{"gene":"ZNF239","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":1990,"finding":"MOK-2 (ZNF239) encodes a protein consisting solely of seven highly homologous zinc finger domains (Krüppel family), with preferential expression in transformed cell lines, brain, and testis, suggesting a role in transcription via its zinc finger domains.","method":"cDNA and genomic cloning, sequencing, Northern blot","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural characterization by sequencing plus expression analysis, single lab, foundational characterization paper","pmids":["2104662"],"is_preprint":false},{"year":1995,"finding":"Human MOK2 (ZNF239) protein differs structurally from mouse MOK2: it contains three additional N-terminal zinc finger motifs and an acidic domain of 173 amino acids at the NH2-terminus, while sharing 94% identity in the seven core zinc fingers; the human gene maps to chromosome 19q13.2-q13.3.","method":"cDNA and genomic cloning, sequencing, Southern blot, FISH chromosomal mapping","journal":"Journal of molecular evolution","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing and genomic mapping, single lab, multiple orthogonal methods","pmids":["8587123"],"is_preprint":false},{"year":1994,"finding":"The MOK-2 promoter lacks TATA and CCAAT boxes, and two B2 (mouse Alu type-2) repetitive elements in the 5'-flanking region exert a negative cis-acting effect on MOK-2 promoter activity.","method":"Promoter deletion/reporter assays, DNA sequence analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter reporter assays, single lab","pmids":["7959005"],"is_preprint":false},{"year":1997,"finding":"MOK2 proteins are associated with nuclear ribonucleoprotein components (nucleoli and extranucleolar structures) and exhibit specific RNA homopolymer binding activity; an identical 18-bp specific DNA-binding sequence was identified for both human and mouse MOK2, with the DNA-binding domain localized to the seven adjacent zinc finger motifs.","method":"Immunofluorescence/immunoelectron microscopy, RNA-binding assays, SELEX (random oligonucleotide pool binding), subnuclear fractionation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (RNA binding assay, SELEX, subcellular localization), replicated across human and mouse orthologs in one study","pmids":["9121460"],"is_preprint":false},{"year":2001,"finding":"MOK2 binds an 8-bp core sequence (TAAAGGCT) in the IRBP promoter that overlaps with the CRX-binding element, represses IRBP transcription by competing with the CRX transcriptional activator for DNA binding, as demonstrated by transient overexpression in retinoblastoma Weri-RB1 cells.","method":"DNA-binding assays, transient transfection/reporter assay, competition binding with CRX","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — binding assays plus functional transcription repression assay with mechanistic competition demonstrated, single lab, multiple orthogonal methods","pmids":["11278819"],"is_preprint":false},{"year":2002,"finding":"hsMOK2 physically interacts with nuclear lamin A/C; the interaction requires the N-terminal acidic domain of hsMOK2 and the coiled-2 domain of lamin A/C. A fraction of hsMOK2 is associated with the nuclear matrix.","method":"Yeast two-hybrid, GST pull-down assay, co-immunolocalization (in vivo), nuclear matrix fractionation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — yeast two-hybrid confirmed by GST pull-down and co-immunolocalization, multiple orthogonal methods, domain mapping performed","pmids":["12409453"],"is_preprint":false},{"year":2008,"finding":"Pathogenic missense mutations of lamin A/C located in the hsMOK2-binding domain do not disrupt the hsMOK2–lamin A/C interaction in vitro or in vivo; however, expression of mutant lamin A/C causes aberrant sequestration of hsMOK2 into nuclear aggregates, potentially deregulating MOK2 target genes.","method":"In vitro binding assays, co-immunolocalization/immunofluorescence in cells expressing lamin A/C mutants","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus in vivo localization assays, single lab, two orthogonal methods","pmids":["17760566"],"is_preprint":false},{"year":2009,"finding":"hsMOK2 is phosphorylated at Ser38 and Ser129 by JNK3 kinase, and at Ser46 by Aurora A and protein kinase A; these phosphorylation sites are located in the lamin A/C-binding domain. Phosphorylation of hsMOK2 interferes with its ability to bind lamin A/C. JNK-associated leucine zipper (JLP) and JSAP1 scaffold proteins were identified as hsMOK2 binding partners.","method":"Co-immunoprecipitation/pulldown for partner identification, site-directed mutagenesis of phosphorylation sites, in vitro kinase assays, binding assays with phosphorylated vs. non-phosphorylated hsMOK2","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — kinase assays with mutagenesis, functional binding consequence demonstrated, multiple orthogonal methods in single rigorous study","pmids":["19490114"],"is_preprint":false}],"current_model":"ZNF239/MOK2 is a Krüppel-family zinc finger transcriptional repressor that binds both DNA (via a specific 18-bp sequence recognized by its seven conserved zinc finger motifs) and RNA (RNA homopolymers), represses target gene transcription (e.g., IRBP) by competing with activators such as CRX for promoter binding, associates with nuclear ribonucleoprotein components and the nuclear matrix, and interacts with nuclear lamin A/C through its N-terminal acidic domain; this lamin A/C interaction is regulated by phosphorylation of hsMOK2 at Ser38/Ser129 (by JNK3) and Ser46 (by Aurora A/PKA), and is disrupted by pathogenic lamin A/C mutations that sequester hsMOK2 into nuclear aggregates."},"narrative":{"mechanistic_narrative":"ZNF239/MOK2 is a Krüppel-family zinc finger protein that functions as a sequence-specific transcriptional repressor and nuclear matrix-associated factor [PMID:2104662, PMID:9121460]. Its DNA-binding activity resides in seven adjacent zinc finger motifs that recognize a defined 18-bp element, and the same protein binds RNA homopolymers while associating with nucleolar and extranucleolar ribonucleoprotein structures [PMID:9121460]. At target promoters such as IRBP, MOK2 represses transcription by competing with the activator CRX for an overlapping core binding sequence [PMID:11278819]. The human ortholog carries an N-terminal acidic domain that mediates a direct physical interaction with nuclear lamin A/C through the lamin coiled-2 domain, tethering a fraction of MOK2 to the nuclear matrix [PMID:12409453]. This interaction is regulated by phosphorylation within the lamin A/C-binding domain — at Ser38/Ser129 by JNK3 and at Ser46 by Aurora A and PKA — which interferes with lamin A/C binding, and MOK2 additionally associates with the JLP and JSAP1 scaffold proteins [PMID:19490114]. Pathogenic lamin A/C missense mutations do not abolish the interaction itself but sequester MOK2 into aberrant nuclear aggregates, providing a route to deregulation of its target genes [PMID:17760566].","teleology":[{"year":1990,"claim":"Established the gene product as a Krüppel-family zinc finger protein composed almost entirely of zinc finger domains, implicating it in transcription before any target was known.","evidence":"cDNA/genomic cloning, sequencing and Northern blot expression profiling in mouse","pmids":["2104662"],"confidence":"Medium","gaps":["No DNA target or transcriptional activity demonstrated","Functional role inferred only from domain structure"]},{"year":1994,"claim":"Characterized the MOK-2 promoter architecture, showing it is TATA/CCAAT-less and subject to negative cis-regulation by repetitive B2 elements, addressing how the gene's own expression is controlled.","evidence":"Promoter deletion/reporter assays and DNA sequence analysis","pmids":["7959005"],"confidence":"Medium","gaps":["Trans-acting factors controlling the promoter not identified","Physiological contexts of regulation unknown"]},{"year":1995,"claim":"Defined structural divergence between human and mouse orthologs, revealing that human MOK2 carries extra N-terminal zinc fingers and a 173-aa acidic domain absent in mouse, while the seven core fingers are conserved.","evidence":"cDNA/genomic cloning, sequencing, Southern blot and FISH mapping to 19q13.2-q13.3","pmids":["8587123"],"confidence":"Medium","gaps":["Function of the human-specific acidic domain not yet defined","Functional consequence of extra zinc fingers unknown"]},{"year":1997,"claim":"Identified the dual nucleic-acid binding capacity and defined the specific 18-bp DNA recognition sequence, localizing DNA binding to the seven zinc fingers and linking the protein to nuclear RNP structures.","evidence":"SELEX, RNA homopolymer binding assays, and immunofluorescence/immunoelectron microscopy across human and mouse orthologs","pmids":["9121460"],"confidence":"High","gaps":["No endogenous genomic targets identified","Functional role of RNA binding unresolved"]},{"year":2001,"claim":"Demonstrated a concrete repressor mechanism by showing MOK2 binds a core element in the IRBP promoter overlapping the CRX site and represses transcription through competition with the CRX activator.","evidence":"DNA-binding assays, transient transfection reporter assays and CRX competition binding in Weri-RB1 retinoblastoma cells","pmids":["11278819"],"confidence":"High","gaps":["Repression shown by overexpression, not endogenous loss-of-function","Broader target gene set not defined"]},{"year":2002,"claim":"Connected MOK2 to nuclear architecture by mapping a direct lamin A/C interaction to its N-terminal acidic domain and the lamin coiled-2 domain, with a fraction in the nuclear matrix.","evidence":"Yeast two-hybrid, GST pull-down, co-immunolocalization and nuclear matrix fractionation","pmids":["12409453"],"confidence":"High","gaps":["Functional consequence of tethering for transcription not established","Dynamics of matrix association unknown"]},{"year":2008,"claim":"Linked MOK2 to laminopathy mechanisms by showing pathogenic lamin A/C mutations sequester MOK2 into nuclear aggregates despite preserving the binding interaction, suggesting target-gene deregulation.","evidence":"In vitro binding assays and co-immunolocalization in cells expressing lamin A/C mutants","pmids":["17760566"],"confidence":"Medium","gaps":["Target-gene deregulation only inferred, not directly measured","Disease relevance to specific laminopathy phenotypes not demonstrated"]},{"year":2009,"claim":"Revealed phosphoregulation of the lamin interaction, identifying JNK3, Aurora A and PKA sites in the lamin A/C-binding domain whose phosphorylation disrupts lamin binding, plus scaffold partners JLP and JSAP1.","evidence":"In vitro kinase assays, site-directed mutagenesis, phospho-dependent binding assays and co-IP for partner identification","pmids":["19490114"],"confidence":"High","gaps":["Signaling stimuli that trigger these phosphorylations in vivo unknown","Transcriptional output of release from lamin not measured"]},{"year":null,"claim":"The genome-wide target repertoire and the physiological/developmental processes governed by ZNF239 repression remain undefined.","evidence":"No endogenous loss-of-function or genome-wide binding study present in the corpus","pmids":[],"confidence":"Low","gaps":["No ChIP-seq or knockout phenotype available","RNA-binding function lacks a defined biological role","In vivo significance of nuclear aggregation untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,4]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4]}],"complexes":[],"partners":["LMNA","CRX","SPAG9","MAPK8IP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16600","full_name":"Zinc finger protein 239","aliases":["Zinc finger protein HOK-2","Zinc finger protein MOK-2"],"length_aa":458,"mass_kda":51.6,"function":"May be involved in transcriptional regulation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q16600/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF239","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZNF239","total_profiled":1310},"omim":[{"mim_id":"601069","title":"ZINC FINGER PROTEIN 239; ZNF239","url":"https://www.omim.org/entry/601069"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZNF239"},"hgnc":{"alias_symbol":["MOK2","HOK-2"],"prev_symbol":[]},"alphafold":{"accession":"Q16600","domains":[{"cath_id":"3.30.160.60","chopping":"402-458","consensus_level":"medium","plddt":91.3098,"start":402,"end":458}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16600","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16600-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16600-F1-predicted_aligned_error_v6.png","plddt_mean":62.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF239","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF239"},"sequence":{"accession":"Q16600","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16600.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16600/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16600"}},"corpus_meta":[{"pmid":"12409453","id":"PMC_12409453","title":"In vivo and in vitro interaction between human transcription factor MOK2 and nuclear lamin A/C.","date":"2002","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/12409453","citation_count":107,"is_preprint":false},{"pmid":"22529894","id":"PMC_22529894","title":"Amerind ancestry, socioeconomic status and the genetics of type 2 diabetes in a Colombian population.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22529894","citation_count":41,"is_preprint":false},{"pmid":"2104662","id":"PMC_2104662","title":"A gene that encodes a protein consisting solely of zinc finger domains is preferentially expressed in transformed mouse cells.","date":"1990","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2104662","citation_count":26,"is_preprint":false},{"pmid":"9121460","id":"PMC_9121460","title":"Human and mouse MOK2 proteins are associated with nuclear ribonucleoprotein components and bind specifically to RNA and DNA through their zinc finger domains.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9121460","citation_count":25,"is_preprint":false},{"pmid":"7959005","id":"PMC_7959005","title":"The gene encoding the MOK-2 zinc-finger protein: characterization of its promoter and negative regulation by mouse Alu type-2 repetitive elements.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/7959005","citation_count":20,"is_preprint":false},{"pmid":"17760566","id":"PMC_17760566","title":"Mislocalization of human transcription factor MOK2 in the presence of pathogenic mutations of lamin A/C.","date":"2008","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17760566","citation_count":19,"is_preprint":false},{"pmid":"33297932","id":"PMC_33297932","title":"Identification of an RNA binding protein-related gene signature in hepatocellular carcinoma patients.","date":"2020","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/33297932","citation_count":15,"is_preprint":false},{"pmid":"11278819","id":"PMC_11278819","title":"The zinc finger transcription factor, MOK2, negatively modulates expression of the interphotoreceptor retinoid-binding protein gene, IRBP.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278819","citation_count":14,"is_preprint":false},{"pmid":"19490114","id":"PMC_19490114","title":"Phosphorylation-dependent binding of human transcription factor MOK2 to lamin A/C.","date":"2009","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/19490114","citation_count":14,"is_preprint":false},{"pmid":"8587123","id":"PMC_8587123","title":"Human and mouse Krüppel-like (MOK2) orthologue genes encode two different zinc finger proteins.","date":"1995","source":"Journal of molecular evolution","url":"https://pubmed.ncbi.nlm.nih.gov/8587123","citation_count":12,"is_preprint":false},{"pmid":"3207504","id":"PMC_3207504","title":"Immunological relationships between rabies virus and rabies-related viruses studied with monoclonal antibodies to Mokola virus.","date":"1988","source":"Annales de l'Institut Pasteur. Virology","url":"https://pubmed.ncbi.nlm.nih.gov/3207504","citation_count":10,"is_preprint":false},{"pmid":"8634327","id":"PMC_8634327","title":"A novel zinc finger gene preferentially expressed in the retina and the organ of Corti localizes to human chromosome 12q24.3.","date":"1996","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8634327","citation_count":7,"is_preprint":false},{"pmid":"7139591","id":"PMC_7139591","title":"Influence of strain difference on the karyotypic changes in N-nitroso-N-butylurea--induced mouse lymphomas.","date":"1982","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/7139591","citation_count":4,"is_preprint":false},{"pmid":"39411371","id":"PMC_39411371","title":"MicroRNA binding site variants-new potential markers of primary osteoporosis in men and women.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39411371","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7793,"output_tokens":1975,"usd":0.026502,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8939,"output_tokens":2700,"usd":0.056098,"stage2_stop_reason":"end_turn"},"total_usd":0.0826,"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\": 1990,\n      \"finding\": \"MOK-2 (ZNF239) encodes a protein consisting solely of seven highly homologous zinc finger domains (Krüppel family), with preferential expression in transformed cell lines, brain, and testis, suggesting a role in transcription via its zinc finger domains.\",\n      \"method\": \"cDNA and genomic cloning, sequencing, Northern blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural characterization by sequencing plus expression analysis, single lab, foundational characterization paper\",\n      \"pmids\": [\"2104662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human MOK2 (ZNF239) protein differs structurally from mouse MOK2: it contains three additional N-terminal zinc finger motifs and an acidic domain of 173 amino acids at the NH2-terminus, while sharing 94% identity in the seven core zinc fingers; the human gene maps to chromosome 19q13.2-q13.3.\",\n      \"method\": \"cDNA and genomic cloning, sequencing, Southern blot, FISH chromosomal mapping\",\n      \"journal\": \"Journal of molecular evolution\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing and genomic mapping, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"8587123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The MOK-2 promoter lacks TATA and CCAAT boxes, and two B2 (mouse Alu type-2) repetitive elements in the 5'-flanking region exert a negative cis-acting effect on MOK-2 promoter activity.\",\n      \"method\": \"Promoter deletion/reporter assays, DNA sequence analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter reporter assays, single lab\",\n      \"pmids\": [\"7959005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MOK2 proteins are associated with nuclear ribonucleoprotein components (nucleoli and extranucleolar structures) and exhibit specific RNA homopolymer binding activity; an identical 18-bp specific DNA-binding sequence was identified for both human and mouse MOK2, with the DNA-binding domain localized to the seven adjacent zinc finger motifs.\",\n      \"method\": \"Immunofluorescence/immunoelectron microscopy, RNA-binding assays, SELEX (random oligonucleotide pool binding), subnuclear fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (RNA binding assay, SELEX, subcellular localization), replicated across human and mouse orthologs in one study\",\n      \"pmids\": [\"9121460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MOK2 binds an 8-bp core sequence (TAAAGGCT) in the IRBP promoter that overlaps with the CRX-binding element, represses IRBP transcription by competing with the CRX transcriptional activator for DNA binding, as demonstrated by transient overexpression in retinoblastoma Weri-RB1 cells.\",\n      \"method\": \"DNA-binding assays, transient transfection/reporter assay, competition binding with CRX\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — binding assays plus functional transcription repression assay with mechanistic competition demonstrated, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"11278819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"hsMOK2 physically interacts with nuclear lamin A/C; the interaction requires the N-terminal acidic domain of hsMOK2 and the coiled-2 domain of lamin A/C. A fraction of hsMOK2 is associated with the nuclear matrix.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down assay, co-immunolocalization (in vivo), nuclear matrix fractionation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — yeast two-hybrid confirmed by GST pull-down and co-immunolocalization, multiple orthogonal methods, domain mapping performed\",\n      \"pmids\": [\"12409453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pathogenic missense mutations of lamin A/C located in the hsMOK2-binding domain do not disrupt the hsMOK2–lamin A/C interaction in vitro or in vivo; however, expression of mutant lamin A/C causes aberrant sequestration of hsMOK2 into nuclear aggregates, potentially deregulating MOK2 target genes.\",\n      \"method\": \"In vitro binding assays, co-immunolocalization/immunofluorescence in cells expressing lamin A/C mutants\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus in vivo localization assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"17760566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"hsMOK2 is phosphorylated at Ser38 and Ser129 by JNK3 kinase, and at Ser46 by Aurora A and protein kinase A; these phosphorylation sites are located in the lamin A/C-binding domain. Phosphorylation of hsMOK2 interferes with its ability to bind lamin A/C. JNK-associated leucine zipper (JLP) and JSAP1 scaffold proteins were identified as hsMOK2 binding partners.\",\n      \"method\": \"Co-immunoprecipitation/pulldown for partner identification, site-directed mutagenesis of phosphorylation sites, in vitro kinase assays, binding assays with phosphorylated vs. non-phosphorylated hsMOK2\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — kinase assays with mutagenesis, functional binding consequence demonstrated, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"19490114\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF239/MOK2 is a Krüppel-family zinc finger transcriptional repressor that binds both DNA (via a specific 18-bp sequence recognized by its seven conserved zinc finger motifs) and RNA (RNA homopolymers), represses target gene transcription (e.g., IRBP) by competing with activators such as CRX for promoter binding, associates with nuclear ribonucleoprotein components and the nuclear matrix, and interacts with nuclear lamin A/C through its N-terminal acidic domain; this lamin A/C interaction is regulated by phosphorylation of hsMOK2 at Ser38/Ser129 (by JNK3) and Ser46 (by Aurora A/PKA), and is disrupted by pathogenic lamin A/C mutations that sequester hsMOK2 into nuclear aggregates.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZNF239/MOK2 is a Krüppel-family zinc finger protein that functions as a sequence-specific transcriptional repressor and nuclear matrix-associated factor [#0, #3]. Its DNA-binding activity resides in seven adjacent zinc finger motifs that recognize a defined 18-bp element, and the same protein binds RNA homopolymers while associating with nucleolar and extranucleolar ribonucleoprotein structures [#3]. At target promoters such as IRBP, MOK2 represses transcription by competing with the activator CRX for an overlapping core binding sequence [#4]. The human ortholog carries an N-terminal acidic domain that mediates a direct physical interaction with nuclear lamin A/C through the lamin coiled-2 domain, tethering a fraction of MOK2 to the nuclear matrix [#5]. This interaction is regulated by phosphorylation within the lamin A/C-binding domain — at Ser38/Ser129 by JNK3 and at Ser46 by Aurora A and PKA — which interferes with lamin A/C binding, and MOK2 additionally associates with the JLP and JSAP1 scaffold proteins [#7]. Pathogenic lamin A/C missense mutations do not abolish the interaction itself but sequester MOK2 into aberrant nuclear aggregates, providing a route to deregulation of its target genes [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established the gene product as a Krüppel-family zinc finger protein composed almost entirely of zinc finger domains, implicating it in transcription before any target was known.\",\n      \"evidence\": \"cDNA/genomic cloning, sequencing and Northern blot expression profiling in mouse\",\n      \"pmids\": [\"2104662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No DNA target or transcriptional activity demonstrated\", \"Functional role inferred only from domain structure\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Characterized the MOK-2 promoter architecture, showing it is TATA/CCAAT-less and subject to negative cis-regulation by repetitive B2 elements, addressing how the gene's own expression is controlled.\",\n      \"evidence\": \"Promoter deletion/reporter assays and DNA sequence analysis\",\n      \"pmids\": [\"7959005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-acting factors controlling the promoter not identified\", \"Physiological contexts of regulation unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined structural divergence between human and mouse orthologs, revealing that human MOK2 carries extra N-terminal zinc fingers and a 173-aa acidic domain absent in mouse, while the seven core fingers are conserved.\",\n      \"evidence\": \"cDNA/genomic cloning, sequencing, Southern blot and FISH mapping to 19q13.2-q13.3\",\n      \"pmids\": [\"8587123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the human-specific acidic domain not yet defined\", \"Functional consequence of extra zinc fingers unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified the dual nucleic-acid binding capacity and defined the specific 18-bp DNA recognition sequence, localizing DNA binding to the seven zinc fingers and linking the protein to nuclear RNP structures.\",\n      \"evidence\": \"SELEX, RNA homopolymer binding assays, and immunofluorescence/immunoelectron microscopy across human and mouse orthologs\",\n      \"pmids\": [\"9121460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No endogenous genomic targets identified\", \"Functional role of RNA binding unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated a concrete repressor mechanism by showing MOK2 binds a core element in the IRBP promoter overlapping the CRX site and represses transcription through competition with the CRX activator.\",\n      \"evidence\": \"DNA-binding assays, transient transfection reporter assays and CRX competition binding in Weri-RB1 retinoblastoma cells\",\n      \"pmids\": [\"11278819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Repression shown by overexpression, not endogenous loss-of-function\", \"Broader target gene set not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected MOK2 to nuclear architecture by mapping a direct lamin A/C interaction to its N-terminal acidic domain and the lamin coiled-2 domain, with a fraction in the nuclear matrix.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-immunolocalization and nuclear matrix fractionation\",\n      \"pmids\": [\"12409453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of tethering for transcription not established\", \"Dynamics of matrix association unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked MOK2 to laminopathy mechanisms by showing pathogenic lamin A/C mutations sequester MOK2 into nuclear aggregates despite preserving the binding interaction, suggesting target-gene deregulation.\",\n      \"evidence\": \"In vitro binding assays and co-immunolocalization in cells expressing lamin A/C mutants\",\n      \"pmids\": [\"17760566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target-gene deregulation only inferred, not directly measured\", \"Disease relevance to specific laminopathy phenotypes not demonstrated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed phosphoregulation of the lamin interaction, identifying JNK3, Aurora A and PKA sites in the lamin A/C-binding domain whose phosphorylation disrupts lamin binding, plus scaffold partners JLP and JSAP1.\",\n      \"evidence\": \"In vitro kinase assays, site-directed mutagenesis, phospho-dependent binding assays and co-IP for partner identification\",\n      \"pmids\": [\"19490114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling stimuli that trigger these phosphorylations in vivo unknown\", \"Transcriptional output of release from lamin not measured\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The genome-wide target repertoire and the physiological/developmental processes governed by ZNF239 repression remain undefined.\",\n      \"evidence\": \"No endogenous loss-of-function or genome-wide binding study present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ChIP-seq or knockout phenotype available\", \"RNA-binding function lacks a defined biological role\", \"In vivo significance of nuclear aggregation untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LMNA\", \"CRX\", \"SPAG9\", \"MAPK8IP3\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}