{"gene":"ZNF280C","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":2018,"finding":"ZPET/ZNF280C binds single-stranded DNA (ssDNA) and localizes to DNA double-strand breaks (DSBs) and stalled replication forks, where it inhibits MRE11 binding to ssDNA in vitro and delays MRE11 chromatin association after DSB formation in cells, thereby slowing DNA end resection independently of 53BP1 and HELB.","method":"Localized protein biotinylation (BioID with RAD18-BirAR118G fusion), in vitro ssDNA-binding assay, in vitro MRE11-inhibition assay, chromatin fractionation, loss-of-function (ZPET-depleted cells) with DNA resection and HR frequency readouts","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods in a single study: in vitro biochemical assays, proximity biotinylation proteomics, cell-based KD with defined molecular phenotypes (resection, HR, fork speed)","pmids":["30567999"],"is_preprint":false},{"year":2018,"finding":"Cells lacking ZPET/ZNF280C display enhanced homologous recombination, accelerated replication forks under replication stress, and increased resistance to DSBs and PARP inhibition, establishing ZPET as a repressor of homologous recombination.","method":"Loss-of-function (ZPET-depleted cells) with HR frequency assay, replication fork speed measurement (DNA fiber assay), clonogenic survival after DSB-inducing agents and PARP inhibitor treatment","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple defined cellular phenotypes and pharmacological validation in a single rigorous study","pmids":["30567999"],"is_preprint":false},{"year":2022,"finding":"ZNF280C occupies genomic loci marked by H3K27me3 as well as transcriptionally active regions, co-localizes with CTCF and cohesin, counteracts CTCF/cohesin activities to condense chromatin at tumor suppressor gene cis-elements, and recruits the epigenetic repressor SMCHD1 to maintain both focal and broad H3K27me3 levels.","method":"ChIP-seq (ZNF280C, H3K27me3, CTCF, cohesin), ATAC-seq, ZNF280C silencing (RNAi/CRISPRi) with H3K27me3 level quantification, co-immunoprecipitation (ZNF280C–SMCHD1 interaction), xenograft and in vivo colorectal tumorigenesis models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (ChIP-seq, ATAC-seq, Co-IP, KD with defined epigenetic and cellular phenotypes) in a single study","pmids":["35605119"],"is_preprint":false},{"year":2026,"finding":"ZNF280C physically interacts with KMT5C (the H4K20me3 methyltransferase) and localizes specifically at H3K9me3-negative/H4K20me3-positive genomic sites, identifying ZNF280C as a novel binding partner that may recruit KMT5C to non-canonical, non-heterochromatic loci independently of HP1.","method":"Biochemical co-immunoprecipitation/pulldown (ZNF280C–KMT5C interaction), ChIP-seq co-localization analysis (ZNF280C at H3K9me3-/H4K20me3+ sites)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — biochemical interaction + genomic co-localization in a single preprint; not yet peer-reviewed and single lab","pmids":["42182233"],"is_preprint":true}],"current_model":"ZNF280C (ZPET) is a C2H2 zinc finger protein that functions at the nexus of DNA damage response and epigenetic repression: it binds ssDNA at DSBs and stalled forks to inhibit MRE11-mediated resection and suppress homologous recombination; it also acts as a transcription factor that maintains H3K27me3-dependent gene silencing by counteracting CTCF/cohesin and recruiting SMCHD1, thereby sustaining epigenetic repression at tumor suppressor loci; additionally, ZNF280C interacts with the H4K20me3 methyltransferase KMT5C and localizes to non-canonical H4K20me3 sites independent of H3K9me3."},"narrative":{"mechanistic_narrative":"ZNF280C (ZPET) is a C2H2 zinc finger protein operating at the interface of the DNA damage response and chromatin-based gene repression [PMID:30567999, PMID:35605119]. As a single-stranded DNA-binding protein, it localizes to double-strand breaks and stalled replication forks, where it blocks MRE11 association with ssDNA to slow DNA end resection independently of 53BP1 and HELB, thereby acting as a repressor of homologous recombination; its loss elevates HR, accelerates forks under replication stress, and confers resistance to DSB-inducing agents and PARP inhibition [PMID:30567999]. In a parallel chromatin role, ZNF280C occupies H3K27me3-marked loci, co-localizes with and counteracts CTCF/cohesin to condense chromatin at tumor suppressor cis-elements, and recruits SMCHD1 to sustain focal and broad H3K27me3, promoting colorectal tumorigenesis [PMID:35605119]. Beyond these two arms, no unifying mechanism connecting its resection-control and transcriptional-repression activities has been characterized in the available corpus.","teleology":[{"year":2018,"claim":"Established ZNF280C as a direct biochemical regulator of DNA end resection, answering how an ssDNA-binding factor restrains the nuclease step of repair.","evidence":"BioID proximity proteomics, in vitro ssDNA-binding and MRE11-inhibition assays, chromatin fractionation in depleted cells","pmids":["30567999"],"confidence":"High","gaps":["Does not define how ZPET is recruited to or removed from breaks","Structural basis of ssDNA binding and MRE11 competition unresolved"]},{"year":2018,"claim":"Defined the cellular consequence of ZNF280C activity by showing its loss enhances HR and alters fork dynamics, framing it as an HR repressor with therapeutic relevance to PARP inhibition.","evidence":"Loss-of-function with HR assay, DNA fiber assay, clonogenic survival after DSB agents and PARPi","pmids":["30567999"],"confidence":"High","gaps":["Does not address pathway choice regulation at the chromatin level","Relationship to other resection antagonists not delineated"]},{"year":2022,"claim":"Revealed a distinct transcriptional/epigenetic function, showing ZNF280C maintains H3K27me3-dependent silencing by opposing CTCF/cohesin and recruiting SMCHD1 at tumor suppressor loci.","evidence":"ChIP-seq, ATAC-seq, CRISPRi/RNAi with H3K27me3 quantification, Co-IP, xenograft and colorectal tumorigenesis models","pmids":["35605119"],"confidence":"High","gaps":["Mechanism linking DNA-binding to chromatin condensation unclear","Whether DSB and chromatin-repression roles are coupled is unknown"]},{"year":2026,"claim":"Identified a new physical partner (KMT5C) and a non-canonical chromatin context, raising the possibility that ZNF280C directs H4K20me3 deposition outside classical heterochromatin.","evidence":"Co-IP/pulldown and ChIP-seq co-localization at H3K9me3-/H4K20me3+ sites (preprint)","pmids":["42182233"],"confidence":"Medium","gaps":["Single preprint, not peer-reviewed","Functional consequence of KMT5C recruitment not tested","Reciprocal interaction validation lacking"]},{"year":null,"claim":"Whether the resection-control and chromatin-repression functions of ZNF280C reflect one integrated mechanism or two separable activities remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ZNF280C","No unifying model connecting DSB and transcriptional roles","Domain requirements for each function undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[1]}],"complexes":[],"partners":["MRE11","SMCHD1","CTCF","KMT5C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8ND82","full_name":"Zinc finger protein 280C","aliases":["Suppressor of hairy wing homolog 3","Zinc finger protein 633"],"length_aa":737,"mass_kda":83.1,"function":"May function as a transcription factor","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8ND82/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF280C","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUCKS1","stoichiometry":4.0},{"gene":"RAB8B","stoichiometry":4.0},{"gene":"CBX1","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN2","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"PHGDH","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZNF280C","total_profiled":1310},"omim":[{"mim_id":"301166","title":"ZINC FINGER PROTEIN 280C; ZNF280C","url":"https://www.omim.org/entry/301166"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":8.8}],"url":"https://www.proteinatlas.org/search/ZNF280C"},"hgnc":{"alias_symbol":["FLJ20095","ZNF633","ZPET"],"prev_symbol":["SUHW3"]},"alphafold":{"accession":"Q8ND82","domains":[{"cath_id":"-","chopping":"295-514","consensus_level":"high","plddt":85.7431,"start":295,"end":514},{"cath_id":"-","chopping":"622-663","consensus_level":"medium","plddt":83.4345,"start":622,"end":663},{"cath_id":"-","chopping":"680-721","consensus_level":"medium","plddt":81.2898,"start":680,"end":721}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8ND82","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8ND82-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8ND82-F1-predicted_aligned_error_v6.png","plddt_mean":59.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF280C","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF280C"},"sequence":{"accession":"Q8ND82","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8ND82.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8ND82/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8ND82"}},"corpus_meta":[{"pmid":"35323665","id":"PMC_35323665","title":"Can Exercise Training Alter Human Skeletal Muscle DNA Methylation?","date":"2022","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/35323665","citation_count":20,"is_preprint":false},{"pmid":"30567999","id":"PMC_30567999","title":"Localized protein biotinylation at DNA damage sites identifies ZPET, a repressor of homologous recombination.","date":"2018","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/30567999","citation_count":17,"is_preprint":false},{"pmid":"35605119","id":"PMC_35605119","title":"Zinc finger protein 280C contributes to colorectal tumorigenesis by maintaining epigenetic repression at H3K27me3-marked loci.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35605119","citation_count":14,"is_preprint":false},{"pmid":"38412785","id":"PMC_38412785","title":"Human transcriptome array analysis and diffusion tensor imaging in attention-deficit/hyperactivity disorder.","date":"2024","source":"Journal of psychiatric research","url":"https://pubmed.ncbi.nlm.nih.gov/38412785","citation_count":3,"is_preprint":false},{"pmid":"42182233","id":"PMC_42182233","title":"KMT5C-H4K20me3 drives changes in epigenetic landscape independent of H3K9me3.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42182233","citation_count":0,"is_preprint":false},{"pmid":"39834547","id":"PMC_39834547","title":"An investigation of a hemophilia A female with heterozygous intron 22 inversion and skewed X chromosome inactivation.","date":"2025","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39834547","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5229,"output_tokens":1330,"usd":0.017819,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7914,"output_tokens":1864,"usd":0.043085,"stage2_stop_reason":"end_turn"},"total_usd":0.060904,"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\": 2018,\n      \"finding\": \"ZPET/ZNF280C binds single-stranded DNA (ssDNA) and localizes to DNA double-strand breaks (DSBs) and stalled replication forks, where it inhibits MRE11 binding to ssDNA in vitro and delays MRE11 chromatin association after DSB formation in cells, thereby slowing DNA end resection independently of 53BP1 and HELB.\",\n      \"method\": \"Localized protein biotinylation (BioID with RAD18-BirAR118G fusion), in vitro ssDNA-binding assay, in vitro MRE11-inhibition assay, chromatin fractionation, loss-of-function (ZPET-depleted cells) with DNA resection and HR frequency readouts\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods in a single study: in vitro biochemical assays, proximity biotinylation proteomics, cell-based KD with defined molecular phenotypes (resection, HR, fork speed)\",\n      \"pmids\": [\"30567999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cells lacking ZPET/ZNF280C display enhanced homologous recombination, accelerated replication forks under replication stress, and increased resistance to DSBs and PARP inhibition, establishing ZPET as a repressor of homologous recombination.\",\n      \"method\": \"Loss-of-function (ZPET-depleted cells) with HR frequency assay, replication fork speed measurement (DNA fiber assay), clonogenic survival after DSB-inducing agents and PARP inhibitor treatment\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple defined cellular phenotypes and pharmacological validation in a single rigorous study\",\n      \"pmids\": [\"30567999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZNF280C occupies genomic loci marked by H3K27me3 as well as transcriptionally active regions, co-localizes with CTCF and cohesin, counteracts CTCF/cohesin activities to condense chromatin at tumor suppressor gene cis-elements, and recruits the epigenetic repressor SMCHD1 to maintain both focal and broad H3K27me3 levels.\",\n      \"method\": \"ChIP-seq (ZNF280C, H3K27me3, CTCF, cohesin), ATAC-seq, ZNF280C silencing (RNAi/CRISPRi) with H3K27me3 level quantification, co-immunoprecipitation (ZNF280C–SMCHD1 interaction), xenograft and in vivo colorectal tumorigenesis models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (ChIP-seq, ATAC-seq, Co-IP, KD with defined epigenetic and cellular phenotypes) in a single study\",\n      \"pmids\": [\"35605119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZNF280C physically interacts with KMT5C (the H4K20me3 methyltransferase) and localizes specifically at H3K9me3-negative/H4K20me3-positive genomic sites, identifying ZNF280C as a novel binding partner that may recruit KMT5C to non-canonical, non-heterochromatic loci independently of HP1.\",\n      \"method\": \"Biochemical co-immunoprecipitation/pulldown (ZNF280C–KMT5C interaction), ChIP-seq co-localization analysis (ZNF280C at H3K9me3-/H4K20me3+ sites)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — biochemical interaction + genomic co-localization in a single preprint; not yet peer-reviewed and single lab\",\n      \"pmids\": [\"42182233\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ZNF280C (ZPET) is a C2H2 zinc finger protein that functions at the nexus of DNA damage response and epigenetic repression: it binds ssDNA at DSBs and stalled forks to inhibit MRE11-mediated resection and suppress homologous recombination; it also acts as a transcription factor that maintains H3K27me3-dependent gene silencing by counteracting CTCF/cohesin and recruiting SMCHD1, thereby sustaining epigenetic repression at tumor suppressor loci; additionally, ZNF280C interacts with the H4K20me3 methyltransferase KMT5C and localizes to non-canonical H4K20me3 sites independent of H3K9me3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZNF280C (ZPET) is a C2H2 zinc finger protein operating at the interface of the DNA damage response and chromatin-based gene repression [#0, #2]. As a single-stranded DNA-binding protein, it localizes to double-strand breaks and stalled replication forks, where it blocks MRE11 association with ssDNA to slow DNA end resection independently of 53BP1 and HELB, thereby acting as a repressor of homologous recombination; its loss elevates HR, accelerates forks under replication stress, and confers resistance to DSB-inducing agents and PARP inhibition [#0, #1]. In a parallel chromatin role, ZNF280C occupies H3K27me3-marked loci, co-localizes with and counteracts CTCF/cohesin to condense chromatin at tumor suppressor cis-elements, and recruits SMCHD1 to sustain focal and broad H3K27me3, promoting colorectal tumorigenesis [#2]. Beyond these two arms, no unifying mechanism connecting its resection-control and transcriptional-repression activities has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established ZNF280C as a direct biochemical regulator of DNA end resection, answering how an ssDNA-binding factor restrains the nuclease step of repair.\",\n      \"evidence\": \"BioID proximity proteomics, in vitro ssDNA-binding and MRE11-inhibition assays, chromatin fractionation in depleted cells\",\n      \"pmids\": [\"30567999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how ZPET is recruited to or removed from breaks\", \"Structural basis of ssDNA binding and MRE11 competition unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the cellular consequence of ZNF280C activity by showing its loss enhances HR and alters fork dynamics, framing it as an HR repressor with therapeutic relevance to PARP inhibition.\",\n      \"evidence\": \"Loss-of-function with HR assay, DNA fiber assay, clonogenic survival after DSB agents and PARPi\",\n      \"pmids\": [\"30567999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address pathway choice regulation at the chromatin level\", \"Relationship to other resection antagonists not delineated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a distinct transcriptional/epigenetic function, showing ZNF280C maintains H3K27me3-dependent silencing by opposing CTCF/cohesin and recruiting SMCHD1 at tumor suppressor loci.\",\n      \"evidence\": \"ChIP-seq, ATAC-seq, CRISPRi/RNAi with H3K27me3 quantification, Co-IP, xenograft and colorectal tumorigenesis models\",\n      \"pmids\": [\"35605119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking DNA-binding to chromatin condensation unclear\", \"Whether DSB and chromatin-repression roles are coupled is unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a new physical partner (KMT5C) and a non-canonical chromatin context, raising the possibility that ZNF280C directs H4K20me3 deposition outside classical heterochromatin.\",\n      \"evidence\": \"Co-IP/pulldown and ChIP-seq co-localization at H3K9me3-/H4K20me3+ sites (preprint)\",\n      \"pmids\": [\"42182233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single preprint, not peer-reviewed\", \"Functional consequence of KMT5C recruitment not tested\", \"Reciprocal interaction validation lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the resection-control and chromatin-repression functions of ZNF280C reflect one integrated mechanism or two separable activities remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ZNF280C\", \"No unifying model connecting DSB and transcriptional roles\", \"Domain requirements for each function undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MRE11\", \"SMCHD1\", \"CTCF\", \"KMT5C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}