{"gene":"DRC9","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2007,"finding":"NUP98-IQCG fusion protein forms homodimers, heterodimerizes with NUP98 or IQCG, binds transcriptional co-activators and/or co-repressors, and shows transcriptional activity in vitro. Expression of NUP98-IQCG inhibits Ara-C-induced apoptosis in 32Dcl3 cells and partially blocks G-CSF-induced granulocyte differentiation. NUP98-IQCG stimulates proliferation and partially blocks differentiation of hematopoietic stem/progenitor cells but is insufficient alone to induce transformation.","method":"Co-immunoprecipitation, in vitro transcriptional assays, colony-forming and serial replating assays, cell differentiation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and multiple functional assays in a single lab; mechanistic characterization of the fusion protein but no structural or reconstitution data","pmids":["18084320"],"is_preprint":false},{"year":2014,"finding":"IQCG (Iqcg) is required for sperm flagellum formation in mice; knockout causes male infertility with disorganized axonemes lacking the typical 9+2 microtubule arrangement and total sperm immobility. Iqcg localizes to the manchette in developing spermatids. Iqcg interacts with calmodulin in a calcium-dependent manner in the testis. Cilia in trachea and oviduct are unaffected, indicating a spermiogenesis-specific requirement.","method":"Gene knockout (targeted null allele), immunofluorescence/localization to manchette, co-immunoprecipitation with calmodulin, electron microscopy of axoneme ultrastructure","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse with defined ultrastructural phenotype, subcellular localization, and biochemical interaction with calmodulin; replicated by independent lab (PMID:24362311)","pmids":["24849454"],"is_preprint":false},{"year":2014,"finding":"Loss of Iqcg in a forward genetic mouse screen disrupts spermiogenesis such that tail formation occurs incompletely or breaks apart from sperm heads (oligoasthenoteratospermia). The orthologous Chlamydomonas protein is present in flagella, consistent with a conserved role in flagellar formation/function. IQ motif-containing proteins typically regulate calmodulin, implicating localized calcium signaling in sperm flagellum morphogenesis.","method":"Forward genetic screen (ENU mutagenesis), targeted null allele confirmation, phylogenetic ortholog analysis, Chlamydomonas flagella proteomics","journal":"G3 (Bethesda, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — independently corroborates PMID:24849454 using a separate mutant allele and forward genetic screen; cross-species localization data","pmids":["24362311"],"is_preprint":false},{"year":2014,"finding":"IQCG is required for haematopoietic stem cell maintenance and multilineage differentiation in zebrafish. Mechanistically, IQCG binds calmodulin (CaM) and acts upstream of CaM-dependent kinase IV (CaMKIV). Crystal structures of CaM–IQCG IQ domain complexes reveal dual CaM-binding footprints within the IQ motif and show that CaM–IQCG affinity is higher in the absence of calcium. The proposed model is that IQCG stores CaM at low calcium and releases it to activate CaMKIV when calcium rises.","method":"Zebrafish iqcg knockdown (morpholino), crystal structure of CaM–IQCG IQ domain complex, co-immunoprecipitation, biochemical binding assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation (zebrafish loss-of-function phenotype) and biochemical CaM-binding characterization, multiple orthogonal methods in one study","pmids":["24787902"],"is_preprint":false},{"year":2016,"finding":"NUP98-IQCG associates with the nuclear export receptor CRM1 and inhibits CRM1-mediated nuclear export of p65 (NF-κB subunit), thereby enhancing NF-κB transcriptional activity. NUP98-IQCG also entraps endogenous IQCG in the nucleus. The fusion protein interacts with calmodulin via its IQ motif in a calcium-independent manner.","method":"Co-immunoprecipitation (NUP98-IQCG with CRM1), nuclear export assays, NF-κB reporter/transcriptional activity assays, subcellular fractionation","journal":"Frontiers of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional transcriptional assays in a single lab; calcium-independent CaM binding by fusion protein contrasts with calcium-dependent binding of wild-type IQCG","pmids":["27864780"],"is_preprint":false},{"year":2023,"finding":"In the nexin-dynein regulatory complex (N-DRC) structure of Tetrahymena thermophila resolved by cryo-EM and integrative modeling, DRC9 (the ortholog of human DRC9/CFAP122) is localized in the linker region of the N-DRC, where it is in close contact with the CCDC96/113 complex.","method":"Cryo-electron microscopy, biochemical cross-linking, integrative structural modeling","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — cryo-EM structure with integrative modeling is high-quality method, but DRC9 localization within the complex is a single study in a non-mammalian ciliate model","pmids":["37714832"],"is_preprint":false},{"year":2024,"finding":"IQCG functions as a novel microtubule nucleation factor with dual roles: it promotes centrosomal microtubule organization during interphase and disperses into the spindle to promote microtubule generation during mitosis, ensuring robust cell division. IQCG interacts with GSK3β via its N2 region, which enhances centrosomal accumulation of IQCG in interphase. The IQCG gene has undergone accelerated evolution and positive selection in the human lineage, particularly in the variable N2 region.","method":"Genetic analyses, cell biological characterization (live imaging/centrosome assays), co-immunoprecipitation (IQCG–GSK3β), evolutionary sequence analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint; single lab; Co-IP and cell biological data without full reconstitution or structural validation; novel claim not yet peer-reviewed","pmids":["bio_10.1101_2024.12.16.628806"],"is_preprint":true}],"current_model":"IQCG (DRC9/CFAP122) is an IQ-motif-containing protein that binds calmodulin (CaM) — with higher affinity in the absence of calcium — and acts upstream of CaMKIV to regulate calcium signaling in haematopoiesis and spermiogenesis; it is essential for axonemal 9+2 microtubule organization during sperm flagellum formation, localizes to the manchette in spermatids, occupies the linker region of the nexin-dynein regulatory complex (N-DRC) in cilia, and has additionally been identified as a microtubule nucleation factor at the centrosome that interacts with GSK3β and supports mitotic spindle formation; its leukemia-associated fusion NUP98-IQCG acts as an aberrant transcriptional regulator that sequesters CRM1 and blocks nuclear export of p65, enhancing NF-κB activity."},"narrative":{"mechanistic_narrative":"IQCG (DRC9/CFAP122) is an IQ-motif-containing calmodulin (CaM)-binding protein that couples localized calcium signaling to microtubule-based structures in ciliated/flagellated cells and to haematopoiesis [PMID:24787902, PMID:24849454]. It binds CaM through dual CaM-binding footprints in its IQ motif with higher affinity in the absence of calcium, and acts upstream of CaM-dependent kinase IV (CaMKIV); the structural and functional data support a model in which IQCG stores CaM at low calcium and releases it to activate CaMKIV when calcium rises, a step required for haematopoietic stem cell maintenance and multilineage differentiation [PMID:24787902]. IQCG is essential for sperm flagellum formation: its loss causes male infertility with disorganized axonemes lacking the 9+2 microtubule arrangement and immotile sperm, and it localizes to the manchette in developing spermatids while binding CaM in a calcium-dependent manner in testis [PMID:24849454, PMID:24362311]. Consistent with a conserved ciliary role, the Tetrahymena ortholog occupies the linker region of the nexin-dynein regulatory complex (N-DRC) in close contact with the CCDC96/113 complex [PMID:37714832]. The leukemia-associated NUP98-IQCG fusion acts as an aberrant regulator that sequesters the export receptor CRM1, blocking nuclear export of the NF-κB subunit p65 and enhancing NF-κB activity, while also entrapping endogenous IQCG in the nucleus; the fusion stimulates proliferation and partially blocks differentiation of haematopoietic progenitors [PMID:18084320, PMID:27864780].","teleology":[{"year":2007,"claim":"Established that the leukemia-associated NUP98-IQCG fusion is a functional transcriptional dysregulator, addressing how the fusion contributes to leukemogenesis.","evidence":"Co-IP, in vitro transcriptional assays, and differentiation/colony assays in 32Dcl3 and haematopoietic progenitor cells","pmids":["18084320"],"confidence":"Medium","gaps":["Mechanism by which transcriptional activity is exerted not defined","Fusion alone insufficient to transform, leaving cooperating events unknown","No structural characterization of the fusion"]},{"year":2014,"claim":"Defined an essential, spermiogenesis-specific role for IQCG in axonemal 9+2 organization and sperm flagellum formation, linking it to CaM in vivo.","evidence":"Knockout/ENU mouse models with axoneme EM, manchette localization, CaM co-IP, and Chlamydomonas ortholog proteomics","pmids":["24849454","24362311"],"confidence":"High","gaps":["Molecular function within the manchette/axoneme not resolved","Why tracheal and oviduct cilia are spared not explained","Direct biochemical activity of IQCG not defined"]},{"year":2014,"claim":"Resolved the structural basis of IQCG–CaM binding and placed IQCG upstream of CaMKIV in haematopoiesis, providing a CaM-storage/release model.","evidence":"Crystal structures of CaM–IQCG IQ-domain complexes, zebrafish morpholino loss-of-function, and biochemical binding assays","pmids":["24787902"],"confidence":"High","gaps":["In vivo demonstration of CaM release driving CaMKIV activation incomplete","Connection between haematopoietic and flagellar roles unclear","Downstream CaMKIV targets in this context not mapped"]},{"year":2016,"claim":"Explained how NUP98-IQCG enhances NF-κB signaling, revealing a CRM1-sequestration mechanism distinct from wild-type IQCG calcium-dependent CaM binding.","evidence":"Co-IP with CRM1, nuclear export and NF-κB reporter assays, and subcellular fractionation","pmids":["27864780"],"confidence":"Medium","gaps":["Single-lab Co-IP without structural validation","Calcium-independent CaM binding of fusion versus calcium-dependent wild-type binding not mechanistically reconciled","Contribution of p65 retention to leukemogenesis in vivo untested"]},{"year":2023,"claim":"Localized the DRC9 ortholog within the N-DRC linker region, positioning it structurally in the ciliary dynein regulatory machinery.","evidence":"Cryo-EM and integrative modeling with cross-linking in Tetrahymena thermophila","pmids":["37714832"],"confidence":"Medium","gaps":["Single non-mammalian ciliate model","Functional consequence of DRC9 within N-DRC not tested by perturbation","Relationship to mammalian IQCG manchette/axoneme role not established"]},{"year":2024,"claim":"Proposed a novel mitotic role for IQCG as a microtubule nucleation factor interacting with GSK3β, extending its function beyond cilia/flagella.","evidence":"Cell biology/centrosome assays, IQCG–GSK3β Co-IP, and evolutionary sequence analysis (preprint)","pmids":["bio_10.1101_2024.12.16.628806"],"confidence":"Low","gaps":["Preprint, not peer-reviewed","No reconstitution or structural validation of nucleation activity","Role of N2/GSK3β interaction in spindle function not mechanistically proven"]},{"year":null,"claim":"How IQCG's calcium/CaM-sensing function is mechanistically unified across haematopoiesis, sperm flagellum morphogenesis, and the N-DRC remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No single model links CaM storage/release to axonemal 9+2 assembly","Direct enzymatic or structural activity of IQCG within the axoneme/manchette undefined","Mitotic microtubule-nucleation role awaits peer-reviewed confirmation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":["nexin-dynein regulatory complex (N-DRC)"],"partners":["CALM1","CAMKIV","CRM1","GSK3B","NUP98","CCDC96","CCDC113"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H095","full_name":"Dynein regulatory complex protein 9","aliases":["IQ domain-containing protein G"],"length_aa":443,"mass_kda":51.9,"function":"Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes. Binds calmodulin when cellular Ca(2+) levels are low and thereby contributes to the regulation of calcium and calmodulin-dependent protein kinase IV (CAMK4) activity; contributes to the regulation of CAMK4 signaling cascades. Required for normal axoneme assembly in sperm flagella, normal sperm tail formation and for male fertility","subcellular_location":"Cytoplasm; Cell projection, cilium, flagellum; Cell projection, cilium; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, flagellum axoneme","url":"https://www.uniprot.org/uniprotkb/Q9H095/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"IQCG","url":"https://depmap.org/portal/gene/IQCG","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DRC9","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"IQCG","reliability":"Approved","locations":[{"location":"Actin filaments","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"choroid plexus","ntpm":51.6},{"tissue":"fallopian tube","ntpm":49.6},{"tissue":"testis","ntpm":41.0}],"url":"https://www.proteinatlas.org/search/IQCG"},"hgnc":{"alias_symbol":["DKFZp434B227","DRC9","CFAP122"],"prev_symbol":["IQCG"]},"alphafold":{"accession":"Q9H095","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H095","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H095-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H095-F1-predicted_aligned_error_v6.png","plddt_mean":71.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DRC9","jax_strain_url":"https://www.jax.org/strain/search?query=DRC9"},"sequence":{"accession":"Q9H095","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H095.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H095/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H095"}},"corpus_meta":[{"pmid":"30109096","id":"PMC_30109096","title":"Identification and characterization of circular RNAs in Qinchuan cattle testis.","date":"2018","source":"Royal Society open science","url":"https://pubmed.ncbi.nlm.nih.gov/30109096","citation_count":44,"is_preprint":false},{"pmid":"24849454","id":"PMC_24849454","title":"Iqcg is essential for sperm flagellum formation in mice.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24849454","citation_count":38,"is_preprint":false},{"pmid":"28717182","id":"PMC_28717182","title":"Widespread alternative exon usage in clinically distinct subtypes of Invasive Ductal Carcinoma.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28717182","citation_count":37,"is_preprint":false},{"pmid":"18084320","id":"PMC_18084320","title":"A new fusion gene NUP98-IQCG identified in an acute T-lymphoid/myeloid leukemia with a t(3;11)(q29q13;p15)del(3)(q29) translocation.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18084320","citation_count":29,"is_preprint":false},{"pmid":"24362311","id":"PMC_24362311","title":"IQ motif-containing G (Iqcg) is required for mouse spermiogenesis.","date":"2014","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/24362311","citation_count":29,"is_preprint":false},{"pmid":"37714832","id":"PMC_37714832","title":"Integrated modeling of the Nexin-dynein regulatory complex reveals its regulatory mechanism.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37714832","citation_count":29,"is_preprint":false},{"pmid":"32241839","id":"PMC_32241839","title":"Genotype-phenotype association and variant characterization in Diamond-Blackfan anemia caused by pathogenic variants in RPL35A.","date":"2021","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/32241839","citation_count":24,"is_preprint":false},{"pmid":"24787902","id":"PMC_24787902","title":"Functional and molecular features of the calmodulin-interacting protein IQCG required for haematopoiesis in zebrafish.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24787902","citation_count":19,"is_preprint":false},{"pmid":"34790699","id":"PMC_34790699","title":"Identification and Analysis of Potential Autophagy-Related Biomarkers in Endometriosis by WGCNA.","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34790699","citation_count":12,"is_preprint":false},{"pmid":"35886074","id":"PMC_35886074","title":"Further Insights on RNA Expression and Sperm Motility.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35886074","citation_count":11,"is_preprint":false},{"pmid":"39470923","id":"PMC_39470923","title":"Dissecting the cell microenvironment of ovarian endometrioma through single-cell RNA sequencing.","date":"2024","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39470923","citation_count":8,"is_preprint":false},{"pmid":"27864780","id":"PMC_27864780","title":"Inhibition of the nuclear export of p65 and IQCG in leukemogenesis by NUP98-IQCG.","date":"2016","source":"Frontiers of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27864780","citation_count":6,"is_preprint":false},{"pmid":"30168948","id":"PMC_30168948","title":"[Expression of IQCG in the human testis and its correlation with asthenospermia].","date":"2018","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/30168948","citation_count":4,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.16.628806","title":"Dual roles of IQCG, a novel microtubule nucleation factor rapidly evolving in humans","date":"2024-12-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.16.628806","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8582,"output_tokens":2243,"usd":0.029695,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9207,"output_tokens":2636,"usd":0.055968,"stage2_stop_reason":"end_turn"},"total_usd":0.085663,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"NUP98-IQCG fusion protein forms homodimers, heterodimerizes with NUP98 or IQCG, binds transcriptional co-activators and/or co-repressors, and shows transcriptional activity in vitro. Expression of NUP98-IQCG inhibits Ara-C-induced apoptosis in 32Dcl3 cells and partially blocks G-CSF-induced granulocyte differentiation. NUP98-IQCG stimulates proliferation and partially blocks differentiation of hematopoietic stem/progenitor cells but is insufficient alone to induce transformation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro transcriptional assays, colony-forming and serial replating assays, cell differentiation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and multiple functional assays in a single lab; mechanistic characterization of the fusion protein but no structural or reconstitution data\",\n      \"pmids\": [\"18084320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQCG (Iqcg) is required for sperm flagellum formation in mice; knockout causes male infertility with disorganized axonemes lacking the typical 9+2 microtubule arrangement and total sperm immobility. Iqcg localizes to the manchette in developing spermatids. Iqcg interacts with calmodulin in a calcium-dependent manner in the testis. Cilia in trachea and oviduct are unaffected, indicating a spermiogenesis-specific requirement.\",\n      \"method\": \"Gene knockout (targeted null allele), immunofluorescence/localization to manchette, co-immunoprecipitation with calmodulin, electron microscopy of axoneme ultrastructure\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse with defined ultrastructural phenotype, subcellular localization, and biochemical interaction with calmodulin; replicated by independent lab (PMID:24362311)\",\n      \"pmids\": [\"24849454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of Iqcg in a forward genetic mouse screen disrupts spermiogenesis such that tail formation occurs incompletely or breaks apart from sperm heads (oligoasthenoteratospermia). The orthologous Chlamydomonas protein is present in flagella, consistent with a conserved role in flagellar formation/function. IQ motif-containing proteins typically regulate calmodulin, implicating localized calcium signaling in sperm flagellum morphogenesis.\",\n      \"method\": \"Forward genetic screen (ENU mutagenesis), targeted null allele confirmation, phylogenetic ortholog analysis, Chlamydomonas flagella proteomics\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independently corroborates PMID:24849454 using a separate mutant allele and forward genetic screen; cross-species localization data\",\n      \"pmids\": [\"24362311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQCG is required for haematopoietic stem cell maintenance and multilineage differentiation in zebrafish. Mechanistically, IQCG binds calmodulin (CaM) and acts upstream of CaM-dependent kinase IV (CaMKIV). Crystal structures of CaM–IQCG IQ domain complexes reveal dual CaM-binding footprints within the IQ motif and show that CaM–IQCG affinity is higher in the absence of calcium. The proposed model is that IQCG stores CaM at low calcium and releases it to activate CaMKIV when calcium rises.\",\n      \"method\": \"Zebrafish iqcg knockdown (morpholino), crystal structure of CaM–IQCG IQ domain complex, co-immunoprecipitation, biochemical binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation (zebrafish loss-of-function phenotype) and biochemical CaM-binding characterization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24787902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NUP98-IQCG associates with the nuclear export receptor CRM1 and inhibits CRM1-mediated nuclear export of p65 (NF-κB subunit), thereby enhancing NF-κB transcriptional activity. NUP98-IQCG also entraps endogenous IQCG in the nucleus. The fusion protein interacts with calmodulin via its IQ motif in a calcium-independent manner.\",\n      \"method\": \"Co-immunoprecipitation (NUP98-IQCG with CRM1), nuclear export assays, NF-κB reporter/transcriptional activity assays, subcellular fractionation\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional transcriptional assays in a single lab; calcium-independent CaM binding by fusion protein contrasts with calcium-dependent binding of wild-type IQCG\",\n      \"pmids\": [\"27864780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In the nexin-dynein regulatory complex (N-DRC) structure of Tetrahymena thermophila resolved by cryo-EM and integrative modeling, DRC9 (the ortholog of human DRC9/CFAP122) is localized in the linker region of the N-DRC, where it is in close contact with the CCDC96/113 complex.\",\n      \"method\": \"Cryo-electron microscopy, biochemical cross-linking, integrative structural modeling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — cryo-EM structure with integrative modeling is high-quality method, but DRC9 localization within the complex is a single study in a non-mammalian ciliate model\",\n      \"pmids\": [\"37714832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IQCG functions as a novel microtubule nucleation factor with dual roles: it promotes centrosomal microtubule organization during interphase and disperses into the spindle to promote microtubule generation during mitosis, ensuring robust cell division. IQCG interacts with GSK3β via its N2 region, which enhances centrosomal accumulation of IQCG in interphase. The IQCG gene has undergone accelerated evolution and positive selection in the human lineage, particularly in the variable N2 region.\",\n      \"method\": \"Genetic analyses, cell biological characterization (live imaging/centrosome assays), co-immunoprecipitation (IQCG–GSK3β), evolutionary sequence analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint; single lab; Co-IP and cell biological data without full reconstitution or structural validation; novel claim not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.12.16.628806\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IQCG (DRC9/CFAP122) is an IQ-motif-containing protein that binds calmodulin (CaM) — with higher affinity in the absence of calcium — and acts upstream of CaMKIV to regulate calcium signaling in haematopoiesis and spermiogenesis; it is essential for axonemal 9+2 microtubule organization during sperm flagellum formation, localizes to the manchette in spermatids, occupies the linker region of the nexin-dynein regulatory complex (N-DRC) in cilia, and has additionally been identified as a microtubule nucleation factor at the centrosome that interacts with GSK3β and supports mitotic spindle formation; its leukemia-associated fusion NUP98-IQCG acts as an aberrant transcriptional regulator that sequesters CRM1 and blocks nuclear export of p65, enhancing NF-κB activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IQCG (DRC9/CFAP122) is an IQ-motif-containing calmodulin (CaM)-binding protein that couples localized calcium signaling to microtubule-based structures in ciliated/flagellated cells and to haematopoiesis [#3, #1]. It binds CaM through dual CaM-binding footprints in its IQ motif with higher affinity in the absence of calcium, and acts upstream of CaM-dependent kinase IV (CaMKIV); the structural and functional data support a model in which IQCG stores CaM at low calcium and releases it to activate CaMKIV when calcium rises, a step required for haematopoietic stem cell maintenance and multilineage differentiation [#3]. IQCG is essential for sperm flagellum formation: its loss causes male infertility with disorganized axonemes lacking the 9+2 microtubule arrangement and immotile sperm, and it localizes to the manchette in developing spermatids while binding CaM in a calcium-dependent manner in testis [#1, #2]. Consistent with a conserved ciliary role, the Tetrahymena ortholog occupies the linker region of the nexin-dynein regulatory complex (N-DRC) in close contact with the CCDC96/113 complex [#5]. The leukemia-associated NUP98-IQCG fusion acts as an aberrant regulator that sequesters the export receptor CRM1, blocking nuclear export of the NF-\\u03baB subunit p65 and enhancing NF-\\u03baB activity, while also entrapping endogenous IQCG in the nucleus; the fusion stimulates proliferation and partially blocks differentiation of haematopoietic progenitors [#0, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that the leukemia-associated NUP98-IQCG fusion is a functional transcriptional dysregulator, addressing how the fusion contributes to leukemogenesis.\",\n      \"evidence\": \"Co-IP, in vitro transcriptional assays, and differentiation/colony assays in 32Dcl3 and haematopoietic progenitor cells\",\n      \"pmids\": [\"18084320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which transcriptional activity is exerted not defined\", \"Fusion alone insufficient to transform, leaving cooperating events unknown\", \"No structural characterization of the fusion\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined an essential, spermiogenesis-specific role for IQCG in axonemal 9+2 organization and sperm flagellum formation, linking it to CaM in vivo.\",\n      \"evidence\": \"Knockout/ENU mouse models with axoneme EM, manchette localization, CaM co-IP, and Chlamydomonas ortholog proteomics\",\n      \"pmids\": [\"24849454\", \"24362311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function within the manchette/axoneme not resolved\", \"Why tracheal and oviduct cilia are spared not explained\", \"Direct biochemical activity of IQCG not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the structural basis of IQCG\\u2013CaM binding and placed IQCG upstream of CaMKIV in haematopoiesis, providing a CaM-storage/release model.\",\n      \"evidence\": \"Crystal structures of CaM\\u2013IQCG IQ-domain complexes, zebrafish morpholino loss-of-function, and biochemical binding assays\",\n      \"pmids\": [\"24787902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration of CaM release driving CaMKIV activation incomplete\", \"Connection between haematopoietic and flagellar roles unclear\", \"Downstream CaMKIV targets in this context not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Explained how NUP98-IQCG enhances NF-\\u03baB signaling, revealing a CRM1-sequestration mechanism distinct from wild-type IQCG calcium-dependent CaM binding.\",\n      \"evidence\": \"Co-IP with CRM1, nuclear export and NF-\\u03baB reporter assays, and subcellular fractionation\",\n      \"pmids\": [\"27864780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without structural validation\", \"Calcium-independent CaM binding of fusion versus calcium-dependent wild-type binding not mechanistically reconciled\", \"Contribution of p65 retention to leukemogenesis in vivo untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Localized the DRC9 ortholog within the N-DRC linker region, positioning it structurally in the ciliary dynein regulatory machinery.\",\n      \"evidence\": \"Cryo-EM and integrative modeling with cross-linking in Tetrahymena thermophila\",\n      \"pmids\": [\"37714832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single non-mammalian ciliate model\", \"Functional consequence of DRC9 within N-DRC not tested by perturbation\", \"Relationship to mammalian IQCG manchette/axoneme role not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed a novel mitotic role for IQCG as a microtubule nucleation factor interacting with GSK3\\u03b2, extending its function beyond cilia/flagella.\",\n      \"evidence\": \"Cell biology/centrosome assays, IQCG\\u2013GSK3\\u03b2 Co-IP, and evolutionary sequence analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.12.16.628806\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"No reconstitution or structural validation of nucleation activity\", \"Role of N2/GSK3\\u03b2 interaction in spindle function not mechanistically proven\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IQCG's calcium/CaM-sensing function is mechanistically unified across haematopoiesis, sperm flagellum morphogenesis, and the N-DRC remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No single model links CaM storage/release to axonemal 9+2 assembly\", \"Direct enzymatic or structural activity of IQCG within the axoneme/manchette undefined\", \"Mitotic microtubule-nucleation role awaits peer-reviewed confirmation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"nexin-dynein regulatory complex (N-DRC)\"],\n    \"partners\": [\"CALM1\", \"CAMKIV\", \"CRM1\", \"GSK3B\", \"NUP98\", \"CCDC96\", \"CCDC113\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}