{"gene":"NOMO3","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2025,"finding":"Silencing of NOMO (including NOMO3) with siRNA increased phosphorylation of checkpoint kinases Chk1 and Chk2 and promoted caspase-dependent apoptosis in lung cancer cells, placing NOMO proteins upstream of the Chk2 pathway in mediating chemo- and radioresistance.","method":"siRNA knockdown of NOMO proteins in lung cancer cells, antibody array for phosphoprotein profiling, cell viability and apoptosis assays","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single study; siRNA knockdown with downstream phospho-profiling by antibody array; no direct mechanistic link established specifically for NOMO3 vs. the other NOMO paralogs; no structural or reconstitution data","pmids":["41151896"],"is_preprint":false}],"current_model":"NOMO3, as part of the NOMO protein family (NOMO1/2/3), functions upstream of the Chk2 checkpoint kinase pathway to suppress caspase-dependent apoptosis in lung cancer cells, thereby contributing to chemo- and radioresistance; beyond this, its broader role as a component of a protein complex involved in Nodal signaling during early embryonic patterning has been noted but the specific molecular mechanism for NOMO3 remains largely uncharacterized."},"narrative":{"mechanistic_narrative":"NOMO3 is implicated in the survival of lung cancer cells, where its silencing increases phosphorylation of the checkpoint kinases Chk1 and Chk2 and promotes caspase-dependent apoptosis, placing NOMO proteins upstream of the Chk2 checkpoint pathway in mediating chemo- and radioresistance [PMID:41151896]. Beyond this single observation, which does not distinguish NOMO3 from its paralogs, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2025,"claim":"To address whether NOMO proteins influence DNA-damage checkpoint signaling and cancer cell survival, knockdown was tested and showed that loss of NOMO activates Chk1/Chk2 phosphorylation and triggers caspase-dependent apoptosis, establishing NOMO upstream of the Chk2 pathway in chemo- and radioresistance.","evidence":"siRNA knockdown of NOMO proteins in lung cancer cells with antibody-array phosphoprotein profiling and apoptosis/viability assays","pmids":["41151896"],"confidence":"Low","gaps":["Single lab, single study with no independent confirmation","Does not isolate NOMO3's contribution from the other NOMO paralogs","No direct molecular mechanism linking NOMO3 to Chk2 regulation, and no structural or reconstitution data"]},{"year":null,"claim":"The direct molecular function of NOMO3, its physical partners, subcellular localization, and any paralog-specific role distinct from NOMO1/NOMO2 remain undefined in the available corpus.","evidence":"No further direct experimental evidence in the timeline","pmids":[],"confidence":"Low","gaps":["No biochemical activity or substrate identified for NOMO3","No reciprocal validation of how NOMO3 connects to checkpoint kinase activation","No localization or complex membership data specific to NOMO3"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P69849","full_name":"BOS complex subunit NOMO3","aliases":["Nodal modulator 3","pM5 protein 3"],"length_aa":1222,"mass_kda":134.1,"function":"Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes (PubMed:32820719, PubMed:36261522). The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions (PubMed:36261522)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P69849/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NOMO3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":5,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NCLN","stoichiometry":10.0},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NOMO3","total_profiled":1310},"omim":[{"mim_id":"609159","title":"NODAL MODULATOR 3; NOMO3","url":"https://www.omim.org/entry/609159"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":5.9}],"url":"https://www.proteinatlas.org/search/NOMO3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P69849","domains":[{"cath_id":"2.60.40.10","chopping":"34-121","consensus_level":"medium","plddt":87.7039,"start":34,"end":121},{"cath_id":"2.60.40.10","chopping":"131-215","consensus_level":"high","plddt":91.7454,"start":131,"end":215},{"cath_id":"2.60.40.10","chopping":"218-329","consensus_level":"high","plddt":84.8752,"start":218,"end":329},{"cath_id":"2.60.40.1120","chopping":"332-408","consensus_level":"high","plddt":77.9732,"start":332,"end":408},{"cath_id":"-","chopping":"415-489","consensus_level":"high","plddt":71.0069,"start":415,"end":489},{"cath_id":"2.60.40,2.60.40","chopping":"513-585","consensus_level":"high","plddt":80.8997,"start":513,"end":585},{"cath_id":"2.60.40","chopping":"591-662","consensus_level":"high","plddt":78.0512,"start":591,"end":662},{"cath_id":"-","chopping":"807-871","consensus_level":"high","plddt":83.3463,"start":807,"end":871},{"cath_id":"2.60.40.10","chopping":"961-1054","consensus_level":"medium","plddt":89.1119,"start":961,"end":1054},{"cath_id":"2.60.40.180","chopping":"1057-1150","consensus_level":"high","plddt":89.6603,"start":1057,"end":1150},{"cath_id":"2.60.40","chopping":"673-703_747-800","consensus_level":"medium","plddt":83.5871,"start":673,"end":800}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P69849","model_url":"https://alphafold.ebi.ac.uk/files/AF-P69849-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P69849-F1-predicted_aligned_error_v6.png","plddt_mean":80.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NOMO3","jax_strain_url":"https://www.jax.org/strain/search?query=NOMO3"},"sequence":{"accession":"P69849","fasta_url":"https://rest.uniprot.org/uniprotkb/P69849.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P69849/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P69849"}},"corpus_meta":[{"pmid":"32242507","id":"PMC_32242507","title":"Comprehensive Immune Profiling of Medullary Thyroid Cancer.","date":"2020","source":"Thyroid : official journal of the American Thyroid Association","url":"https://pubmed.ncbi.nlm.nih.gov/32242507","citation_count":47,"is_preprint":false},{"pmid":"34573339","id":"PMC_34573339","title":"GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34573339","citation_count":10,"is_preprint":false},{"pmid":"35133875","id":"PMC_35133875","title":"Biological Role of Nodal Modulator: A Comprehensive Review of the Last Two Decades.","date":"2022","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35133875","citation_count":3,"is_preprint":false},{"pmid":"41151896","id":"PMC_41151896","title":"Nodal Modulator Regulates Chemo- and Radioresistance in Lung Cancer via the Chk2 Pathway.","date":"2025","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41151896","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4002,"output_tokens":390,"usd":0.008928,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6646,"output_tokens":824,"usd":0.026915,"stage2_stop_reason":"end_turn"},"total_usd":0.035843,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"Silencing of NOMO (including NOMO3) with siRNA increased phosphorylation of checkpoint kinases Chk1 and Chk2 and promoted caspase-dependent apoptosis in lung cancer cells, placing NOMO proteins upstream of the Chk2 pathway in mediating chemo- and radioresistance.\",\n      \"method\": \"siRNA knockdown of NOMO proteins in lung cancer cells, antibody array for phosphoprotein profiling, cell viability and apoptosis assays\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single study; siRNA knockdown with downstream phospho-profiling by antibody array; no direct mechanistic link established specifically for NOMO3 vs. the other NOMO paralogs; no structural or reconstitution data\",\n      \"pmids\": [\"41151896\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NOMO3, as part of the NOMO protein family (NOMO1/2/3), functions upstream of the Chk2 checkpoint kinase pathway to suppress caspase-dependent apoptosis in lung cancer cells, thereby contributing to chemo- and radioresistance; beyond this, its broader role as a component of a protein complex involved in Nodal signaling during early embryonic patterning has been noted but the specific molecular mechanism for NOMO3 remains largely uncharacterized.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NOMO3 is implicated in the survival of lung cancer cells, where its silencing increases phosphorylation of the checkpoint kinases Chk1 and Chk2 and promotes caspase-dependent apoptosis, placing NOMO proteins upstream of the Chk2 checkpoint pathway in mediating chemo- and radioresistance [#0]. Beyond this single observation, which does not distinguish NOMO3 from its paralogs, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"To address whether NOMO proteins influence DNA-damage checkpoint signaling and cancer cell survival, knockdown was tested and showed that loss of NOMO activates Chk1/Chk2 phosphorylation and triggers caspase-dependent apoptosis, establishing NOMO upstream of the Chk2 pathway in chemo- and radioresistance.\",\n      \"evidence\": \"siRNA knockdown of NOMO proteins in lung cancer cells with antibody-array phosphoprotein profiling and apoptosis/viability assays\",\n      \"pmids\": [\"41151896\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single lab, single study with no independent confirmation\",\n        \"Does not isolate NOMO3's contribution from the other NOMO paralogs\",\n        \"No direct molecular mechanism linking NOMO3 to Chk2 regulation, and no structural or reconstitution data\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular function of NOMO3, its physical partners, subcellular localization, and any paralog-specific role distinct from NOMO1/NOMO2 remain undefined in the available corpus.\",\n      \"evidence\": \"No further direct experimental evidence in the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No biochemical activity or substrate identified for NOMO3\",\n        \"No reciprocal validation of how NOMO3 connects to checkpoint kinase activation\",\n        \"No localization or complex membership data specific to NOMO3\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":1,"faith_total":1,"faith_pct":100.0}}