{"gene":"ZCCHC7","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2011,"finding":"ZCCHC7 (hZCCHC7), the human orthologue of yeast Air1, localizes to the nucleolus in human cells and interacts with both mammalian Trf4 orthologues, PAPD5 and PAPD7, indicating it functions as the Air component of a human TRAMP complex involved in nuclear RNA quality control.","method":"Subcellular localization by immunofluorescence; protein interaction by co-immunoprecipitation; sequence analysis identifying conserved IWRXY motif","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, localization and co-IP reported together, two orthogonal methods but no functional reconstitution or mutagenesis of the human protein","pmids":["21878619"],"is_preprint":false},{"year":2011,"finding":"In the yeast Air1/Air2 orthologues, zinc knuckles 4 and 5 are critical for interaction with Trf4 and for TRAMP complex integrity; a conserved IWRXY motif in the ZnK4-5 linker mediates the Trf4 interaction. This IWRXY motif is also present in human ZCCHC7, linking the same structural element to its interaction with mammalian PAPD5/PAPD7.","method":"Random mutagenesis of AIR1/2 genes; in vivo ZnK mutagenesis; functional complementation assays; CUT stabilization assays; TRAMP complex integrity analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genetic and biochemical methods in a single lab; human ZCCHC7 inference is by sequence conservation and co-IP, not direct mutagenesis of the human protein","pmids":["21878619"],"is_preprint":false}],"current_model":"ZCCHC7 is a nucleolar CCHC zinc-knuckle protein that serves as the human Air1 component of a TRAMP-like complex, interacting with the poly(A) polymerase orthologues PAPD5 and PAPD7 (via a conserved IWRXY motif) to couple RNA polyadenylation with nuclear exosome-mediated RNA quality control."},"narrative":{"mechanistic_narrative":"ZCCHC7 is the human orthologue of yeast Air1 and functions as the Air component of a human TRAMP-like complex that couples RNA polyadenylation to nuclear RNA quality control [PMID:21878619]. It localizes to the nucleolus and interacts with the two mammalian Trf4 orthologues, the non-canonical poly(A) polymerases PAPD5 and PAPD7 [PMID:21878619]. This interaction is mediated by a conserved IWRXY motif located in the linker between zinc knuckles 4 and 5, a structural element shown in the yeast Air1/Air2 orthologues to be critical for Trf4 binding and TRAMP complex integrity and conserved in human ZCCHC7 [PMID:21878619]. Beyond its identification as the Air subunit of a human TRAMP complex and the mapping of the IWRXY interaction motif by orthology, no further mechanistic detail — including direct mutagenesis of the human protein or functional reconstitution — has been characterized in the available corpus.","teleology":[{"year":2011,"claim":"Whether humans possess an Air-type adaptor to organize a TRAMP-like RNA surveillance complex was unresolved; identifying ZCCHC7 as nucleolar and as a PAPD5/PAPD7 partner established it as the human Air component coupling polyadenylation to nuclear RNA quality control.","evidence":"Immunofluorescence localization and co-immunoprecipitation with PAPD5/PAPD7 in human cells, with sequence analysis identifying a conserved IWRXY motif","pmids":["21878619"],"confidence":"Medium","gaps":["No mutagenesis of human ZCCHC7 to confirm the IWRXY motif mediates PAPD5/PAPD7 binding directly","No functional reconstitution of a human TRAMP complex or demonstration of RNA quality control activity","RNA substrates targeted by the human complex not identified"]},{"year":2011,"claim":"How the Air adaptor docks onto the poly(A) polymerase was unknown; genetic and biochemical dissection in yeast showed zinc knuckles 4-5 and a conserved IWRXY linker motif mediate the Trf4 interaction and TRAMP integrity, and the conservation of this motif in ZCCHC7 implicates the same element in its PAPD5/PAPD7 binding.","evidence":"Random and targeted zinc-knuckle mutagenesis, functional complementation, CUT stabilization, and TRAMP integrity assays in yeast Air1/Air2; sequence conservation in human ZCCHC7","pmids":["21878619"],"confidence":"Medium","gaps":["Human ZCCHC7 IWRXY requirement inferred from yeast and sequence conservation, not directly tested","Structural basis of the ZCCHC7-PAPD5/PAPD7 interface not determined","Contribution of individual zinc knuckles to human complex assembly unmapped"]},{"year":null,"claim":"The RNA substrate spectrum, catalytic contribution within the human complex, and the link to nuclear exosome-mediated degradation remain to be established experimentally for human ZCCHC7.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified RNA substrates of the human TRAMP-like complex","No direct demonstration of coupling to the nuclear exosome in human cells","No structural or reconstitution data for the human complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]}],"complexes":["TRAMP complex"],"partners":["PAPD5","PAPD7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N3Z6","full_name":"Zinc finger CCHC domain-containing protein 7","aliases":["TRAMP-like complex RNA-binding factor ZCCHC7"],"length_aa":543,"mass_kda":63.1,"function":"","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q8N3Z6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZCCHC7","classification":"Not Classified","n_dependent_lines":34,"n_total_lines":1208,"dependency_fraction":0.028145695364238412},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000147905","cell_line_id":"CID001494","localizations":[{"compartment":"nucleolus_gc","grade":3}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001494","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZCCHC7"},"hgnc":{"alias_symbol":["FLJ22611","AIR1"],"prev_symbol":[]},"alphafold":{"accession":"Q8N3Z6","domains":[{"cath_id":"-","chopping":"231-262","consensus_level":"medium","plddt":70.735,"start":231,"end":262},{"cath_id":"-","chopping":"316-366_373-405","consensus_level":"medium","plddt":79.0927,"start":316,"end":405}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N3Z6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N3Z6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N3Z6-F1-predicted_aligned_error_v6.png","plddt_mean":53.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZCCHC7","jax_strain_url":"https://www.jax.org/strain/search?query=ZCCHC7"},"sequence":{"accession":"Q8N3Z6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N3Z6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N3Z6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N3Z6"}},"corpus_meta":[{"pmid":"9778499","id":"PMC_9778499","title":"A highly conserved centrosomal kinase, AIR-1, is required for accurate cell cycle progression and segregation of developmental factors in Caenorhabditis elegans embryos.","date":"1998","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9778499","citation_count":161,"is_preprint":false},{"pmid":"21878619","id":"PMC_21878619","title":"Air1 zinc knuckles 4 and 5 and a conserved IWRXY motif are critical for the function and integrity of the Trf4/5-Air1/2-Mtr4 polyadenylation (TRAMP) RNA quality control complex.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21878619","citation_count":61,"is_preprint":false},{"pmid":"9670958","id":"PMC_9670958","title":"HLA class II expression in uninducible hepatocarcinoma cells after transfection of AIR-1 gene product CIITA: acquisition of antigen processing and presentation capacity.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9670958","citation_count":47,"is_preprint":false},{"pmid":"10825588","id":"PMC_10825588","title":"Analysis of CIITA encoding AIR-1 gene promoters in insulin-dependent diabetes mellitus and rheumatoid arthritis patients from the northeast of Italy: absence of sequence variability.","date":"2000","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10825588","citation_count":15,"is_preprint":false},{"pmid":"7925569","id":"PMC_7925569","title":"In vivo modification of major histocompatibility complex class II DRA promoter occupancy mediated by the AIR-1 trans-activator.","date":"1994","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7925569","citation_count":14,"is_preprint":false},{"pmid":"2370082","id":"PMC_2370082","title":"Effect of the AIR-1 locus on the activation of an enhancerless HLA-DQA1 promoter.","date":"1990","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/2370082","citation_count":11,"is_preprint":false},{"pmid":"12434334","id":"PMC_12434334","title":"Caenorhabditis elegans Aurora A kinase AIR-1 is required for postembryonic cell divisions and germline development.","date":"2002","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/12434334","citation_count":9,"is_preprint":false},{"pmid":"7693585","id":"PMC_7693585","title":"Physiologic target of the Air-1 trans-activator revealed by stable transfection assay.","date":"1994","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/7693585","citation_count":7,"is_preprint":false},{"pmid":"39592470","id":"PMC_39592470","title":"Recurrent PAX5::ZCCHC7 rearrangement in B-cell acute lymphoblastic leukemia.","date":"2024","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/39592470","citation_count":4,"is_preprint":false},{"pmid":"40082489","id":"PMC_40082489","title":"Asymmetry in centrosome maturation revealed through AIR-1 dynamics in the early Caenorhabditis elegans embryo.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40082489","citation_count":0,"is_preprint":false},{"pmid":"38362120","id":"PMC_38362120","title":"Auxin-induced degradation of the aurora A kinase, AIR-1, in C. elegans does not prevent assembly of bipolar meiotic spindles.","date":"2024","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/38362120","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.20.619262","title":"Dissecting Breast Cancer Heterogeneity Through Transcriptomics Insights of Diverse Etiological Factors for Common Biomarker Discovery","date":"2024-10-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.20.619262","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.25.605035","title":"TRAMP assembly alters the conformation and RNA binding of Mtr4 and Trf4-Air2","date":"2024-07-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.25.605035","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8057,"output_tokens":651,"usd":0.016968,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6987,"output_tokens":1574,"usd":0.037143,"stage2_stop_reason":"end_turn"},"total_usd":0.054111,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"ZCCHC7 (hZCCHC7), the human orthologue of yeast Air1, localizes to the nucleolus in human cells and interacts with both mammalian Trf4 orthologues, PAPD5 and PAPD7, indicating it functions as the Air component of a human TRAMP complex involved in nuclear RNA quality control.\",\n      \"method\": \"Subcellular localization by immunofluorescence; protein interaction by co-immunoprecipitation; sequence analysis identifying conserved IWRXY motif\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, localization and co-IP reported together, two orthogonal methods but no functional reconstitution or mutagenesis of the human protein\",\n      \"pmids\": [\"21878619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In the yeast Air1/Air2 orthologues, zinc knuckles 4 and 5 are critical for interaction with Trf4 and for TRAMP complex integrity; a conserved IWRXY motif in the ZnK4-5 linker mediates the Trf4 interaction. This IWRXY motif is also present in human ZCCHC7, linking the same structural element to its interaction with mammalian PAPD5/PAPD7.\",\n      \"method\": \"Random mutagenesis of AIR1/2 genes; in vivo ZnK mutagenesis; functional complementation assays; CUT stabilization assays; TRAMP complex integrity analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genetic and biochemical methods in a single lab; human ZCCHC7 inference is by sequence conservation and co-IP, not direct mutagenesis of the human protein\",\n      \"pmids\": [\"21878619\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZCCHC7 is a nucleolar CCHC zinc-knuckle protein that serves as the human Air1 component of a TRAMP-like complex, interacting with the poly(A) polymerase orthologues PAPD5 and PAPD7 (via a conserved IWRXY motif) to couple RNA polyadenylation with nuclear exosome-mediated RNA quality control.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZCCHC7 is the human orthologue of yeast Air1 and functions as the Air component of a human TRAMP-like complex that couples RNA polyadenylation to nuclear RNA quality control [#0]. It localizes to the nucleolus and interacts with the two mammalian Trf4 orthologues, the non-canonical poly(A) polymerases PAPD5 and PAPD7 [#0]. This interaction is mediated by a conserved IWRXY motif located in the linker between zinc knuckles 4 and 5, a structural element shown in the yeast Air1/Air2 orthologues to be critical for Trf4 binding and TRAMP complex integrity and conserved in human ZCCHC7 [#1]. Beyond its identification as the Air subunit of a human TRAMP complex and the mapping of the IWRXY interaction motif by orthology, no further mechanistic detail — including direct mutagenesis of the human protein or functional reconstitution — has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether humans possess an Air-type adaptor to organize a TRAMP-like RNA surveillance complex was unresolved; identifying ZCCHC7 as nucleolar and as a PAPD5/PAPD7 partner established it as the human Air component coupling polyadenylation to nuclear RNA quality control.\",\n      \"evidence\": \"Immunofluorescence localization and co-immunoprecipitation with PAPD5/PAPD7 in human cells, with sequence analysis identifying a conserved IWRXY motif\",\n      \"pmids\": [\"21878619\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"single lab, two orthogonal methods, no functional reconstitution of the human protein\",\n      \"gaps\": [\n        \"No mutagenesis of human ZCCHC7 to confirm the IWRXY motif mediates PAPD5/PAPD7 binding directly\",\n        \"No functional reconstitution of a human TRAMP complex or demonstration of RNA quality control activity\",\n        \"RNA substrates targeted by the human complex not identified\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"How the Air adaptor docks onto the poly(A) polymerase was unknown; genetic and biochemical dissection in yeast showed zinc knuckles 4-5 and a conserved IWRXY linker motif mediate the Trf4 interaction and TRAMP integrity, and the conservation of this motif in ZCCHC7 implicates the same element in its PAPD5/PAPD7 binding.\",\n      \"evidence\": \"Random and targeted zinc-knuckle mutagenesis, functional complementation, CUT stabilization, and TRAMP integrity assays in yeast Air1/Air2; sequence conservation in human ZCCHC7\",\n      \"pmids\": [\"21878619\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"multiple orthogonal yeast methods; human inference by conservation and co-IP only\",\n      \"gaps\": [\n        \"Human ZCCHC7 IWRXY requirement inferred from yeast and sequence conservation, not directly tested\",\n        \"Structural basis of the ZCCHC7-PAPD5/PAPD7 interface not determined\",\n        \"Contribution of individual zinc knuckles to human complex assembly unmapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The RNA substrate spectrum, catalytic contribution within the human complex, and the link to nuclear exosome-mediated degradation remain to be established experimentally for human ZCCHC7.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No identified RNA substrates of the human TRAMP-like complex\",\n        \"No direct demonstration of coupling to the nuclear exosome in human cells\",\n        \"No structural or reconstitution data for the human complex\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"TRAMP complex\"],\n    \"partners\": [\"PAPD5\", \"PAPD7\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"faith_supported":1,"faith_total":3,"faith_pct":33.333333333333336}}