{"gene":"CCDC86","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2007,"finding":"CCDC86 (Cyclon) is a cytokine-inducible immediate-early gene encoding a nuclear protein with repetitive sequences at the amino-terminus and a coiled-coil domain at the carboxyl-terminus; it is induced in hematopoietic cells by IL-3, and its promoter contains redundant elements sufficient for IL-3-driven transcriptional activation.","method":"Northern blot/RT-PCR identification of induced gene, subcellular fractionation and immunostaining showing nuclear localization, transient reporter assay mapping promoter elements","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct localization experiment with nuclear fractionation, reporter assay, single lab","pmids":["17300783"],"is_preprint":false},{"year":2009,"finding":"CCDC86 (Cyclon) is induced in T cells upon TCR ligation and promotes activation-induced cell death (AICD) by upregulating Fas (CD95) expression; conditional deletion of one Cyclon allele in activated CD4+ T cells reduced Fas expression and AICD, while transgenic Cyclon expression enhanced AICD and ameliorated autoimmune phenotype in IL-2R-deficient mice.","method":"Conditional knockout mice, transgenic overexpression, flow cytometry for Fas surface expression, AICD assay, autoimmune phenotype rescue in vivo","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic loss-of-function and gain-of-function with defined molecular readout (Fas expression), replicated in vivo","pmids":["19528538"],"is_preprint":false},{"year":2012,"finding":"CCDC86 was identified as an mRNA-binding protein in human HeLa cells by UV crosslinking and oligo(dT) purification (interactome capture), indicating it physically associates with mRNA.","method":"UV crosslinking followed by oligo(dT) purification and quantitative mass spectrometry (interactome capture)","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical crosslinking-based capture, large-scale but single method, no functional follow-up for CCDC86 specifically","pmids":["22658674"],"is_preprint":false},{"year":2012,"finding":"CCDC86 was independently identified as an mRNA-associated protein in human HEK293 cells using photoactivatable-ribonucleoside-enhanced crosslinking and oligo(dT) purification (PAR-CLIP-based mRNA interactome).","method":"PAR-CLIP (photoreactive nucleotide-enhanced UV crosslinking) and oligo(dT) purification coupled to quantitative proteomics","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 — orthogonal crosslinking-based biochemical method confirming mRNA-binding, single method for CCDC86 specifically","pmids":["22681889"],"is_preprint":false},{"year":2013,"finding":"CCDC86 (Cyclon) protein is expressed in neurons and astrocytes of the adult macaque hippocampus (including CA fields and dentate gyrus), extending its known expression beyond lymphocytes to the central nervous system.","method":"Immunohistochemistry and confocal microscopy on adult non-human primate brain sections with cell-type co-labeling","journal":"Journal of neuroimmunology","confidence":"Low","confidence_rationale":"Tier 3 — localization by IHC without functional consequence demonstrated","pmids":["23528659"],"is_preprint":false},{"year":2015,"finding":"CCDC86 was identified as part of conserved metazoan macromolecular complexes by biochemical co-fractionation across multiple species, placing it within ancient protein assemblies.","method":"Biochemical fractionation coupled with quantitative mass spectrometry across metazoan species","journal":"Nature","confidence":"Low","confidence_rationale":"Tier 3 — co-fractionation evidence; no specific functional data for CCDC86 reported","pmids":["26344197"],"is_preprint":false},{"year":2016,"finding":"CCDC86 was identified among Ki-67 interactors in proliferating cells, connecting it to the Ki-67 nuclear protein network involved in heterochromatin organisation.","method":"Ki-67 immunoaffinity purification followed by mass spectrometry identification of interacting proteins","journal":"eLife","confidence":"Low","confidence_rationale":"Tier 3 — single co-purification identification, no reciprocal validation or functional follow-up specific to CCDC86","pmids":["26949251"],"is_preprint":false},{"year":2020,"finding":"CCDC86 was identified as a host protein that physically associates with SARS-CoV-2 Nsp8 by affinity-purification mass spectrometry, placing it in the viral-host protein interaction network.","method":"AP-MS (affinity purification coupled to mass spectrometry) in HEK293T cells expressing tagged SARS-CoV-2 proteins","journal":"Nature","confidence":"Low","confidence_rationale":"Tier 3 — single AP-MS identification in a large-scale screen, no CCDC86-specific functional validation","pmids":["32353859"],"is_preprint":false},{"year":2021,"finding":"CCDC86 (CYCLON) physically interacts with NPM1 (nucleophosmin) and participates in a protein interaction network connecting it to the nucleolus, RNA processing, MYC signalling, and cell cycle progression in diffuse large B-cell lymphoma cells.","method":"Immunoprecipitation/co-IP, mass spectrometry-based interactome mapping, immunohistochemistry for subcellular localization (extra-nucleolar vs. nucleolar)","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 3 + multiple methods — co-IP/MS interactome plus IHC sub-localisation, single lab","pmids":["34885010"],"is_preprint":false},{"year":2023,"finding":"CCDC86 localises to the chromosome periphery during mitosis and physically interacts with Ki-67 (MKI67); RNAi-mediated depletion of CCDC86 causes disorganisation of the chromosome periphery with altered localisation of Ki-67 and nucleolin, formation of cytoplasmic aggregates, chromosome alignment errors, altered spindle length, and increased apoptosis, indicating that CCDC86 is part of subcomplexes with nucleolin and NPM1 (B23) required for mitotic spindle regulation and correct kinetochore-microtubule attachments.","method":"RNA interference (siRNA/shRNA), live-cell and fixed immunofluorescence microscopy, co-immunoprecipitation, biochemical fractionation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — RNAi loss-of-function with defined mitotic phenotypes, reciprocal Co-IP, direct localization with functional consequence, multiple orthogonal methods","pmids":["36695333"],"is_preprint":false},{"year":2023,"finding":"CCDC86 promotes proliferation, invasion, and migration of nasopharyngeal carcinoma cells by binding NPM1, which positively regulates EGFR transcription/expression; activated EGFR in turn activates downstream PI3K/Akt signalling to drive EMT and MMP upregulation. CCDC86 does not directly bind EGFR but acts through NPM1.","method":"siRNA knockdown and overexpression in NPC cell lines, in vivo xenograft assays, co-immunoprecipitation (CCDC86–NPM1 interaction), Western blotting for EGFR/PI3K/Akt pathway components, invasion/migration assays","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP for direct binding partner (NPM1), KD/OE with defined pathway readout, in vivo validation, single lab","pmids":["38247332"],"is_preprint":false},{"year":2025,"finding":"CCDC86 promotes glioma cell proliferation and migration and inhibits apoptosis by interacting with the transcription factor BHLHE40, stabilising ATF3 expression; CCDC86 then activates the ERK signalling pathway through ATF3 to enhance aerobic glycolysis and tumour progression.","method":"siRNA knockdown and overexpression in glioma cell lines and in vivo xenograft models, co-immunoprecipitation (CCDC86–BHLHE40), chromatin-immunoprecipitation/luciferase reporter for ATF3 transcription, ERK pathway Western blotting, glycolysis assays","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP for CCDC86–BHLHE40 interaction, reporter assay for downstream transcription, KD/OE with pathway readout, single lab","pmids":["40837407"],"is_preprint":false}],"current_model":"CCDC86 (Cyclon) is a cytokine-inducible nuclear protein that localises to the chromosome periphery during mitosis where it forms subcomplexes with Ki-67, nucleolin, and NPM1 to regulate mitotic spindle length and kinetochore-microtubule attachments; in interphase it binds mRNA and interacts with NPM1 to modulate downstream oncogenic signalling (EGFR/PI3K/Akt and ERK pathways via BHLHE40-ATF3), and in T cells it promotes Fas expression and activation-induced cell death downstream of TCR stimulation."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing CCDC86 as a cytokine-responsive nuclear protein answered the question of whether the gene encodes a regulated transcription unit and where the product resides, placing it as an immediate-early gene in hematopoietic signaling.","evidence":"Northern blot, nuclear fractionation, promoter-reporter assays in IL-3-stimulated hematopoietic cells","pmids":["17300783"],"confidence":"Medium","gaps":["No molecular function identified beyond nuclear localization","Protein binding partners unknown","Relevance beyond IL-3-responsive hematopoietic cells undefined"]},{"year":2009,"claim":"Demonstrating that CCDC86 drives Fas upregulation and activation-induced cell death in T cells answered how TCR-stimulated lymphocytes integrate cytokine-inducible gene products into apoptotic control, revealing a physiological function in immune homeostasis.","evidence":"Conditional Ccdc86 heterozygous knockout and transgenic overexpression in mice, flow cytometry for Fas, AICD assays, rescue of autoimmunity in IL-2R-deficient mice","pmids":["19528538"],"confidence":"High","gaps":["Mechanism by which CCDC86 upregulates Fas transcription not resolved","Whether CCDC86 directly binds the Fas promoter or acts through intermediaries unknown","Homozygous deletion phenotype not reported"]},{"year":2012,"claim":"Two independent mRNA interactome captures identified CCDC86 as a physical mRNA-binding protein, revealing an unexpected RNA-binding capacity for a coiled-coil protein and expanding its potential functional repertoire beyond transcriptional regulation.","evidence":"UV crosslinking/oligo(dT) capture (HeLa) and PAR-CLIP/oligo(dT) capture (HEK293) with quantitative mass spectrometry","pmids":["22658674","22681889"],"confidence":"Medium","gaps":["Identity of bound RNA targets unknown","RNA-binding domain not mapped","Functional consequence of mRNA binding not tested"]},{"year":2016,"claim":"Identification of CCDC86 as a Ki-67 interactor connected it to the perichromosomal layer and heterochromatin organization, raising the question of whether CCDC86 has a mitotic structural role.","evidence":"Ki-67 immunoaffinity purification with mass spectrometry in proliferating cells","pmids":["26949251"],"confidence":"Low","gaps":["Single co-purification without reciprocal validation for CCDC86","No functional consequence of the interaction tested","Whether CCDC86 is a stoichiometric or transient Ki-67 partner unclear"]},{"year":2021,"claim":"Demonstrating a physical CCDC86–NPM1 interaction in lymphoma cells placed CCDC86 in the nucleolar/RNA-processing network and linked it to MYC signaling and cell cycle control, bridging its nuclear localization with oncogenic pathways.","evidence":"Co-immunoprecipitation, mass spectrometry interactome, immunohistochemistry in DLBCL cells","pmids":["34885010"],"confidence":"Medium","gaps":["Direct versus indirect nature of the CCDC86–NPM1 interaction not resolved by structural data","Functional consequence of disrupting the interaction not shown","Whether NPM1 interaction is required for CCDC86 nucleolar retention unknown"]},{"year":2023,"claim":"RNAi depletion of CCDC86 established that it is required for chromosome periphery integrity, correct Ki-67 and nucleolin localization, spindle length control, and proper kinetochore–microtubule attachments, answering the key question of whether its mitotic localization is functionally meaningful.","evidence":"siRNA/shRNA knockdown, live-cell and fixed immunofluorescence, co-immunoprecipitation, biochemical fractionation in human cell lines","pmids":["36695333"],"confidence":"High","gaps":["Whether CCDC86 contributes structural scaffolding or recruits other factors to the periphery is not distinguished","No rescue experiment reported to confirm specificity","Relationship between mRNA-binding activity and mitotic function unexplored"]},{"year":2023,"claim":"Showing that CCDC86 acts through NPM1 to upregulate EGFR and activate PI3K/Akt signaling in nasopharyngeal carcinoma resolved how CCDC86 promotes tumor cell invasion and connected its NPM1 interaction to a defined oncogenic pathway.","evidence":"Knockdown/overexpression in NPC cell lines, co-IP for CCDC86–NPM1, xenograft models, Western blotting for EGFR/PI3K/Akt","pmids":["38247332"],"confidence":"Medium","gaps":["Mechanism by which NPM1 regulates EGFR transcription not delineated","Whether CCDC86 stabilizes NPM1 protein or modulates its transcriptional activity not resolved","Relevance to non-cancer contexts not tested"]},{"year":2025,"claim":"Identification of BHLHE40 as a direct CCDC86 interactor and ATF3 as a downstream transcriptional target driving ERK-dependent glycolysis in glioma provided a second interphase signaling axis, revealing that CCDC86 engages distinct transcription factor complexes to activate oncogenic programs.","evidence":"Co-IP for CCDC86–BHLHE40, ChIP and luciferase reporter for ATF3 transcription, knockdown/overexpression in glioma lines and xenografts, glycolysis assays","pmids":["40837407"],"confidence":"Medium","gaps":["Whether CCDC86 acts as a co-activator or a scaffold for BHLHE40 is unknown","Overlap between NPM1- and BHLHE40-dependent CCDC86 functions not investigated","Single-lab study; independent replication pending"]},{"year":null,"claim":"It remains unknown how CCDC86's mRNA-binding activity relates to its mitotic and interphase functions, whether it possesses intrinsic enzymatic activity, and what structural features mediate its incorporation into the chromosome periphery versus its engagement with NPM1 and BHLHE40 in transcriptional signaling.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model or domain-resolution interaction mapping available","mRNA targets and functional consequence of RNA binding uncharacterized","Relationship between T-cell AICD function and mitotic/oncogenic roles unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[8]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]}],"complexes":[],"partners":["NPM1","MKI67","NCL","BHLHE40"],"other_free_text":[]},"mechanistic_narrative":"CCDC86 (Cyclon) is a cytokine-inducible, coiled-coil domain-containing nuclear protein that functions at the interface of ribosome biogenesis, chromosome periphery organization, and mitotic fidelity. During mitosis, CCDC86 localizes to the chromosome periphery where it forms subcomplexes with Ki-67, nucleolin, and NPM1 to regulate spindle length and kinetochore–microtubule attachments; its depletion causes chromosome alignment errors, cytoplasmic aggregation of perichromosomal components, and increased apoptosis [PMID:36695333]. In interphase, CCDC86 physically binds mRNA [PMID:22658674, PMID:22681889] and interacts with NPM1 to promote EGFR transcription and PI3K/Akt signaling in cancer cells, and with BHLHE40 to stabilize ATF3 expression and activate ERK-driven glycolysis in glioma [PMID:38247332, PMID:40837407]. In T cells, CCDC86 is induced by TCR ligation and promotes activation-induced cell death by upregulating Fas (CD95) expression, as demonstrated by conditional knockout and transgenic rescue of autoimmune pathology in IL-2R-deficient mice [PMID:19528538]."},"prefetch_data":{"uniprot":{"accession":"Q9H6F5","full_name":"Coiled-coil domain-containing protein 86","aliases":["Cytokine-induced protein with coiled-coil domain"],"length_aa":360,"mass_kda":40.2,"function":"Required for proper chromosome segregation during mitosis and error-free mitotic progression","subcellular_location":"Nucleus; Chromosome; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9H6F5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC86","classification":"Common Essential","n_dependent_lines":1094,"n_total_lines":1208,"dependency_fraction":0.9056291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000110104","cell_line_id":"CID001930","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGB2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"TPT1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001930","total_profiled":1310},"omim":[{"mim_id":"611293","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 86; CCDC86","url":"https://www.omim.org/entry/611293"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Nucleoli rim","reliability":"Enhanced"},{"location":"Mitotic chromosome","reliability":"Enhanced"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"parathyroid gland","ntpm":355.2}],"url":"https://www.proteinatlas.org/search/CCDC86"},"hgnc":{"alias_symbol":["MGC2574","cyclon","Cgr1"],"prev_symbol":[]},"alphafold":{"accession":"Q9H6F5","domains":[{"cath_id":"1.20.5","chopping":"269-316","consensus_level":"medium","plddt":94.0481,"start":269,"end":316}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6F5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6F5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6F5-F1-predicted_aligned_error_v6.png","plddt_mean":61.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC86","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC86"},"sequence":{"accession":"Q9H6F5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H6F5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H6F5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6F5"}},"corpus_meta":[{"pmid":"12672226","id":"PMC_12672226","title":"A novel N-terminal cyclic dynorphin A analogue cyclo(N,5)[Trp(3),Trp(4),Glu(5)] dynorphin A-(1-11)NH(2) that lacks the basic N-terminus.","date":"2003","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12672226","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17300783","id":"PMC_17300783","title":"Redundant promoter elements mediate IL-3-induced expression of a novel cytokine-inducible gene, cyclon.","date":"2007","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/17300783","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19528538","id":"PMC_19528538","title":"Regulation of Fas-mediated immune homeostasis by an activation-induced protein, Cyclon.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19528538","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31231525","id":"PMC_31231525","title":"Cgr1, a ripe rot resistance QTL in Vitis amurensis 'Shuang Hong' grapevine.","date":"2019","source":"Horticulture research","url":"https://pubmed.ncbi.nlm.nih.gov/31231525","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36695333","id":"PMC_36695333","title":"CCDC86 is a novel Ki-67-interacting protein important for cell division.","date":"2023","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/36695333","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11342110","id":"PMC_11342110","title":"Isolation and expression of a gene (CGR1) regulated during the yeast-hyphal transition in Candida albicans.","date":"2001","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11342110","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38247332","id":"PMC_38247332","title":"CCDC86 promotes the aggressive behavior of nasopharyngeal carcinoma by positively regulating EGFR and activating the PI3K/Akt signaling.","date":"2023","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/38247332","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23528659","id":"PMC_23528659","title":"Expression of Cyclon/CCDC86, a novel nuclear protein, in the hippocampus of adult non-human primates.","date":"2013","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/23528659","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23439384","id":"PMC_23439384","title":"Expression and differential response to haloperidol treatment of Cyclon/CCDC86 mRNA in schizophrenia patients.","date":"2013","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/23439384","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26521698","id":"PMC_26521698","title":"Complete genome sequence of Microbacterium sp. 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     \"finding\": \"Cyclon/CCDC86 is required for Fas expression in activated CD4+ T cells and promotes activation-induced cell death (AICD); transgenic overexpression enhanced AICD through increased Fas, while targeted deletion of one Cyclon allele reduced AICD and Fas expression in activated but not resting T cells.\",\n      \"method\": \"Transgenic overexpression, conditional allele knockout, AICD assay, flow cytometry for Fas expression\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain- and loss-of-function in primary T cells with defined molecular readout (Fas expression), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19528538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCDC86 (CYCLON) interacts with NPM1 (nucleophosmin) and its protein interaction network connects it to the nucleolus, RNA processing, MYC signaling, and cell cycle progression; alternative sub-cellular localizations (extra-nucleolar CYCLON and pan-cellular NPM1) are functionally relevant in DLBCL.\",\n      \"method\": \"Protein interaction network characterization (proteomics/co-immunoprecipitation), immunohistochemistry for sub-cellular localization\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — interactome characterization with localization data, single lab\",\n      \"pmids\": [\"34885010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC86 is a chromosome periphery-associated protein that interacts with Ki-67 (MKI67); its depletion by RNAi causes partial disorganisation of the chromosome periphery, altered localization of Ki-67 and nucleolin (NCL), formation of abnormal cytoplasmic aggregates, errors in chromosome alignment, altered spindle length, and increased apoptosis, implicating CCDC86—together with nucleolin and B23/NPM1—in mitotic spindle regulation and correct kinetochore-microtubule attachments.\",\n      \"method\": \"RNA interference (RNAi) depletion, fluorescence microscopy, biochemical fractionation, Co-immunoprecipitation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi knockdown with multiple orthogonal readouts (localization, spindle length, chromosome alignment, apoptosis) plus biochemical interaction data, moderate evidence\",\n      \"pmids\": [\"36695333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC86 does not directly bind EGFR but positively regulates EGFR expression by binding to NPM1, thereby activating the PI3K/Akt signaling pathway to promote proliferation, invasion, and migration of nasopharyngeal carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (binding to NPM1), in vitro and in vivo functional assays (siRNA knockdown, xenograft), western blot for EGFR/PI3K/Akt\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — co-IP for NPM1 interaction combined with in vivo rescue experiments; single lab\",\n      \"pmids\": [\"38247332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC86 promotes transcriptional upregulation of ATF3 by interacting with and stabilizing BHLHE40, thereby activating ERK signaling and aerobic glycolysis to drive glioma tumor progression.\",\n      \"method\": \"Co-immunoprecipitation (CCDC86–BHLHE40 interaction), siRNA knockdown, overexpression rescue, in vitro proliferation/migration assays, in vivo tumorigenesis assay, glycolysis measurement\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — co-IP for interaction plus loss- and gain-of-function with multiple readouts; single lab\",\n      \"pmids\": [\"40837407\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC86 (Cyclon) is a cytokine-inducible nuclear/chromosome periphery protein that, in interphase, interacts with NPM1 to regulate Fas expression in activated T cells and EGFR/PI3K–Akt signaling in cancer cells, and in mitosis localizes to the chromosome periphery where it forms sub-complexes with Ki-67, nucleolin, and NPM1/B23 to regulate mitotic spindle length, kinetochore-microtubule attachments, and chromosome segregation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper before extracting discoveries.\n\n**Classification:**\n\nRetrieved papers:\n1. Dynorphin analogue — EXCLUDE (alias collision, opioid peptide)\n2. cyclon/CCDC86 IL-3 induction — KEEP (describes CCDC86/Cyclon)\n3. Cyclon/CCDC86 Fas/AICD — KEEP\n4. Cgr1 grapevine QTL — EXCLUDE (symbol collision, plant)\n5. CCDC86 Ki-67 mitosis — KEEP\n6. CGR1 Candida albicans — EXCLUDE (symbol collision, fungus)\n7. CCDC86 NPC/EGFR/PI3K — KEEP\n8. Cyclon/CCDC86 hippocampus — KEEP\n9. Cyclon/CCDC86 schizophrenia — EXCLUDE (expression/biomarker only)\n10. Microbacterium CGR1 — EXCLUDE (symbol collision, bacterium)\n11. CYCLON/NPM1 DLBCL — KEEP\n12. CGR1 C. elegans CRAL/TRIO — EXCLUDE (symbol collision, different protein family)\n13. cgrA Aspergillus — EXCLUDE (symbol collision, fungus)\n14. CCDC86-BHLHE40-ATF3 glioma — KEEP\n15. TN-cyclon™ assay — EXCLUDE (alias collision, detection method)\n16. CCDC86 HNSCC immune — EXCLUDE (expression/biomarker/bioinformatics only)\n17. CCDC86 HNSCC scRNA — EXCLUDE (mostly bioinformatics, minimal mechanistic)\n\nGene2pubmed papers:\n1. SARS-CoV-2 interactome (Gordon 2020) — KEEP (CCDC86 appears as host interactor)\n2. mRNA-binding proteins (Castello 2012) — KEEP (CCDC86 identified as RBP)\n3. Human PPI network (Stelzl 2005) — KEEP (Y2H interactions)\n4. MGC cDNA — EXCLUDE (no mechanistic data)\n5. piRNA/MIWI — EXCLUDE (not about CCDC86)\n6. HeLa phosphoproteomics (Beausoleil 2004) — KEEP (phosphorylation site identified)\n7. BioPlex (Huttlin 2015) — KEEP (interaction data)\n8. BioPlex 2.0 (Huttlin 2017) — KEEP (interaction data)\n9. Human interactome quantitative (Hein 2015) — KEEP (interaction/localization)\n10. mRNA-bound proteome (Baltz 2012) — KEEP (RBP identification)\n11. BioPlex 3.0 (Huttlin 2021) — KEEP (interaction data)\n12. GO propagation — EXCLUDE (computational only)\n13. Comparative coronavirus (Gordon 2020 Science) — KEEP\n14. OpenCell (Cho 2022) — KEEP (localization data)\n15. Alternative promoters (Kimura 2005) — EXCLUDE (no mechanistic data for CCDC86)\n16. Metazoan complexes (Wan 2015) — KEEP\n17. BioID human cell (Go 2021) — KEEP\n18. SARS-CoV-2 virulence (Li 2020) — KEEP\n19. Ki-67 heterochromatin (Sobecki 2016) — KEEP (Ki-67 interactors)\n20. BioID chromatin (Lambert 2014) — EXCLUDE (no specific CCDC86 data)\n21. MAC-tag (Liu 2018) — EXCLUDE (no specific CCDC86 data)\n22. RhoGEF/RhoGAP (Müller 2020) — EXCLUDE (no specific CCDC86 data)\n23. CMGC kinase interactome (Varjosalo 2013) — EXCLUDE (no specific CCDC86 data)\n24. Herpesvirus-host (Davis 2014) — EXCLUDE (no specific CCDC86 data)\n25. UFMylation p53 — EXCLUDE (no specific CCDC86 data)\n26. HumanCVD lipids GWAS — EXCLUDE (no mechanistic CCDC86 data)\n27. H4K20me0/BRCA1 — EXCLUDE (no specific CCDC86 data)\n28. SIRT7 functional proteomics — EXCLUDE (no specific CCDC86 data)\n29. BET bromodomain interactome — EXCLUDE (no specific CCDC86 data)\n30. GPA GWAS — EXCLUDE (no specific CCDC86 data)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"CCDC86 (Cyclon) is a cytokine-inducible immediate-early gene encoding a nuclear protein with repetitive sequences at the amino-terminus and a coiled-coil domain at the carboxyl-terminus; it is induced in hematopoietic cells by IL-3, and its promoter contains redundant elements sufficient for IL-3-driven transcriptional activation.\",\n      \"method\": \"Northern blot/RT-PCR identification of induced gene, subcellular fractionation and immunostaining showing nuclear localization, transient reporter assay mapping promoter elements\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct localization experiment with nuclear fractionation, reporter assay, single lab\",\n      \"pmids\": [\"17300783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CCDC86 (Cyclon) is induced in T cells upon TCR ligation and promotes activation-induced cell death (AICD) by upregulating Fas (CD95) expression; conditional deletion of one Cyclon allele in activated CD4+ T cells reduced Fas expression and AICD, while transgenic Cyclon expression enhanced AICD and ameliorated autoimmune phenotype in IL-2R-deficient mice.\",\n      \"method\": \"Conditional knockout mice, transgenic overexpression, flow cytometry for Fas surface expression, AICD assay, autoimmune phenotype rescue in vivo\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic loss-of-function and gain-of-function with defined molecular readout (Fas expression), replicated in vivo\",\n      \"pmids\": [\"19528538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CCDC86 was identified as an mRNA-binding protein in human HeLa cells by UV crosslinking and oligo(dT) purification (interactome capture), indicating it physically associates with mRNA.\",\n      \"method\": \"UV crosslinking followed by oligo(dT) purification and quantitative mass spectrometry (interactome capture)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical crosslinking-based capture, large-scale but single method, no functional follow-up for CCDC86 specifically\",\n      \"pmids\": [\"22658674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CCDC86 was independently identified as an mRNA-associated protein in human HEK293 cells using photoactivatable-ribonucleoside-enhanced crosslinking and oligo(dT) purification (PAR-CLIP-based mRNA interactome).\",\n      \"method\": \"PAR-CLIP (photoreactive nucleotide-enhanced UV crosslinking) and oligo(dT) purification coupled to quantitative proteomics\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal crosslinking-based biochemical method confirming mRNA-binding, single method for CCDC86 specifically\",\n      \"pmids\": [\"22681889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCDC86 (Cyclon) protein is expressed in neurons and astrocytes of the adult macaque hippocampus (including CA fields and dentate gyrus), extending its known expression beyond lymphocytes to the central nervous system.\",\n      \"method\": \"Immunohistochemistry and confocal microscopy on adult non-human primate brain sections with cell-type co-labeling\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization by IHC without functional consequence demonstrated\",\n      \"pmids\": [\"23528659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCDC86 was identified as part of conserved metazoan macromolecular complexes by biochemical co-fractionation across multiple species, placing it within ancient protein assemblies.\",\n      \"method\": \"Biochemical fractionation coupled with quantitative mass spectrometry across metazoan species\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — co-fractionation evidence; no specific functional data for CCDC86 reported\",\n      \"pmids\": [\"26344197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCDC86 was identified among Ki-67 interactors in proliferating cells, connecting it to the Ki-67 nuclear protein network involved in heterochromatin organisation.\",\n      \"method\": \"Ki-67 immunoaffinity purification followed by mass spectrometry identification of interacting proteins\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single co-purification identification, no reciprocal validation or functional follow-up specific to CCDC86\",\n      \"pmids\": [\"26949251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCDC86 was identified as a host protein that physically associates with SARS-CoV-2 Nsp8 by affinity-purification mass spectrometry, placing it in the viral-host protein interaction network.\",\n      \"method\": \"AP-MS (affinity purification coupled to mass spectrometry) in HEK293T cells expressing tagged SARS-CoV-2 proteins\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single AP-MS identification in a large-scale screen, no CCDC86-specific functional validation\",\n      \"pmids\": [\"32353859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCDC86 (CYCLON) physically interacts with NPM1 (nucleophosmin) and participates in a protein interaction network connecting it to the nucleolus, RNA processing, MYC signalling, and cell cycle progression in diffuse large B-cell lymphoma cells.\",\n      \"method\": \"Immunoprecipitation/co-IP, mass spectrometry-based interactome mapping, immunohistochemistry for subcellular localization (extra-nucleolar vs. nucleolar)\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 + multiple methods — co-IP/MS interactome plus IHC sub-localisation, single lab\",\n      \"pmids\": [\"34885010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC86 localises to the chromosome periphery during mitosis and physically interacts with Ki-67 (MKI67); RNAi-mediated depletion of CCDC86 causes disorganisation of the chromosome periphery with altered localisation of Ki-67 and nucleolin, formation of cytoplasmic aggregates, chromosome alignment errors, altered spindle length, and increased apoptosis, indicating that CCDC86 is part of subcomplexes with nucleolin and NPM1 (B23) required for mitotic spindle regulation and correct kinetochore-microtubule attachments.\",\n      \"method\": \"RNA interference (siRNA/shRNA), live-cell and fixed immunofluorescence microscopy, co-immunoprecipitation, biochemical fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi loss-of-function with defined mitotic phenotypes, reciprocal Co-IP, direct localization with functional consequence, multiple orthogonal methods\",\n      \"pmids\": [\"36695333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC86 promotes proliferation, invasion, and migration of nasopharyngeal carcinoma cells by binding NPM1, which positively regulates EGFR transcription/expression; activated EGFR in turn activates downstream PI3K/Akt signalling to drive EMT and MMP upregulation. CCDC86 does not directly bind EGFR but acts through NPM1.\",\n      \"method\": \"siRNA knockdown and overexpression in NPC cell lines, in vivo xenograft assays, co-immunoprecipitation (CCDC86–NPM1 interaction), Western blotting for EGFR/PI3K/Akt pathway components, invasion/migration assays\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP for direct binding partner (NPM1), KD/OE with defined pathway readout, in vivo validation, single lab\",\n      \"pmids\": [\"38247332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC86 promotes glioma cell proliferation and migration and inhibits apoptosis by interacting with the transcription factor BHLHE40, stabilising ATF3 expression; CCDC86 then activates the ERK signalling pathway through ATF3 to enhance aerobic glycolysis and tumour progression.\",\n      \"method\": \"siRNA knockdown and overexpression in glioma cell lines and in vivo xenograft models, co-immunoprecipitation (CCDC86–BHLHE40), chromatin-immunoprecipitation/luciferase reporter for ATF3 transcription, ERK pathway Western blotting, glycolysis assays\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP for CCDC86–BHLHE40 interaction, reporter assay for downstream transcription, KD/OE with pathway readout, single lab\",\n      \"pmids\": [\"40837407\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC86 (Cyclon) is a cytokine-inducible nuclear protein that localises to the chromosome periphery during mitosis where it forms subcomplexes with Ki-67, nucleolin, and NPM1 to regulate mitotic spindle length and kinetochore-microtubule attachments; in interphase it binds mRNA and interacts with NPM1 to modulate downstream oncogenic signalling (EGFR/PI3K/Akt and ERK pathways via BHLHE40-ATF3), and in T cells it promotes Fas expression and activation-induced cell death downstream of TCR stimulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCDC86 (Cyclon) is a cytokine-inducible, coiled-coil domain–containing nuclear protein that functions both in interphase gene regulation and in mitotic chromosome organization. In interphase, CCDC86 interacts with NPM1/nucleophosmin to regulate Fas expression in activated CD4+ T cells—thereby promoting activation-induced cell death—and to upregulate EGFR expression and PI3K/Akt signaling in nasopharyngeal carcinoma cells [PMID:19528538, PMID:38247332]. During mitosis, CCDC86 localizes to the chromosome periphery where it forms sub-complexes with Ki-67, nucleolin, and NPM1; its depletion causes altered spindle length, chromosome alignment errors, kinetochore-microtubule attachment defects, and increased apoptosis [PMID:36695333]. CCDC86 also interacts with and stabilizes BHLHE40 to transcriptionally upregulate ATF3, activating ERK signaling and aerobic glycolysis in glioma [PMID:40837407].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying CCDC86 as a cytokine-inducible nuclear gene established it as a previously uncharacterized coiled-coil protein whose expression is transcriptionally controlled by IL-3 in hematopoietic cells, raising the question of its functional role.\",\n      \"evidence\": \"Promoter-reporter assays and expression analysis in hematopoietic cell lines\",\n      \"pmids\": [\"17300783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Promoter regulation characterized only in mouse hematopoietic cells\",\n        \"No protein-level function or interaction partners identified\",\n        \"Coiled-coil domain function uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Reciprocal gain- and loss-of-function experiments revealed that CCDC86 is required for Fas expression and activation-induced cell death in CD4+ T cells, establishing its first defined biological function.\",\n      \"evidence\": \"Transgenic overexpression and conditional allele knockout in primary T cells with AICD assays and Fas flow cytometry\",\n      \"pmids\": [\"19528538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which CCDC86 regulates Fas transcription unknown\",\n        \"Whether CCDC86 acts through a binding partner to control Fas not addressed\",\n        \"Role beyond T cell AICD not explored\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of NPM1 as a direct interaction partner of CCDC86 connected it to the nucleolar proteome, RNA processing, MYC signaling, and cell cycle networks, providing a molecular framework for its diverse functions.\",\n      \"evidence\": \"Proteomic interaction network characterization with co-immunoprecipitation and immunohistochemistry in DLBCL samples\",\n      \"pmids\": [\"34885010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the CCDC86–NPM1 interaction not directly tested\",\n        \"Relevance of extra-nucleolar CCDC86 localization mechanistically unexplored\",\n        \"Single-lab interactome without independent validation\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that CCDC86 is a chromosome periphery protein that interacts with Ki-67 and is required for proper spindle length, chromosome alignment, and kinetochore-microtubule attachments revealed its essential mitotic function, distinct from its interphase roles.\",\n      \"evidence\": \"RNAi depletion with fluorescence microscopy, biochemical fractionation, and co-immunoprecipitation\",\n      \"pmids\": [\"36695333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct versus indirect nature of CCDC86–Ki-67 interaction not resolved\",\n        \"Structural basis of chromosome periphery recruitment unknown\",\n        \"Whether CCDC86 mitotic function depends on its NPM1 interaction not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that CCDC86 positively regulates EGFR expression through NPM1 binding and consequent PI3K/Akt activation extended its interphase function to oncogenic signaling in nasopharyngeal carcinoma, demonstrating the CCDC86–NPM1 axis operates beyond the immune system.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, xenograft models, and western blot in nasopharyngeal carcinoma cells\",\n      \"pmids\": [\"38247332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which CCDC86–NPM1 complex upregulates EGFR transcription not defined\",\n        \"Single-lab study without independent replication\",\n        \"Whether NPM1 interaction is required or merely correlative for EGFR regulation not resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that CCDC86 stabilizes BHLHE40 to transcriptionally activate ATF3 and drive ERK signaling and aerobic glycolysis identified a second interphase binding partner and a distinct oncogenic mechanism in glioma.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA/overexpression rescue, in vivo tumorigenesis, and glycolysis measurements in glioma models\",\n      \"pmids\": [\"40837407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding not independently confirmed\",\n        \"Whether BHLHE40 stabilization is direct (e.g., preventing ubiquitination) or indirect not determined\",\n        \"Relationship between CCDC86–BHLHE40 and CCDC86–NPM1 axes unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis by which CCDC86 is recruited to the chromosome periphery, whether its coiled-coil domain mediates partner selectivity (NPM1 vs. Ki-67 vs. BHLHE40), and how its interphase transcriptional roles relate to its mitotic function remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or domain-mapping data for any CCDC86 interaction\",\n        \"No reconstitution of CCDC86 complexes with purified components\",\n        \"Mechanism connecting CCDC86 to Fas transcription still unknown after 15 years\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NPM1\",\n      \"MKI67\",\n      \"NCL\",\n      \"BHLHE40\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"CCDC86 (Cyclon) is a cytokine-inducible, coiled-coil domain-containing nuclear protein that functions at the interface of ribosome biogenesis, chromosome periphery organization, and mitotic fidelity. During mitosis, CCDC86 localizes to the chromosome periphery where it forms subcomplexes with Ki-67, nucleolin, and NPM1 to regulate spindle length and kinetochore–microtubule attachments; its depletion causes chromosome alignment errors, cytoplasmic aggregation of perichromosomal components, and increased apoptosis [PMID:36695333]. In interphase, CCDC86 physically binds mRNA [PMID:22658674, PMID:22681889] and interacts with NPM1 to promote EGFR transcription and PI3K/Akt signaling in cancer cells, and with BHLHE40 to stabilize ATF3 expression and activate ERK-driven glycolysis in glioma [PMID:38247332, PMID:40837407]. In T cells, CCDC86 is induced by TCR ligation and promotes activation-induced cell death by upregulating Fas (CD95) expression, as demonstrated by conditional knockout and transgenic rescue of autoimmune pathology in IL-2R-deficient mice [PMID:19528538].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing CCDC86 as a cytokine-responsive nuclear protein answered the question of whether the gene encodes a regulated transcription unit and where the product resides, placing it as an immediate-early gene in hematopoietic signaling.\",\n      \"evidence\": \"Northern blot, nuclear fractionation, promoter-reporter assays in IL-3-stimulated hematopoietic cells\",\n      \"pmids\": [\"17300783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No molecular function identified beyond nuclear localization\",\n        \"Protein binding partners unknown\",\n        \"Relevance beyond IL-3-responsive hematopoietic cells undefined\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that CCDC86 drives Fas upregulation and activation-induced cell death in T cells answered how TCR-stimulated lymphocytes integrate cytokine-inducible gene products into apoptotic control, revealing a physiological function in immune homeostasis.\",\n      \"evidence\": \"Conditional Ccdc86 heterozygous knockout and transgenic overexpression in mice, flow cytometry for Fas, AICD assays, rescue of autoimmunity in IL-2R-deficient mice\",\n      \"pmids\": [\"19528538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which CCDC86 upregulates Fas transcription not resolved\",\n        \"Whether CCDC86 directly binds the Fas promoter or acts through intermediaries unknown\",\n        \"Homozygous deletion phenotype not reported\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two independent mRNA interactome captures identified CCDC86 as a physical mRNA-binding protein, revealing an unexpected RNA-binding capacity for a coiled-coil protein and expanding its potential functional repertoire beyond transcriptional regulation.\",\n      \"evidence\": \"UV crosslinking/oligo(dT) capture (HeLa) and PAR-CLIP/oligo(dT) capture (HEK293) with quantitative mass spectrometry\",\n      \"pmids\": [\"22658674\", \"22681889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of bound RNA targets unknown\",\n        \"RNA-binding domain not mapped\",\n        \"Functional consequence of mRNA binding not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of CCDC86 as a Ki-67 interactor connected it to the perichromosomal layer and heterochromatin organization, raising the question of whether CCDC86 has a mitotic structural role.\",\n      \"evidence\": \"Ki-67 immunoaffinity purification with mass spectrometry in proliferating cells\",\n      \"pmids\": [\"26949251\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single co-purification without reciprocal validation for CCDC86\",\n        \"No functional consequence of the interaction tested\",\n        \"Whether CCDC86 is a stoichiometric or transient Ki-67 partner unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating a physical CCDC86–NPM1 interaction in lymphoma cells placed CCDC86 in the nucleolar/RNA-processing network and linked it to MYC signaling and cell cycle control, bridging its nuclear localization with oncogenic pathways.\",\n      \"evidence\": \"Co-immunoprecipitation, mass spectrometry interactome, immunohistochemistry in DLBCL cells\",\n      \"pmids\": [\"34885010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct versus indirect nature of the CCDC86–NPM1 interaction not resolved by structural data\",\n        \"Functional consequence of disrupting the interaction not shown\",\n        \"Whether NPM1 interaction is required for CCDC86 nucleolar retention unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"RNAi depletion of CCDC86 established that it is required for chromosome periphery integrity, correct Ki-67 and nucleolin localization, spindle length control, and proper kinetochore–microtubule attachments, answering the key question of whether its mitotic localization is functionally meaningful.\",\n      \"evidence\": \"siRNA/shRNA knockdown, live-cell and fixed immunofluorescence, co-immunoprecipitation, biochemical fractionation in human cell lines\",\n      \"pmids\": [\"36695333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CCDC86 contributes structural scaffolding or recruits other factors to the periphery is not distinguished\",\n        \"No rescue experiment reported to confirm specificity\",\n        \"Relationship between mRNA-binding activity and mitotic function unexplored\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that CCDC86 acts through NPM1 to upregulate EGFR and activate PI3K/Akt signaling in nasopharyngeal carcinoma resolved how CCDC86 promotes tumor cell invasion and connected its NPM1 interaction to a defined oncogenic pathway.\",\n      \"evidence\": \"Knockdown/overexpression in NPC cell lines, co-IP for CCDC86–NPM1, xenograft models, Western blotting for EGFR/PI3K/Akt\",\n      \"pmids\": [\"38247332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which NPM1 regulates EGFR transcription not delineated\",\n        \"Whether CCDC86 stabilizes NPM1 protein or modulates its transcriptional activity not resolved\",\n        \"Relevance to non-cancer contexts not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of BHLHE40 as a direct CCDC86 interactor and ATF3 as a downstream transcriptional target driving ERK-dependent glycolysis in glioma provided a second interphase signaling axis, revealing that CCDC86 engages distinct transcription factor complexes to activate oncogenic programs.\",\n      \"evidence\": \"Co-IP for CCDC86–BHLHE40, ChIP and luciferase reporter for ATF3 transcription, knockdown/overexpression in glioma lines and xenografts, glycolysis assays\",\n      \"pmids\": [\"40837407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CCDC86 acts as a co-activator or a scaffold for BHLHE40 is unknown\",\n        \"Overlap between NPM1- and BHLHE40-dependent CCDC86 functions not investigated\",\n        \"Single-lab study; independent replication pending\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how CCDC86's mRNA-binding activity relates to its mitotic and interphase functions, whether it possesses intrinsic enzymatic activity, and what structural features mediate its incorporation into the chromosome periphery versus its engagement with NPM1 and BHLHE40 in transcriptional signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model or domain-resolution interaction mapping available\",\n        \"mRNA targets and functional consequence of RNA binding uncharacterized\",\n        \"Relationship between T-cell AICD function and mitotic/oncogenic roles unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NPM1\",\n      \"MKI67\",\n      \"NCL\",\n      \"BHLHE40\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}