{"gene":"NOM1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2005,"finding":"NOM1 (nucleolar protein with MIF4G domain 1) was identified as containing one MIF4G domain and one MA3 domain, and was shown to interact with members of the eIF4A family of ATP-dependent DEAD-box RNA helicases. NOM1 localizes predominantly to the nucleolus, consistent with its yeast homolog Sgd1p.","method":"Protein domain analysis, co-immunoprecipitation/binding assay with eIF4A family members, subcellular localization imaging","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, domain-based interaction assay and localization, replicated conceptually by later studies","pmids":["15715967"],"is_preprint":false},{"year":2007,"finding":"NOM1 was identified as a PP1-interacting protein via an RVXF motif required for PP1 binding. NOM1 targets PP1 (protein phosphatase I) to the nucleolus, acting as the first identified nucleolar targeting subunit for PP1 in eukaryotic cells. Both the RVXF motif and the NOM1 nucleolar localization sequence are required for this targeting activity.","method":"Co-immunoprecipitation, RVXF motif mutagenesis, subcellular localization (fluorescence microscopy), functional targeting assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of RVXF motif, localization with functional consequence, single lab with multiple orthogonal methods","pmids":["17965019"],"is_preprint":false},{"year":2011,"finding":"Human NOM1 is the eIF4G-like interacting partner of eIF4AIII. Direct physical interaction between NOM1 and eIF4AIII was demonstrated in vitro and in vivo. This interaction is evolutionarily conserved (yeast Sgd1p–Fal1p). Knockdown of eIF4AIII and NOM1 in human cells revealed that this complex acts in pre-rRNA processing (18S rRNA biogenesis), distinct from the EJC role of eIF4AIII.","method":"Yeast genetic complementation (fal1Δ rescued by human eIF4AIII), in vitro binding assay, co-immunoprecipitation in human cells, siRNA knockdown with rRNA processing readout, structural comparison to eIF4A/eIF4G crystal structure","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding, reciprocal Co-IP in vivo, genetic complementation, knockdown with defined molecular phenotype, multiple orthogonal methods in one study","pmids":["21576267"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, nom1 mutants exhibit defects in exocrine pancreas development due to impaired proliferation of ptf1a-expressing pancreatic progenitor cells. Loss of nom1 disrupts pre-rRNA processing and ribosome biogenesis in a p53-independent manner. Targeting PP1α into the nucleolus (by adding a nucleolar localization signal) partially rescued the pancreatic defect in nom1 morphants, demonstrating that nucleolar targeting of PP1α by Nom1 is functionally important for pancreatic proliferation.","method":"Forward genetic screen, positional cloning, RNA-seq, morpholino knockdown, rescue with PP1α + nucleolar localization signal, p53 loss-of-function epistasis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic screen with positional cloning, molecular rescue experiment, epistasis with p53, multiple orthogonal methods","pmids":["24967912"],"is_preprint":false},{"year":2019,"finding":"NOM1 was identified as a nuclear IGF1R-interacting protein by mass spectrometry-based proteomics. Co-immunoprecipitation confirmed a complex between nuclear IGF1R and NOM1. Inhibition of nuclear IGF1R translocation reduced NOM1 levels in the nuclear fraction; IGF1R overexpression enhanced NOM1 nuclear levels. NOM1 silencing led to increased IGF1R biosynthesis, indicating a bi-directional interplay.","method":"Mass spectrometry-based nuclear proteomics, co-immunoprecipitation, siRNA silencing, pharmacological inhibition of IGF1R nuclear translocation (dansylcadaverine), western blot quantification","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus silencing with functional readout, single lab, two orthogonal methods","pmids":["30639046"],"is_preprint":false},{"year":2019,"finding":"Nom1 (mouse/yeast ortholog) is a downstream transcriptional target of KDM4 (H3K9/H3K36 demethylases). In Kdm4a/b/c triple-knockout hematopoietic stem cells, H3K9me3 accumulates at the Nom1 transcription start site, leading to downregulation of Nom1 expression. Nom1 was shown to be essential for maintenance of hematopoietic cells by knockdown experiments.","method":"Conditional triple-knockout mice (Kdm4a/b/c), ChIP-seq for H3K9me3, RNA-seq, knockdown of Nom1 with hematopoietic cell maintenance readout","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with ChIP-seq and RNA-seq, KD with defined cellular phenotype, single lab","pmids":["31434704"],"is_preprint":false},{"year":2020,"finding":"Yeast Sgd1 (ortholog of human NOM1) interacts directly with the RNA helicase Fal1 (ortholog of human eIF4AIII) via its MIF4G domain. The MIF4G domain of Sgd1 stimulates the ATPase/helicase catalytic activity of Fal1 in vitro. The Fal1–Sgd1 interaction is required for efficient pre-rRNA processing at sites A0, A1, and A2. Sgd1 co-purifies early SSU processome factors Lcp5 and Rok1. In vivo crosslinking (CRAC) showed Sgd1 binds helix H12 of 18S rRNA via its C-terminal region, which is essential for ribosome biogenesis function.","method":"In vitro ATPase/helicase stimulation assay, co-purification/pull-down, in vivo UV crosslinking (CRAC), domain mutagenesis/truncation, pre-rRNA processing analysis (Northern blot)","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic stimulation assay, in vivo crosslinking, mutagenesis of functional domain, multiple orthogonal methods, consistent with human NOM1 data","pmids":["31994962"],"is_preprint":false},{"year":2000,"finding":"Yeast Sgd1p (ortholog of human NOM1) is an essential nuclear protein. Overexpression of SGD1 partially suppresses osmosensitivity of pbs2Δ and hog1Δ mutants (HOG MAP kinase pathway), partially restoring GPD1 transcription and glycerol production. A GFP-tagged Sgd1p localizes to the cell nucleus.","method":"Gene deletion (lethality), multicopy suppressor assay, GFP localization, quantitative GPD1 expression analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion lethality, genetic suppression with transcriptional readout, GFP localization, single lab","pmids":["11042259"],"is_preprint":false},{"year":2002,"finding":"Yeast Sgd1p (ortholog of human NOM1) physically interacts with phospholipase C (Plc1p), confirmed by two-hybrid screen and affinity chromatography. SGD1 shows genetic interactions with PLC1 and HOG1: overexpression of SGD1 suppresses plc1-4 temperature sensitivity; double mutant plc1Δ sgd1-1 shows enhanced sensitivity; triple mutant plc1Δ hog1Δ sgd1-1 is inviable. These data place Sgd1p at a convergence point of Plc1p- and Hog1p-dependent osmoregulatory pathways controlling GPD1 expression.","method":"Two-hybrid screen, affinity chromatography, genetic epistasis (double/triple mutants), growth assays under osmotic stress, GPD1 expression analysis","journal":"Molecular genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical interaction confirmed by affinity chromatography plus genetic epistasis, single lab, multiple orthogonal methods","pmids":["12073033"],"is_preprint":false},{"year":2016,"finding":"NOM1 knockdown in mouse pancreatic beta cells (MIN6) increases cleaved caspase-3 levels, elevates Bax and reduces Bcl-2 expression, and inhibits cell proliferation. NOM1 silencing reduced insulin 2 mRNA expression. These data suggest NOM1 supports beta cell survival and insulin production, with apoptosis occurring via the Bax/Bcl-2/caspase-3 pathway.","method":"siRNA knockdown in MIN6 cells, western blot (caspase-3, Bcl-2, Bax), MTT proliferation assay, RT-qPCR (insulin 1/2 mRNA)","journal":"Experimental and therapeutic medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA knockdown with downstream marker readout only, no pathway placement beyond apoptosis markers","pmids":["27698723"],"is_preprint":false}],"current_model":"NOM1 is an evolutionarily conserved nucleolar protein containing MIF4G and MA3 domains that functions as an eIF4G-like cofactor for the DEAD-box RNA helicase eIF4AIII (and its yeast ortholog Fal1), stimulating its catalytic activity and enabling pre-rRNA processing (18S rRNA biogenesis) at sites A0/A1/A2; NOM1 also acts as the first identified PP1 nucleolar targeting subunit via an RVXF motif and a nucleolar localization sequence, and this PP1-targeting activity is required for normal pancreatic progenitor cell proliferation in zebrafish, while in hematopoietic stem cells NOM1 expression is regulated by KDM4-mediated H3K9 demethylation at its promoter."},"narrative":{"mechanistic_narrative":"NOM1 is an evolutionarily conserved nucleolar protein that functions as an eIF4G-like cofactor for the DEAD-box RNA helicase eIF4AIII, coupling helicase activity to ribosome biogenesis [PMID:15715967, PMID:21576267]. Through its MIF4G domain it binds eIF4AIII directly (and the yeast Sgd1p–Fal1p pair is conserved), and the resulting complex drives pre-rRNA processing for 18S rRNA biogenesis at cleavage sites A0/A1/A2 — a role distinct from the EJC function of eIF4AIII [PMID:21576267, PMID:31994962]. Work on the yeast ortholog established the molecular basis: the MIF4G domain stimulates the ATPase/helicase activity of Fal1, the protein co-purifies early SSU processome factors, and its C-terminal region crosslinks to helix H12 of 18S rRNA, which is required for ribosome biogenesis [PMID:31994962]. Independently, NOM1 acts as the first identified nucleolar targeting subunit for protein phosphatase 1 (PP1), recruiting PP1 to the nucleolus via an RVXF motif together with its nucleolar localization sequence [PMID:17965019]; this PP1-targeting activity is functionally required for proliferation of ptf1a-expressing pancreatic progenitor cells in zebrafish, where loss of nom1 disrupts ribosome biogenesis in a p53-independent manner [PMID:24967912]. NOM1 expression supports stem and progenitor cell maintenance, being regulated by KDM4-mediated H3K9 demethylation at its promoter in hematopoietic stem cells [PMID:31434704].","teleology":[{"year":2000,"claim":"Established the yeast ortholog Sgd1p as an essential nuclear protein and first linked it to osmoregulatory signaling, raising the question of what essential nuclear function it serves.","evidence":"Gene deletion lethality, multicopy suppression of HOG-pathway mutants, and GFP localization in yeast","pmids":["11042259"],"confidence":"Medium","gaps":["Essential molecular activity not identified","Connection between nuclear localization and HOG suppression unexplained","No biochemical partners defined"]},{"year":2002,"claim":"Placed Sgd1p at a convergence of Plc1p- and Hog1p-dependent osmoregulatory pathways through physical and genetic interactions, though its biochemical role remained undefined.","evidence":"Two-hybrid screen, affinity chromatography, and double/triple-mutant epistasis in yeast","pmids":["12073033"],"confidence":"Medium","gaps":["Direct enzymatic or RNA-related function still unknown","Mechanism connecting Plc1p binding to GPD1 control unresolved"]},{"year":2005,"claim":"Defined human NOM1 domain architecture (MIF4G and MA3) and its eIF4A-family binding and nucleolar localization, framing it as a translation-factor-like nucleolar protein.","evidence":"Domain analysis, binding assays with eIF4A family members, and subcellular imaging in human cells","pmids":["15715967"],"confidence":"Medium","gaps":["Which eIF4A paralog is the functional partner not resolved","No functional readout for the interaction","Nucleolar role not yet defined"]},{"year":2007,"claim":"Revealed a second, distinct function: NOM1 is the first nucleolar targeting subunit for PP1, answering how PP1 is recruited to the nucleolus.","evidence":"Reciprocal Co-IP, RVXF motif mutagenesis, and localization/targeting assays in human cells","pmids":["17965019"],"confidence":"High","gaps":["Nucleolar PP1 substrates not identified","Relationship between PP1-targeting and rRNA processing roles unclear"]},{"year":2011,"claim":"Identified NOM1 as the eIF4G-like partner of eIF4AIII in pre-rRNA processing, establishing a ribosome biogenesis role separate from eIF4AIII's EJC function.","evidence":"In vitro binding, reciprocal Co-IP, yeast complementation of fal1Δ by human eIF4AIII, and siRNA knockdown with rRNA processing readout","pmids":["21576267"],"confidence":"High","gaps":["Mechanism of helicase stimulation not shown in human system","Precise rRNA contact sites undefined at this stage"]},{"year":2014,"claim":"Showed in vivo that NOM1-dependent nucleolar PP1 targeting and ribosome biogenesis are required for pancreatic progenitor proliferation, linking both molecular activities to development.","evidence":"Zebrafish forward genetic screen, positional cloning, RNA-seq, rescue with PP1α plus nucleolar localization signal, and p53 epistasis","pmids":["24967912"],"confidence":"High","gaps":["How impaired ribosome biogenesis specifically limits progenitor proliferation unresolved","PP1 nucleolar substrates in this context unknown"]},{"year":2019,"claim":"Extended the interaction network to nuclear IGF1R, suggesting a bidirectional regulatory relationship, and to KDM4-controlled transcriptional regulation in hematopoietic stem cells.","evidence":"Nuclear proteomics with Co-IP and silencing (IGF1R study); Kdm4a/b/c triple-KO mice with ChIP-seq, RNA-seq and Nom1 knockdown (HSC study)","pmids":["30639046","31434704"],"confidence":"Medium","gaps":["Functional significance of the NOM1–IGF1R complex unclear","Whether HSC maintenance reflects ribosome biogenesis or another role not determined"]},{"year":2020,"claim":"Provided the mechanistic basis for the rRNA processing role: the MIF4G domain stimulates helicase catalysis and the C-terminus engages 18S rRNA helix H12 within the SSU processome.","evidence":"In vitro ATPase/helicase stimulation assay, co-purification of SSU processome factors, in vivo CRAC crosslinking, and domain truncation in yeast","pmids":["31994962"],"confidence":"High","gaps":["Structural model of the Sgd1/NOM1–Fal1/eIF4AIII complex on rRNA lacking","Coordination between PP1-targeting and helicase-cofactor roles unaddressed"]},{"year":null,"claim":"How NOM1's two activities — eIF4AIII helicase cofactor for 18S biogenesis and PP1 nucleolar targeting — are integrated within a single protein, and whether they are mechanistically coupled, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length NOM1","Nucleolar PP1 dephosphorylation substrates unidentified","Whether PP1-targeting and helicase-cofactor functions act on the same biogenesis steps unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,3]}],"complexes":["SSU processome"],"partners":["EIF4A3","PPP1CA","IGF1R","FAL1","PLC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5C9Z4","full_name":"Nucleolar MIF4G domain-containing protein 1","aliases":["SGD1 homolog"],"length_aa":860,"mass_kda":96.3,"function":"Plays a role in targeting PPP1CA to the nucleolus","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q5C9Z4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NOM1","classification":"Common Essential","n_dependent_lines":992,"n_total_lines":1208,"dependency_fraction":0.8211920529801324},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000146909","cell_line_id":"CID001117","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"chromatin","grade":1}],"interactors":[{"gene":"EIF4A3","stoichiometry":0.2},{"gene":"IPO5","stoichiometry":0.2},{"gene":"PSMC4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001117","total_profiled":1310},"omim":[{"mim_id":"611269","title":"NUCLEOLAR PROTEIN WITH MIF4G DOMAIN 1; NOM1","url":"https://www.omim.org/entry/611269"},{"mim_id":"182960","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 1; HMND1","url":"https://www.omim.org/entry/182960"},{"mim_id":"147370","title":"INSULIN-LIKE GROWTH FACTOR I RECEPTOR; IGF1R","url":"https://www.omim.org/entry/147370"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NOM1"},"hgnc":{"alias_symbol":["SGD1","PPP1R113"],"prev_symbol":["C7orf3"]},"alphafold":{"accession":"Q5C9Z4","domains":[{"cath_id":"1.25.40.180","chopping":"346-603","consensus_level":"high","plddt":87.0171,"start":346,"end":603}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5C9Z4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5C9Z4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5C9Z4-F1-predicted_aligned_error_v6.png","plddt_mean":69.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NOM1","jax_strain_url":"https://www.jax.org/strain/search?query=NOM1"},"sequence":{"accession":"Q5C9Z4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5C9Z4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5C9Z4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5C9Z4"}},"corpus_meta":[{"pmid":"11467775","id":"PMC_11467775","title":"Fibronectin 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\"finding\": \"NOM1 (nucleolar protein with MIF4G domain 1) was identified as containing one MIF4G domain and one MA3 domain, and was shown to interact with members of the eIF4A family of ATP-dependent DEAD-box RNA helicases. NOM1 localizes predominantly to the nucleolus, consistent with its yeast homolog Sgd1p.\",\n      \"method\": \"Protein domain analysis, co-immunoprecipitation/binding assay with eIF4A family members, subcellular localization imaging\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, domain-based interaction assay and localization, replicated conceptually by later studies\",\n      \"pmids\": [\"15715967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NOM1 was identified as a PP1-interacting protein via an RVXF motif required for PP1 binding. NOM1 targets PP1 (protein phosphatase I) to the nucleolus, acting as the first identified nucleolar targeting subunit for PP1 in eukaryotic cells. Both the RVXF motif and the NOM1 nucleolar localization sequence are required for this targeting activity.\",\n      \"method\": \"Co-immunoprecipitation, RVXF motif mutagenesis, subcellular localization (fluorescence microscopy), functional targeting assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of RVXF motif, localization with functional consequence, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17965019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human NOM1 is the eIF4G-like interacting partner of eIF4AIII. Direct physical interaction between NOM1 and eIF4AIII was demonstrated in vitro and in vivo. This interaction is evolutionarily conserved (yeast Sgd1p–Fal1p). Knockdown of eIF4AIII and NOM1 in human cells revealed that this complex acts in pre-rRNA processing (18S rRNA biogenesis), distinct from the EJC role of eIF4AIII.\",\n      \"method\": \"Yeast genetic complementation (fal1Δ rescued by human eIF4AIII), in vitro binding assay, co-immunoprecipitation in human cells, siRNA knockdown with rRNA processing readout, structural comparison to eIF4A/eIF4G crystal structure\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding, reciprocal Co-IP in vivo, genetic complementation, knockdown with defined molecular phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21576267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, nom1 mutants exhibit defects in exocrine pancreas development due to impaired proliferation of ptf1a-expressing pancreatic progenitor cells. Loss of nom1 disrupts pre-rRNA processing and ribosome biogenesis in a p53-independent manner. Targeting PP1α into the nucleolus (by adding a nucleolar localization signal) partially rescued the pancreatic defect in nom1 morphants, demonstrating that nucleolar targeting of PP1α by Nom1 is functionally important for pancreatic proliferation.\",\n      \"method\": \"Forward genetic screen, positional cloning, RNA-seq, morpholino knockdown, rescue with PP1α + nucleolar localization signal, p53 loss-of-function epistasis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic screen with positional cloning, molecular rescue experiment, epistasis with p53, multiple orthogonal methods\",\n      \"pmids\": [\"24967912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NOM1 was identified as a nuclear IGF1R-interacting protein by mass spectrometry-based proteomics. Co-immunoprecipitation confirmed a complex between nuclear IGF1R and NOM1. Inhibition of nuclear IGF1R translocation reduced NOM1 levels in the nuclear fraction; IGF1R overexpression enhanced NOM1 nuclear levels. NOM1 silencing led to increased IGF1R biosynthesis, indicating a bi-directional interplay.\",\n      \"method\": \"Mass spectrometry-based nuclear proteomics, co-immunoprecipitation, siRNA silencing, pharmacological inhibition of IGF1R nuclear translocation (dansylcadaverine), western blot quantification\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus silencing with functional readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"30639046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nom1 (mouse/yeast ortholog) is a downstream transcriptional target of KDM4 (H3K9/H3K36 demethylases). In Kdm4a/b/c triple-knockout hematopoietic stem cells, H3K9me3 accumulates at the Nom1 transcription start site, leading to downregulation of Nom1 expression. Nom1 was shown to be essential for maintenance of hematopoietic cells by knockdown experiments.\",\n      \"method\": \"Conditional triple-knockout mice (Kdm4a/b/c), ChIP-seq for H3K9me3, RNA-seq, knockdown of Nom1 with hematopoietic cell maintenance readout\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with ChIP-seq and RNA-seq, KD with defined cellular phenotype, single lab\",\n      \"pmids\": [\"31434704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Yeast Sgd1 (ortholog of human NOM1) interacts directly with the RNA helicase Fal1 (ortholog of human eIF4AIII) via its MIF4G domain. The MIF4G domain of Sgd1 stimulates the ATPase/helicase catalytic activity of Fal1 in vitro. The Fal1–Sgd1 interaction is required for efficient pre-rRNA processing at sites A0, A1, and A2. Sgd1 co-purifies early SSU processome factors Lcp5 and Rok1. In vivo crosslinking (CRAC) showed Sgd1 binds helix H12 of 18S rRNA via its C-terminal region, which is essential for ribosome biogenesis function.\",\n      \"method\": \"In vitro ATPase/helicase stimulation assay, co-purification/pull-down, in vivo UV crosslinking (CRAC), domain mutagenesis/truncation, pre-rRNA processing analysis (Northern blot)\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic stimulation assay, in vivo crosslinking, mutagenesis of functional domain, multiple orthogonal methods, consistent with human NOM1 data\",\n      \"pmids\": [\"31994962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Yeast Sgd1p (ortholog of human NOM1) is an essential nuclear protein. Overexpression of SGD1 partially suppresses osmosensitivity of pbs2Δ and hog1Δ mutants (HOG MAP kinase pathway), partially restoring GPD1 transcription and glycerol production. A GFP-tagged Sgd1p localizes to the cell nucleus.\",\n      \"method\": \"Gene deletion (lethality), multicopy suppressor assay, GFP localization, quantitative GPD1 expression analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion lethality, genetic suppression with transcriptional readout, GFP localization, single lab\",\n      \"pmids\": [\"11042259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Yeast Sgd1p (ortholog of human NOM1) physically interacts with phospholipase C (Plc1p), confirmed by two-hybrid screen and affinity chromatography. SGD1 shows genetic interactions with PLC1 and HOG1: overexpression of SGD1 suppresses plc1-4 temperature sensitivity; double mutant plc1Δ sgd1-1 shows enhanced sensitivity; triple mutant plc1Δ hog1Δ sgd1-1 is inviable. These data place Sgd1p at a convergence point of Plc1p- and Hog1p-dependent osmoregulatory pathways controlling GPD1 expression.\",\n      \"method\": \"Two-hybrid screen, affinity chromatography, genetic epistasis (double/triple mutants), growth assays under osmotic stress, GPD1 expression analysis\",\n      \"journal\": \"Molecular genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical interaction confirmed by affinity chromatography plus genetic epistasis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12073033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NOM1 knockdown in mouse pancreatic beta cells (MIN6) increases cleaved caspase-3 levels, elevates Bax and reduces Bcl-2 expression, and inhibits cell proliferation. NOM1 silencing reduced insulin 2 mRNA expression. These data suggest NOM1 supports beta cell survival and insulin production, with apoptosis occurring via the Bax/Bcl-2/caspase-3 pathway.\",\n      \"method\": \"siRNA knockdown in MIN6 cells, western blot (caspase-3, Bcl-2, Bax), MTT proliferation assay, RT-qPCR (insulin 1/2 mRNA)\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA knockdown with downstream marker readout only, no pathway placement beyond apoptosis markers\",\n      \"pmids\": [\"27698723\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NOM1 is an evolutionarily conserved nucleolar protein containing MIF4G and MA3 domains that functions as an eIF4G-like cofactor for the DEAD-box RNA helicase eIF4AIII (and its yeast ortholog Fal1), stimulating its catalytic activity and enabling pre-rRNA processing (18S rRNA biogenesis) at sites A0/A1/A2; NOM1 also acts as the first identified PP1 nucleolar targeting subunit via an RVXF motif and a nucleolar localization sequence, and this PP1-targeting activity is required for normal pancreatic progenitor cell proliferation in zebrafish, while in hematopoietic stem cells NOM1 expression is regulated by KDM4-mediated H3K9 demethylation at its promoter.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NOM1 is an evolutionarily conserved nucleolar protein that functions as an eIF4G-like cofactor for the DEAD-box RNA helicase eIF4AIII, coupling helicase activity to ribosome biogenesis [#0, #2]. Through its MIF4G domain it binds eIF4AIII directly (and the yeast Sgd1p–Fal1p pair is conserved), and the resulting complex drives pre-rRNA processing for 18S rRNA biogenesis at cleavage sites A0/A1/A2 — a role distinct from the EJC function of eIF4AIII [#2, #6]. Work on the yeast ortholog established the molecular basis: the MIF4G domain stimulates the ATPase/helicase activity of Fal1, the protein co-purifies early SSU processome factors, and its C-terminal region crosslinks to helix H12 of 18S rRNA, which is required for ribosome biogenesis [#6]. Independently, NOM1 acts as the first identified nucleolar targeting subunit for protein phosphatase 1 (PP1), recruiting PP1 to the nucleolus via an RVXF motif together with its nucleolar localization sequence [#1]; this PP1-targeting activity is functionally required for proliferation of ptf1a-expressing pancreatic progenitor cells in zebrafish, where loss of nom1 disrupts ribosome biogenesis in a p53-independent manner [#3]. NOM1 expression supports stem and progenitor cell maintenance, being regulated by KDM4-mediated H3K9 demethylation at its promoter in hematopoietic stem cells [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the yeast ortholog Sgd1p as an essential nuclear protein and first linked it to osmoregulatory signaling, raising the question of what essential nuclear function it serves.\",\n      \"evidence\": \"Gene deletion lethality, multicopy suppression of HOG-pathway mutants, and GFP localization in yeast\",\n      \"pmids\": [\"11042259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Essential molecular activity not identified\", \"Connection between nuclear localization and HOG suppression unexplained\", \"No biochemical partners defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed Sgd1p at a convergence of Plc1p- and Hog1p-dependent osmoregulatory pathways through physical and genetic interactions, though its biochemical role remained undefined.\",\n      \"evidence\": \"Two-hybrid screen, affinity chromatography, and double/triple-mutant epistasis in yeast\",\n      \"pmids\": [\"12073033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic or RNA-related function still unknown\", \"Mechanism connecting Plc1p binding to GPD1 control unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined human NOM1 domain architecture (MIF4G and MA3) and its eIF4A-family binding and nucleolar localization, framing it as a translation-factor-like nucleolar protein.\",\n      \"evidence\": \"Domain analysis, binding assays with eIF4A family members, and subcellular imaging in human cells\",\n      \"pmids\": [\"15715967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which eIF4A paralog is the functional partner not resolved\", \"No functional readout for the interaction\", \"Nucleolar role not yet defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a second, distinct function: NOM1 is the first nucleolar targeting subunit for PP1, answering how PP1 is recruited to the nucleolus.\",\n      \"evidence\": \"Reciprocal Co-IP, RVXF motif mutagenesis, and localization/targeting assays in human cells\",\n      \"pmids\": [\"17965019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nucleolar PP1 substrates not identified\", \"Relationship between PP1-targeting and rRNA processing roles unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified NOM1 as the eIF4G-like partner of eIF4AIII in pre-rRNA processing, establishing a ribosome biogenesis role separate from eIF4AIII's EJC function.\",\n      \"evidence\": \"In vitro binding, reciprocal Co-IP, yeast complementation of fal1Δ by human eIF4AIII, and siRNA knockdown with rRNA processing readout\",\n      \"pmids\": [\"21576267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of helicase stimulation not shown in human system\", \"Precise rRNA contact sites undefined at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed in vivo that NOM1-dependent nucleolar PP1 targeting and ribosome biogenesis are required for pancreatic progenitor proliferation, linking both molecular activities to development.\",\n      \"evidence\": \"Zebrafish forward genetic screen, positional cloning, RNA-seq, rescue with PP1α plus nucleolar localization signal, and p53 epistasis\",\n      \"pmids\": [\"24967912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How impaired ribosome biogenesis specifically limits progenitor proliferation unresolved\", \"PP1 nucleolar substrates in this context unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the interaction network to nuclear IGF1R, suggesting a bidirectional regulatory relationship, and to KDM4-controlled transcriptional regulation in hematopoietic stem cells.\",\n      \"evidence\": \"Nuclear proteomics with Co-IP and silencing (IGF1R study); Kdm4a/b/c triple-KO mice with ChIP-seq, RNA-seq and Nom1 knockdown (HSC study)\",\n      \"pmids\": [\"30639046\", \"31434704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of the NOM1–IGF1R complex unclear\", \"Whether HSC maintenance reflects ribosome biogenesis or another role not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the mechanistic basis for the rRNA processing role: the MIF4G domain stimulates helicase catalysis and the C-terminus engages 18S rRNA helix H12 within the SSU processome.\",\n      \"evidence\": \"In vitro ATPase/helicase stimulation assay, co-purification of SSU processome factors, in vivo CRAC crosslinking, and domain truncation in yeast\",\n      \"pmids\": [\"31994962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the Sgd1/NOM1–Fal1/eIF4AIII complex on rRNA lacking\", \"Coordination between PP1-targeting and helicase-cofactor roles unaddressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NOM1's two activities — eIF4AIII helicase cofactor for 18S biogenesis and PP1 nucleolar targeting — are integrated within a single protein, and whether they are mechanistically coupled, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length NOM1\", \"Nucleolar PP1 dephosphorylation substrates unidentified\", \"Whether PP1-targeting and helicase-cofactor functions act on the same biogenesis steps unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\"SSU processome\"],\n    \"partners\": [\"EIF4A3\", \"PPP1CA\", \"IGF1R\", \"FAL1\", \"PLC1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}