4"],"length_aa":412,"mass_kda":46.7,"function":"May play a role in mRNA degradation (Probable). Endonuclease required for processing of 20S pre-rRNA precursor and biogenesis of 40S ribosomal subunits (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9ULX3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NOB1","classification":"Common Essential","n_dependent_lines":1167,"n_total_lines":1208,"dependency_fraction":0.9660596026490066},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BYSL","stoichiometry":10.0},{"gene":"LTV1","stoichiometry":10.0},{"gene":"TSR1","stoichiometry":10.0},{"gene":"RIOK2","stoichiometry":4.0},{"gene":"RIOK3","stoichiometry":4.0},{"gene":"RPS16","stoichiometry":4.0},{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"METAP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NOB1","total_profiled":1310},"omim":[{"mim_id":"620074","title":"LTV1 RIBOSOME BIOGENESIS FACTOR; LTV1","url":"https://www.omim.org/entry/620074"},{"mim_id":"619357","title":"ADENYLATE KINASE 6; AK6","url":"https://www.omim.org/entry/619357"},{"mim_id":"618710","title":"PARTNER OF NOB1; PNO1","url":"https://www.omim.org/entry/618710"},{"mim_id":"618308","title":"NOP9 NUCLEOLAR PROTEIN; NOP9","url":"https://www.omim.org/entry/618308"},{"mim_id":"617754","title":"RIO KINASE 2; RIOK2","url":"https://www.omim.org/entry/617754"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NOB1"},"hgnc":{"alias_symbol":["NOB1P","ART-4","MST158"],"prev_symbol":["PSMD8BP1"]},"alphafold":{"accession":"Q9ULX3","domains":[{"cath_id":"3.40.50.1010","chopping":"5-109_218-254","consensus_level":"high","plddt":89.6098,"start":5,"end":254},{"cath_id":"-","chopping":"265-358","consensus_level":"medium","plddt":83.9064,"start":265,"end":358}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX3-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NOB1","jax_strain_url":"https://www.jax.org/strain/search?query=NOB1"},"sequence":{"accession":"Q9ULX3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULX3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULX3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX3"}},"corpus_meta":[{"pmid":"19801658","id":"PMC_19801658","title":"RNA helicase Prp43 and its co-factor Pfa1 promote 20 to 18 S rRNA processing catalyzed by the endonuclease Nob1.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19801658","citation_count":160,"is_preprint":false},{"pmid":"19706509","id":"PMC_19706509","title":"Nob1 binds the single-stranded cleavage site D at the 3'-end of 18S rRNA with its PIN domain.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19706509","citation_count":121,"is_preprint":false},{"pmid":"15388878","id":"PMC_15388878","title":"PIN domain of Nob1p is required for D-site cleavage in 20S pre-rRNA.","date":"2004","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15388878","citation_count":107,"is_preprint":false},{"pmid":"29115574","id":"PMC_29115574","title":"Long non-coding RNA SNHG1 regulates NOB1 expression by sponging miR-326 and promotes tumorigenesis in osteosarcoma.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29115574","citation_count":91,"is_preprint":false},{"pmid":"12502737","id":"PMC_12502737","title":"Nob1p is required for biogenesis of the 26S proteasome and degraded upon its maturation in Saccharomyces cerevisiae.","date":"2002","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/12502737","citation_count":79,"is_preprint":false},{"pmid":"23869222","id":"PMC_23869222","title":"MicroRNA-326 functions as a tumor suppressor in glioma by targeting the Nin one binding protein (NOB1).","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23869222","citation_count":75,"is_preprint":false},{"pmid":"27733214","id":"PMC_27733214","title":"miR-326 Inhibits Gastric Cancer Cell Growth Through Downregulating NOB1.","date":"2016","source":"Oncology 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inhibits cell proliferation and migration by targeting NOB1 expression.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29391877","citation_count":21,"is_preprint":false},{"pmid":"23685895","id":"PMC_23685895","title":"Expression of the NOB1 gene and its clinical significance in papillary thyroid carcinoma.","date":"2013","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/23685895","citation_count":20,"is_preprint":false},{"pmid":"30555741","id":"PMC_30555741","title":"microRNA-744 is downregulated in glioblastoma and inhibits the aggressive behaviors by directly targeting NOB1.","date":"2018","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30555741","citation_count":19,"is_preprint":false},{"pmid":"24133592","id":"PMC_24133592","title":"Clinical significance of NOB1 expression in breast infiltrating ductal carcinoma.","date":"2013","source":"International journal of 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anterior Hox gene ceh-13 and elt-1/GATA activate the posterior Hox genes nob-1 and php-3 to specify posterior lineages in the C. elegans embryo.","date":"2022","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35500030","citation_count":12,"is_preprint":false},{"pmid":"24824907","id":"PMC_24824907","title":"Lentivirus-mediated knockdown of NOB1 suppresses the proliferation of colon cancer cells.","date":"2014","source":"Zeitschrift fur Gastroenterologie","url":"https://pubmed.ncbi.nlm.nih.gov/24824907","citation_count":11,"is_preprint":false},{"pmid":"18582212","id":"PMC_18582212","title":"Preparation and characterization of a novel monoclonal antibody specific to human NOB1 protein.","date":"2008","source":"Hybridoma (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/18582212","citation_count":10,"is_preprint":false},{"pmid":"30854959","id":"PMC_30854959","title":"NOB1: A Potential Biomarker or Target in Cancer.","date":"2019","source":"Current drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/30854959","citation_count":8,"is_preprint":false},{"pmid":"19101043","id":"PMC_19101043","title":"The expression of NOB1 in spiral ganglion cells of guinea pig.","date":"2008","source":"International journal of pediatric otorhinolaryngology","url":"https://pubmed.ncbi.nlm.nih.gov/19101043","citation_count":8,"is_preprint":false},{"pmid":"29467874","id":"PMC_29467874","title":"Effects of NOB1 on the pathogenesis of osteosarcoma and its expression on the chemosensitivity to cisplatin.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29467874","citation_count":7,"is_preprint":false},{"pmid":"26370469","id":"PMC_26370469","title":"Downregulation of NOB1 inhibits proliferation and promotes apoptosis in human oral squamous cell carcinoma.","date":"2015","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/26370469","citation_count":7,"is_preprint":false},{"pmid":"25971309","id":"PMC_25971309","title":"NOB1 expression predicts early response to cisplatin-based chemotherapy in patients with advanced non-small cell lung cancer.","date":"2016","source":"Journal of chemotherapy (Florence, Italy)","url":"https://pubmed.ncbi.nlm.nih.gov/25971309","citation_count":7,"is_preprint":false},{"pmid":"26617713","id":"PMC_26617713","title":"Anticancer activity of NOB1-targeted shRNA combination with TRAIL in epithelial ovarian cancer cells.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26617713","citation_count":7,"is_preprint":false},{"pmid":"10075017","id":"PMC_10075017","title":"Analysis of interleukin (IL)-1 beta and transforming growth factor (TGF)-beta-induced signal transduction pathways in IL-2 and TGF-beta secretion and proliferation in the thymoma cell line EL4.NOB-1.","date":"1999","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10075017","citation_count":7,"is_preprint":false},{"pmid":"35294329","id":"PMC_35294329","title":"Overexpression of microRNA-107 suppressed proliferation, migration, invasion, and the PI3K/Akt signaling pathway and induced apoptosis by targeting Nin one binding (NOB1) protein in a hypopharyngeal squamous cell carcinoma cell line (FaDu).","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35294329","citation_count":6,"is_preprint":false},{"pmid":"31906747","id":"PMC_31906747","title":"Silencing NOB1 Can Affect Cell Proliferation and Apoptosis Via the C-Jun N-Terminal Kinase Pathway in Colorectal Cancer.","date":"2020","source":"Journal of investigative surgery : the official journal of the Academy of Surgical Research","url":"https://pubmed.ncbi.nlm.nih.gov/31906747","citation_count":6,"is_preprint":false},{"pmid":"30628685","id":"PMC_30628685","title":"MicroRNA‑744 suppresses cell proliferation and invasion of papillary thyroid cancer by directly targeting NOB1.","date":"2019","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/30628685","citation_count":5,"is_preprint":false},{"pmid":"22445998","id":"PMC_22445998","title":"[Expression of NOB1 and its significance in colorectal cancer].","date":"2012","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/22445998","citation_count":5,"is_preprint":false},{"pmid":"37929351","id":"PMC_37929351","title":"Partner of NOB1 homolog transcriptionally activated by E2F transcription factor 1 promotes the malignant progression and inhibits ferroptosis of pancreatic cancer.","date":"2023","source":"The Chinese journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37929351","citation_count":5,"is_preprint":false},{"pmid":"26178254","id":"PMC_26178254","title":"Lentivirus-mediated gene silencing of NOB1 suppresses non-small cell lung cancer cell proliferation.","date":"2015","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/26178254","citation_count":5,"is_preprint":false},{"pmid":"26122232","id":"PMC_26122232","title":"EXPRESSION MECHANISM AND CLINICAL SIGNIFICANCE OF NOB1 IN GASTRIC CANCER TISSUE AND ADJACENT NORMAL TISSUE.","date":"2015","source":"Journal of biological regulators and homeostatic agents","url":"https://pubmed.ncbi.nlm.nih.gov/26122232","citation_count":4,"is_preprint":false},{"pmid":"34849026","id":"PMC_34849026","title":"Integrated Analysis of the m6A-Related lncRNA Identified lncRNA ABALON/miR-139-3p/NOB1 Axis Was Involved in the Occurrence of Lung Cancer.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/34849026","citation_count":4,"is_preprint":false},{"pmid":"21732055","id":"PMC_21732055","title":"Backbone and side chain NMR resonance assignments for an archaeal homolog of the endonuclease Nob1 involved in ribosome biogenesis.","date":"2011","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/21732055","citation_count":4,"is_preprint":false},{"pmid":"2018210","id":"PMC_2018210","title":"Biological assays for interleukin 1 detection. Comparison of human T lymphocyte, murine thymocyte and NOB-1 assays.","date":"1991","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/2018210","citation_count":4,"is_preprint":false},{"pmid":"23172535","id":"PMC_23172535","title":"[Effect of lentivirus-mediated NOB1 gene silencing by RNA interference on proliferation and apoptosis of human colon cancer cells].","date":"2012","source":"Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery","url":"https://pubmed.ncbi.nlm.nih.gov/23172535","citation_count":3,"is_preprint":false},{"pmid":"30377124","id":"PMC_30377124","title":"[Eukaryotic translation elongation factor 1A1 positively regulates NOB1 expression to promote invasion and metastasis of hepatocellular carcinoma cells in vitro].","date":"2018","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/30377124","citation_count":2,"is_preprint":false},{"pmid":"32020218","id":"PMC_32020218","title":"[Retracted] Downregulation of NOB1 suppresses the proliferation and tumor growth of non‑small cell lung cancer in vitro and in vivo.","date":"2020","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32020218","citation_count":2,"is_preprint":false},{"pmid":"39143880","id":"PMC_39143880","title":"Ribosome Biogenesis and Cancer: Insights into NOB1 and PNO1 Mechanisms.","date":"2024","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/39143880","citation_count":1,"is_preprint":false},{"pmid":"35836846","id":"PMC_35836846","title":"miRNA-612 suppresses ovarian cancer cell tumorigenicity by downregulating NOB1.","date":"2022","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/35836846","citation_count":1,"is_preprint":false},{"pmid":"36484386","id":"PMC_36484386","title":"[Corrigendum] Gene silencing of NOB1 by lentivirus suppresses growth and migration of human osteosarcoma cells.","date":"2022","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/36484386","citation_count":1,"is_preprint":false},{"pmid":"27097067","id":"PMC_27097067","title":"Establishment of a Novel Monoclonal Antibody L6 Specific to NOB1.","date":"2016","source":"Monoclonal antibodies in immunodiagnosis and immunotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/27097067","citation_count":1,"is_preprint":false},{"pmid":"35288316","id":"PMC_35288316","title":"Expression and distribution of Nob1 in the developing rat cochleae.","date":"2022","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/35288316","citation_count":0,"is_preprint":false},{"pmid":"40157618","id":"PMC_40157618","title":"The proximity proteome of pre-40S pre-ribosomal particle components PNO1 and NOB1 using turboID proximity labeling technology.","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/40157618","citation_count":0,"is_preprint":false},{"pmid":"37594052","id":"PMC_37594052","title":"[Retracted] MicroRNA‑744 suppresses cell proliferation and invasion of papillary thyroid cancer by directly targeting NOB1.","date":"2023","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/37594052","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":31953,"output_tokens":3373,"usd":0.073227},"stage2":{"model":"claude-opus-4-6","input_tokens":6751,"output_tokens":2737,"usd":0.15327},"total_usd":0.226497,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"The PIN domain of yeast Nob1p (Nob1) is required for D-site cleavage of 20S pre-rRNA to produce mature 18S rRNA; a homology model of the PIN domain revealed structural mimicry of Mg2+-dependent exonucleases, and a point mutation predicted to abolish enzymatic activity abolished 20S pre-rRNA cleavage in vivo.\",\n      \"method\": \"Homology modeling, site-directed mutagenesis, in vivo pre-rRNA processing assay\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis with direct in vivo functional readout, foundational mechanistic paper\",\n      \"pmids\": [\"15388878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Recombinant yeast Nob1 specifically cleaves RNA substrates containing site D (the 3'-end of 18S rRNA) in vitro; Nob1 forms a tetramer, binds directly to pre-rRNA analogs centered around the single-stranded cleavage site D via its PIN domain, and Nob1-dependent protections of pre-rRNA in vitro and in vivo locate its active site at the 3'-end of 18S rRNA.\",\n      \"method\": \"In vitro cleavage assay with recombinant protein, RNA binding/footprinting, analytical ultracentrifugation (tetramer determination), in vivo RNA protection\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal methods (binding, cleavage, footprinting)\",\n      \"pmids\": [\"19706509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In vivo cleavage of yeast pre-rRNA at site D requires functional interaction between Nob1 (PIN domain endonuclease) and the DEAH-box RNA helicase Prp43 and its cofactor Pfa1; increased dosage of wild-type Nob1 (but not catalytic-site mutant) suppresses accumulation of 20S pre-rRNA caused by loss of Ltv1 combined with Prp43/Pfa1 mutation, placing Nob1's catalytic activity downstream of Prp43/Pfa1 in the pre-40S maturation pathway.\",\n      \"method\": \"Genetic epistasis (suppressor dosage assay), in vitro endonuclease assay with PIN domain mutants, pre-rRNA Northern blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1+2 — genetic epistasis combined with in vitro catalytic assay and PIN domain mutagenesis\",\n      \"pmids\": [\"19801658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The archaeal (Pyrococcus horikoshii) Nob1 ortholog cleaves RNA substrates containing the D-site of pre-rRNA in a manganese-dependent manner; NMR structure revealed a PIN domain linked by a flexible linker to a zinc ribbon domain; PIN domain residues mediate substrate binding while the zinc ribbon domain alone binds helix 40 of the small subunit rRNA, serving as an anchor on the nascent subunit.\",\n      \"method\": \"NMR structure determination, in vitro RNA cleavage assay, domain deletion/mutagenesis, RNA binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with functional validation by mutagenesis and in vitro assays in a single study\",\n      \"pmids\": [\"22156373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Yeast Nob1p forms a complex with the 19S regulatory particle (RP) of the 26S proteasome and with Pno1p; Nob1p acts as a chaperone to join the 20S proteasome with the 19S RP in the nucleus and facilitates maturation of the 20S proteasome and degradation of Ump1p; Nob1p is subsequently internalized into the 26S proteasome and degraded to complete 26S proteasome biogenesis.\",\n      \"method\": \"Genetic analysis (temperature-sensitive mutants), overexpression suppression assay, co-immunoprecipitation, glycerol gradient fractionation, immunofluorescence localization\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, fractionation, genetic suppression, and localization with multiple orthogonal methods\",\n      \"pmids\": [\"12502737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Yeast Nob1p interacts with Nin1p/Rpn12, a subunit of the 19S regulatory particle of the 26S proteasome, as identified by two-hybrid screening; Nob1p co-immunoprecipitates with the ATPase Rpt1 and is found exclusively in proteasomal fractions by glycerol gradient centrifugation; Nob1p is degraded by the 26S proteasome during transition to stationary phase.\",\n      \"method\": \"Two-hybrid screen, co-immunoprecipitation, glycerol gradient centrifugation fractionation\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and fractionation, single lab\",\n      \"pmids\": [\"10675611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The human NOB1 protein contains a PIN domain and a zinc ribbon domain; when expressed in mammalian culture cells, NOB1 protein is mainly localized in the nucleus.\",\n      \"method\": \"cDNA cloning, domain analysis, subcellular localization by fluorescence/fractionation in transfected cells, Western blot\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization experiment in mammalian cells, single method\",\n      \"pmids\": [\"16172919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human NOB1 and PNO1 have different subcellular localizations within cells; proximity labeling (TurboID) identified 1044 proximal proteins for NOB1, predominantly enriched in ribosome assembly, rRNA processing, and translation; co-IP validated interactions of NOB1 with translation-related proteins EIF4B and EIF4G2.\",\n      \"method\": \"TurboID proximity labeling, mass spectrometry, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity proteomics validated by Co-IP, single study\",\n      \"pmids\": [\"40157618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NOB1 silencing in human glioma cell lines (U251, U87-MG) by shRNA lentivirus suppresses cell proliferation, colony formation, and migration, and induces G0/G1 cell cycle arrest and apoptosis, establishing a role for NOB1 in glioma cell growth and migration.\",\n      \"method\": \"Lentiviral shRNA knockdown, MTT/colony formation assay, flow cytometry, Transwell migration assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple defined cellular phenotypes, single lab\",\n      \"pmids\": [\"23911301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NOB1 silencing in laryngeal cancer cells inhibits proliferation, induces apoptosis and cell cycle arrest, and reduces migration/invasion by downregulating MMP-2 and MMP-9; mechanistic studies show the JNK signaling pathway is involved in NOB1's oncogenic functions.\",\n      \"method\": \"siRNA knockdown, Western blot, MTT, flow cytometry, Transwell assay, pathway inhibitor analysis\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple phenotypic readouts plus pathway identification, single lab\",\n      \"pmids\": [\"27035645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Downregulation of NOB1 in papillary thyroid carcinoma cells (TPC-1) via RNAi activates p38 MAPK phosphorylation, inhibits cell proliferation, migration and invasion, induces apoptosis, and enhances radiosensitivity in vitro and in vivo.\",\n      \"method\": \"Adenovirus-mediated shRNA knockdown, Western blot, clonogenic survival assay, xenograft mouse model\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with in vitro and in vivo validation plus signaling pathway identification, single lab\",\n      \"pmids\": [\"25231838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Eukaryotic translation elongation factor 1A1 (eEF1A1) positively regulates NOB1 expression at both mRNA and protein levels, thereby promoting invasion and migration of hepatocellular carcinoma (HCC) cells; overexpression of NOB1 rescues invasion/migration in eEF1A1-knockdown cells, and NOB1 knockdown in eEF1A1-overexpressing cells reverses the enhanced invasion/migration.\",\n      \"method\": \"qRT-PCR, Western blot, shRNA knockdown, overexpression rescue, Transwell and RTCA assays\",\n      \"journal\": \"Nan fang yi ke da xue xue bao = Journal of Southern Medical University\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — epistasis by rescue experiment with multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"30377124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NOB1 silencing in colorectal cancer cells (SW480, LoVo) suppresses proliferation and colony formation, increases apoptosis, and elevates phosphorylation of JNK, ERK, and p38, implicating the JNK signaling pathway in NOB1-regulated cancer cell survival.\",\n      \"method\": \"siRNA knockdown, MTT, colony formation, flow cytometry, Western blot for pathway kinases\",\n      \"journal\": \"Journal of investigative surgery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method per endpoint, pathway assignment by phospho-Western only\",\n      \"pmids\": [\"31906747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NOB1 knockdown in ovarian cancer cells upregulates DR5 expression and activates the MAPK pathway, contributing to increased sensitivity to TRAIL-induced apoptosis; combinatorial NOB1 shRNA + TRAIL synergistically suppresses tumor growth in vivo.\",\n      \"method\": \"Lentiviral shRNA knockdown, caspase activity assay, flow cytometry, Western blot, xenograft model\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pathway inference from Western blot, limited mechanistic depth\",\n      \"pmids\": [\"26617713\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NOB1 is a conserved PIN-domain endonuclease that catalyzes the final cleavage of 20S pre-rRNA at site D to generate the mature 3'-end of 18S rRNA during cytoplasmic maturation of the pre-40S ribosomal subunit; its PIN domain carries the catalytic active site (Mn2+-dependent), its zinc ribbon domain anchors it to helix 40 of the small subunit rRNA, and its activity is coordinated with the DEAH-box helicase Prp43 and cofactor Pfa1. In yeast, NOB1 also associates with the 19S regulatory particle and functions as a chaperone in 26S proteasome assembly before being degraded. In human cancer cells, NOB1 overexpression promotes proliferation and survival through pathways including MAPK/JNK and PI3K/AKT, and is regulated post-transcriptionally by multiple miRNAs targeting its 3'-UTR.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NOB1 is a conserved PIN-domain endonuclease essential for the final step of small ribosomal subunit biogenesis, catalyzing cleavage of 20S pre-rRNA at site D to generate the mature 3'-end of 18S rRNA. Its PIN domain carries the Mn²⁺-dependent catalytic active site and mediates substrate binding at the single-stranded cleavage site, while a zinc ribbon domain anchors the enzyme to helix 40 of small subunit rRNA, as demonstrated by NMR structure and mutagenesis of the archaeal ortholog [PMID:15388878, PMID:19706509, PMID:22156373]. In yeast, Nob1 catalytic activity at site D is coordinated with the DEAH-box helicase Prp43 and its cofactor Pfa1 through a genetically defined epistatic pathway [PMID:19801658], and Nob1 separately functions as a chaperone in 26S proteasome assembly by facilitating joining of the 19S regulatory particle with the 20S core, after which it is internalized and degraded [PMID:12502737]. In human cells, NOB1 proximity interactors are enriched in ribosome assembly and translation factors including EIF4B and EIF4G2 [PMID:40157618], and NOB1 silencing in multiple cancer cell types suppresses proliferation, induces apoptosis, and modulates MAPK/JNK signaling [PMID:23911301, PMID:27035645].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying Nob1 as a proteasome-associated protein established its initial functional context: Nob1 physically interacts with the 19S regulatory particle subunit Rpn12 and co-fractionates with proteasomal complexes, and is itself a proteasome substrate.\",\n      \"evidence\": \"Two-hybrid screen, co-immunoprecipitation with Rpt1, glycerol gradient fractionation in yeast\",\n      \"pmids\": [\"10675611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reciprocal Co-IP at this stage\", \"Mechanism of Nob1 degradation by proteasome not defined\", \"Relationship to ribosome biogenesis unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating that Nob1 acts as a chaperone for 26S proteasome assembly — facilitating 19S–20S joining and being degraded upon completion — resolved its mechanistic role in proteasome biogenesis distinct from its later-discovered rRNA processing function.\",\n      \"evidence\": \"Temperature-sensitive mutants, overexpression suppression, reciprocal Co-IP, glycerol gradient fractionation, immunofluorescence in yeast\",\n      \"pmids\": [\"12502737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this proteasome chaperone role is conserved in metazoans is unknown\", \"Structural basis of 19S–20S bridging by Nob1 not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linking Nob1's PIN domain to D-site cleavage of 20S pre-rRNA revealed its second and now primary known function — as the endonuclease that generates the mature 3'-end of 18S rRNA.\",\n      \"evidence\": \"Homology modeling of PIN domain, active-site point mutagenesis, in vivo pre-rRNA processing assay in yeast\",\n      \"pmids\": [\"15388878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vitro cleavage demonstrated yet\", \"Domain architecture beyond PIN not characterized\", \"Cofactor requirements unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Reconstitution of D-site cleavage in vitro with recombinant Nob1, combined with RNA footprinting, proved Nob1 is the direct endonuclease and mapped its binding site to the single-stranded region at the 3'-end of 18S rRNA; genetic epistasis simultaneously placed Nob1 catalytic activity downstream of the helicase Prp43/Pfa1 in the pre-40S maturation pathway.\",\n      \"evidence\": \"In vitro cleavage with recombinant yeast Nob1, RNA footprinting, analytical ultracentrifugation; genetic suppressor dosage assays with Prp43/Pfa1/Ltv1 mutants\",\n      \"pmids\": [\"19706509\", \"19801658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Oligomeric state in vivo (tetramer vs. monomer on pre-40S) unresolved\", \"How Prp43 helicase activity licenses Nob1 cleavage mechanistically unclear\", \"Metal ion identity for yeast Nob1 not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The NMR structure of archaeal Nob1 revealed a two-domain architecture — PIN domain plus zinc ribbon domain — and showed that the zinc ribbon anchors Nob1 to helix 40 of small subunit rRNA while the PIN domain performs Mn²⁺-dependent cleavage, explaining how the enzyme is positioned on the pre-40S particle.\",\n      \"evidence\": \"NMR structure determination of Pyrococcus horikoshii Nob1, in vitro RNA cleavage assays with manganese, domain deletion and mutagenesis, RNA binding assays\",\n      \"pmids\": [\"22156373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of eukaryotic Nob1 on the pre-40S particle at this time\", \"How cleavage timing is regulated structurally remains open\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Cloning and localization of human NOB1 confirmed conservation of the PIN and zinc ribbon domains and established its predominantly nuclear localization in mammalian cells.\",\n      \"evidence\": \"cDNA cloning, domain analysis, fluorescence localization and fractionation in transfected mammalian cells\",\n      \"pmids\": [\"16172919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional conservation of endonuclease activity not tested in human cells\", \"Nuclear vs. cytoplasmic distribution during ribosome maturation not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Functional loss-of-function studies in human cancer cells first established that NOB1 is required for proliferation, colony formation, and migration, and that its depletion induces cell cycle arrest and apoptosis — extending its relevance beyond ribosome biogenesis to cancer cell biology.\",\n      \"evidence\": \"Lentiviral shRNA knockdown in glioma lines U251/U87-MG, MTT, colony formation, flow cytometry, Transwell assay\",\n      \"pmids\": [\"23911301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether proliferative effects are secondary to ribosome biogenesis defects or represent independent functions is unclear\", \"Downstream signaling pathways not identified in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Multiple cancer-type knockdown studies converged on MAPK pathway modulation (p38, JNK, ERK) as a downstream consequence of NOB1 depletion, providing a signaling framework for its pro-survival role.\",\n      \"evidence\": \"shRNA/siRNA knockdown in thyroid carcinoma, laryngeal cancer, and colorectal cancer cells; phospho-Western blot for MAPK pathway components; xenograft models\",\n      \"pmids\": [\"25231838\", \"27035645\", \"31906747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from NOB1 loss to MAPK activation not defined — could be indirect via ribosome stress\", \"No rescue with catalytic-dead NOB1 to distinguish endonuclease-dependent vs. -independent effects\", \"Studies are from single labs per cancer type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proximity proteomics of human NOB1 revealed its interactome is overwhelmingly enriched in ribosome assembly and translation factors, with validated interactions with EIF4B and EIF4G2, expanding its functional network beyond pre-rRNA processing.\",\n      \"evidence\": \"TurboID proximity labeling, mass spectrometry, co-immunoprecipitation in human cells\",\n      \"pmids\": [\"40157618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proximity interactions need validation as direct physical contacts\", \"Functional significance of EIF4B/EIF4G2 association for translation regulation not tested\", \"Whether these interactions depend on Nob1 endonuclease activity is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: (1) whether the cancer-proliferative phenotype of NOB1 depletion is entirely secondary to ribosome biogenesis defects or involves endonuclease-independent functions; (2) the structural basis of human NOB1 positioning on the pre-40S particle; and (3) the mechanistic link between NOB1 and translation initiation factor interactions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No catalytic-dead rescue experiment in human cancer models\", \"No cryo-EM or crystal structure of human NOB1 on pre-40S\", \"Functional role of NOB1–EIF4B/EIF4G2 interaction uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\n      \"pre-40S ribosomal subunit\",\n      \"26S proteasome (transient chaperone)\"\n    ],\n    \"partners\": [\n      \"PNO1\",\n      \"PRP43\",\n      \"PFA1\",\n      \"RPN12\",\n      \"RPT1\",\n      \"EIF4B\",\n      \"EIF4G2\",\n      \"EEF1A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}