{"gene":"ZNHIT2","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":2017,"finding":"ZNHIT2 mediates the interaction between the R2TP/Prefoldin-like (R2TP/PFDL) cochaperone complex and the U5 small nuclear ribonucleoprotein (snRNP). Affinity purification coupled to mass spectrometry showed that R2TP/PFDL associates with the U5 snRNP mostly through ZNHIT2. The zinc-finger HIT domain of ZNHIT2 directly binds RUVBL2. Disruption of ZNHIT2 or RUVBL2 expression impacts the protein composition of the U5 snRNP, indicating a role for these proteins in promoting U5 snRNP assembly.","method":"Multiple target affinity purification coupled to mass spectrometry (AP-MS); siRNA knockdown of ZNHIT2 and RUVBL2 followed by analysis of U5 snRNP protein composition","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal AP-MS with multiple targets, knockdown functional validation, and identification of direct binding partner (RUVBL2), all in a single rigorous study with orthogonal methods","pmids":["28561026"],"is_preprint":false},{"year":2007,"finding":"The zinc-finger HIT domain of human ZNHIT2 (protein FON) adopts a novel zinc-binding fold consisting of two consecutive antiparallel beta-sheets and two short C-terminal helices, coordinating two zinc ions tetrahedrally via a CCCC-CCHC motif in an interleaved cross-brace manner. The tertiary structure resembles the B-box, RING finger, and PHD domain family (treble clef superfamily) but is distinct from all of them.","method":"NMR solution structure determination using 3D NOESY spectra (567 upper distance limits); backbone RMSD 0.19 Å for structured residues 12–48","journal":"Protein Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution NMR structure with quantitative restraints and RMSD reporting; directly characterizes the domain architecture and zinc-coordination mechanism of ZNHIT2","pmids":["17656577"],"is_preprint":false},{"year":2024,"finding":"Knockout of Znhit2 in mouse embryos causes embryonic lethality at peri-implantation stages. Znhit2 mutant embryos display a complete lack of nuclear EFTUD2 (a key U5 spliceosome component), indicating a global splicing deficiency. This is mechanistically distinct from Znhit1 loss, which impairs H2A.Z incorporation at gene promoters. Znhit2 mutant embryos also show reduced SOX2-positive inner cell mass cells, absent Fgf4 expression, and aberrant NANOG/SOX17 expression.","method":"Knockout mouse genetics; immunofluorescence for EFTUD2 nuclear localization; quantification of pluripotency markers (SOX2, NANOG, SOX17) and Fgf4 expression in mutant blastocysts","journal":"Biology of Reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined cellular phenotype (loss of nuclear EFTUD2) directly linking ZNHIT2 to U5 spliceosome integrity in vivo, orthogonal to the in vitro AP-MS data from PMID 28561026","pmids":["39194072"],"is_preprint":false}],"current_model":"ZNHIT2 is a zinc-finger HIT domain-containing protein that adopts a novel treble-clef zinc-binding fold (two CCCC-CCHC-coordinated zinc ions); it functions as a bridging factor between the R2TP/Prefoldin-like cochaperone complex (binding directly to RUVBL2 via its HIT domain) and the U5 snRNP, thereby promoting U5 snRNP assembly, and its loss in mouse embryos abolishes nuclear localization of the U5 spliceosome component EFTUD2, causing global splicing deficiency and peri-implantation lethality."},"narrative":{"mechanistic_narrative":"ZNHIT2 is a zinc-finger HIT domain protein that acts as a bridging factor coupling the R2TP/Prefoldin-like (R2TP/PFDL) cochaperone machinery to U5 snRNP assembly [PMID:28561026]. Its HIT domain adopts a novel treble-clef-like zinc-binding fold that coordinates two zinc ions tetrahedrally through an interleaved CCCC-CCHC cross-brace motif, structurally related to but distinct from B-box, RING, and PHD domains [PMID:17656577]. Through this domain ZNHIT2 binds directly to the AAA+ ATPase RUVBL2, and disruption of either ZNHIT2 or RUVBL2 alters the protein composition of the U5 snRNP, establishing ZNHIT2 as a promoter of U5 snRNP biogenesis [PMID:28561026]. In vivo, loss of Znhit2 in mouse embryos abolishes nuclear localization of the U5 component EFTUD2, producing a global splicing deficiency, disrupted pluripotency marker expression, and peri-implantation lethality, a phenotype mechanistically distinct from Znhit1 loss [PMID:39194072].","teleology":[{"year":2007,"claim":"Before any functional assignment, the structural basis of the ZNHIT2 zinc-finger HIT domain was unknown; solving it defined a distinct zinc-coordination architecture that would later rationalize its protein-binding role.","evidence":"NMR solution structure of the human ZNHIT2 (FON) HIT domain with quantitative NOE restraints","pmids":["17656577"],"confidence":"High","gaps":["Structure covers only the isolated HIT domain, not the full-length protein","Does not identify any binding partner or functional interface","No link to spliceosome biology established at this stage"]},{"year":2017,"claim":"It was unclear how the R2TP/PFDL cochaperone complex connects to spliceosomal snRNPs; ZNHIT2 was identified as the bridging adaptor that binds RUVBL2 and promotes U5 snRNP assembly.","evidence":"Reciprocal AP-MS across multiple targets plus siRNA knockdown of ZNHIT2 and RUVBL2 with analysis of U5 snRNP composition in human cells","pmids":["28561026"],"confidence":"High","gaps":["Stoichiometry and exact assembly intermediate captured by ZNHIT2 not resolved","Whether ZNHIT2 acts catalytically or as a one-time scaffold unclear","In vivo physiological consequence of disrupting the bridge not tested here"]},{"year":2024,"claim":"The organismal requirement for ZNHIT2 was unknown; knockout showed it is essential for U5 spliceosome integrity in vivo, with loss abolishing nuclear EFTUD2 and causing peri-implantation lethality.","evidence":"Znhit2 knockout mouse genetics with EFTUD2 immunofluorescence and pluripotency marker quantification in blastocysts","pmids":["39194072"],"confidence":"High","gaps":["Direct splicing targets affected genome-wide not enumerated","Mechanism by which EFTUD2 fails to enter the nucleus not resolved at molecular level","Relationship between the in vitro RUVBL2-bridging role and the in vivo EFTUD2 phenotype not directly connected"]},{"year":null,"claim":"How ZNHIT2-directed U5 snRNP assembly is coupled to ATP-dependent RUVBL1/2 remodeling and how the chaperone hands off mature components remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No reconstituted assembly assay defining the ZNHIT2-dependent step","Structure of ZNHIT2 bound to RUVBL2 or U5 components not determined","Regulation of ZNHIT2 activity across cell types and conditions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2]}],"complexes":["R2TP/Prefoldin-like cochaperone complex","U5 snRNP"],"partners":["RUVBL2","EFTUD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHR6","full_name":"Zinc finger HIT domain-containing protein 2","aliases":["Protein FON"],"length_aa":403,"mass_kda":42.9,"function":"May act as a bridging factor mediating the interaction between the R2TP/Prefoldin-like (R2TP/PFDL) complex and U5 small nuclear ribonucleoprotein (U5 snRNP) (PubMed:28561026). Required for the interaction of R2TP complex subunit RPAP3 and prefoldin-like subunit URI1 with U5 snRNP proteins EFTUD2 and PRPF8 (PubMed:28561026). May play a role in regulating the composition of the U5 snRNP complex (PubMed:28561026)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9UHR6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNHIT2","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLNS1A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZNHIT2","total_profiled":1310},"omim":[{"mim_id":"604575","title":"ZINC FINGER HIT DOMAIN-CONTAINING PROTEIN 2; ZNHIT2","url":"https://www.omim.org/entry/604575"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":65.5}],"url":"https://www.proteinatlas.org/search/ZNHIT2"},"hgnc":{"alias_symbol":["FON"],"prev_symbol":["C11orf5"]},"alphafold":{"accession":"Q9UHR6","domains":[{"cath_id":"3.30.60.190","chopping":"2-55","consensus_level":"medium","plddt":81.052,"start":2,"end":55},{"cath_id":"-","chopping":"200-387","consensus_level":"high","plddt":93.7872,"start":200,"end":387}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHR6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHR6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHR6-F1-predicted_aligned_error_v6.png","plddt_mean":78.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNHIT2","jax_strain_url":"https://www.jax.org/strain/search?query=ZNHIT2"},"sequence":{"accession":"Q9UHR6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHR6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHR6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHR6"}},"corpus_meta":[{"pmid":"34278827","id":"PMC_34278827","title":"Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA.","date":"2021","source":"Future oncology (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34278827","citation_count":178,"is_preprint":false},{"pmid":"14602237","id":"PMC_14602237","title":"Exosomes bearing HLA-G are released by melanoma cells.","date":"2003","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14602237","citation_count":107,"is_preprint":false},{"pmid":"28561026","id":"PMC_28561026","title":"R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28561026","citation_count":96,"is_preprint":false},{"pmid":"15514928","id":"PMC_15514928","title":"HLA-G gene activation in tumor cells involves cis-acting epigenetic changes.","date":"2005","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15514928","citation_count":55,"is_preprint":false},{"pmid":"31001229","id":"PMC_31001229","title":"Comparative Transcriptome Analysis Reveals the Biocontrol Mechanism of Bacillus velezensis F21 Against Fusarium Wilt on Watermelon.","date":"2019","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31001229","citation_count":54,"is_preprint":false},{"pmid":"15834900","id":"PMC_15834900","title":"Craniofacial and axial skeletal defects induced by the fungicide triadimefon in the mouse.","date":"2005","source":"Birth defects research. 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Affinity purification coupled to mass spectrometry showed that R2TP/PFDL associates with the U5 snRNP mostly through ZNHIT2. The zinc-finger HIT domain of ZNHIT2 directly binds RUVBL2. Disruption of ZNHIT2 or RUVBL2 expression impacts the protein composition of the U5 snRNP, indicating a role for these proteins in promoting U5 snRNP assembly.\",\n      \"method\": \"Multiple target affinity purification coupled to mass spectrometry (AP-MS); siRNA knockdown of ZNHIT2 and RUVBL2 followed by analysis of U5 snRNP protein composition\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal AP-MS with multiple targets, knockdown functional validation, and identification of direct binding partner (RUVBL2), all in a single rigorous study with orthogonal methods\",\n      \"pmids\": [\"28561026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The zinc-finger HIT domain of human ZNHIT2 (protein FON) adopts a novel zinc-binding fold consisting of two consecutive antiparallel beta-sheets and two short C-terminal helices, coordinating two zinc ions tetrahedrally via a CCCC-CCHC motif in an interleaved cross-brace manner. The tertiary structure resembles the B-box, RING finger, and PHD domain family (treble clef superfamily) but is distinct from all of them.\",\n      \"method\": \"NMR solution structure determination using 3D NOESY spectra (567 upper distance limits); backbone RMSD 0.19 Å for structured residues 12–48\",\n      \"journal\": \"Protein Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution NMR structure with quantitative restraints and RMSD reporting; directly characterizes the domain architecture and zinc-coordination mechanism of ZNHIT2\",\n      \"pmids\": [\"17656577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockout of Znhit2 in mouse embryos causes embryonic lethality at peri-implantation stages. Znhit2 mutant embryos display a complete lack of nuclear EFTUD2 (a key U5 spliceosome component), indicating a global splicing deficiency. This is mechanistically distinct from Znhit1 loss, which impairs H2A.Z incorporation at gene promoters. Znhit2 mutant embryos also show reduced SOX2-positive inner cell mass cells, absent Fgf4 expression, and aberrant NANOG/SOX17 expression.\",\n      \"method\": \"Knockout mouse genetics; immunofluorescence for EFTUD2 nuclear localization; quantification of pluripotency markers (SOX2, NANOG, SOX17) and Fgf4 expression in mutant blastocysts\",\n      \"journal\": \"Biology of Reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined cellular phenotype (loss of nuclear EFTUD2) directly linking ZNHIT2 to U5 spliceosome integrity in vivo, orthogonal to the in vitro AP-MS data from PMID 28561026\",\n      \"pmids\": [\"39194072\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNHIT2 is a zinc-finger HIT domain-containing protein that adopts a novel treble-clef zinc-binding fold (two CCCC-CCHC-coordinated zinc ions); it functions as a bridging factor between the R2TP/Prefoldin-like cochaperone complex (binding directly to RUVBL2 via its HIT domain) and the U5 snRNP, thereby promoting U5 snRNP assembly, and its loss in mouse embryos abolishes nuclear localization of the U5 spliceosome component EFTUD2, causing global splicing deficiency and peri-implantation lethality.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZNHIT2 is a zinc-finger HIT domain protein that acts as a bridging factor coupling the R2TP/Prefoldin-like (R2TP/PFDL) cochaperone machinery to U5 snRNP assembly [#0]. Its HIT domain adopts a novel treble-clef-like zinc-binding fold that coordinates two zinc ions tetrahedrally through an interleaved CCCC-CCHC cross-brace motif, structurally related to but distinct from B-box, RING, and PHD domains [#1]. Through this domain ZNHIT2 binds directly to the AAA+ ATPase RUVBL2, and disruption of either ZNHIT2 or RUVBL2 alters the protein composition of the U5 snRNP, establishing ZNHIT2 as a promoter of U5 snRNP biogenesis [#0]. In vivo, loss of Znhit2 in mouse embryos abolishes nuclear localization of the U5 component EFTUD2, producing a global splicing deficiency, disrupted pluripotency marker expression, and peri-implantation lethality, a phenotype mechanistically distinct from Znhit1 loss [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Before any functional assignment, the structural basis of the ZNHIT2 zinc-finger HIT domain was unknown; solving it defined a distinct zinc-coordination architecture that would later rationalize its protein-binding role.\",\n      \"evidence\": \"NMR solution structure of the human ZNHIT2 (FON) HIT domain with quantitative NOE restraints\",\n      \"pmids\": [\"17656577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure covers only the isolated HIT domain, not the full-length protein\",\n        \"Does not identify any binding partner or functional interface\",\n        \"No link to spliceosome biology established at this stage\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"It was unclear how the R2TP/PFDL cochaperone complex connects to spliceosomal snRNPs; ZNHIT2 was identified as the bridging adaptor that binds RUVBL2 and promotes U5 snRNP assembly.\",\n      \"evidence\": \"Reciprocal AP-MS across multiple targets plus siRNA knockdown of ZNHIT2 and RUVBL2 with analysis of U5 snRNP composition in human cells\",\n      \"pmids\": [\"28561026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and exact assembly intermediate captured by ZNHIT2 not resolved\",\n        \"Whether ZNHIT2 acts catalytically or as a one-time scaffold unclear\",\n        \"In vivo physiological consequence of disrupting the bridge not tested here\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The organismal requirement for ZNHIT2 was unknown; knockout showed it is essential for U5 spliceosome integrity in vivo, with loss abolishing nuclear EFTUD2 and causing peri-implantation lethality.\",\n      \"evidence\": \"Znhit2 knockout mouse genetics with EFTUD2 immunofluorescence and pluripotency marker quantification in blastocysts\",\n      \"pmids\": [\"39194072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct splicing targets affected genome-wide not enumerated\",\n        \"Mechanism by which EFTUD2 fails to enter the nucleus not resolved at molecular level\",\n        \"Relationship between the in vitro RUVBL2-bridging role and the in vivo EFTUD2 phenotype not directly connected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZNHIT2-directed U5 snRNP assembly is coupled to ATP-dependent RUVBL1/2 remodeling and how the chaperone hands off mature components remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No reconstituted assembly assay defining the ZNHIT2-dependent step\",\n        \"Structure of ZNHIT2 bound to RUVBL2 or U5 components not determined\",\n        \"Regulation of ZNHIT2 activity across cell types and conditions unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\n      \"R2TP/Prefoldin-like cochaperone complex\",\n      \"U5 snRNP\"\n    ],\n    \"partners\": [\n      \"RUVBL2\",\n      \"EFTUD2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}