{"gene":"ZNF280A","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2025,"finding":"ZNF280A is recruited to DNA double-strand break (DSB) sites and promotes long-range DNA-end resection by facilitating the recruitment of the BLM-DNA2 helicase-nuclease complex to DSB sites, enhancing the enzymatic activity of this complex at DNA damage sites, thereby enabling homologous recombination repair.","method":"High-throughput microscopy with cDNA 'chromORFeome' library screen, loss-of-function assays, recruitment/localization experiments, epistasis with BLM-DNA2 complex, functional rescue in patient-derived cells from 22q11.2 distal deletion syndrome","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including genome-wide screen, mechanistic epistasis with BLM-DNA2, functional rescue in human disease cells; single study but rigorous and comprehensive","pmids":["40523937"],"is_preprint":false},{"year":2021,"finding":"ZNF280A promotes lung adenocarcinoma cell proliferation, survival, and migration by regulating the expression of EIF3C; EIF3C knockdown in ZNF280A-overexpressing cells attenuates ZNF280A-induced promotion of LUAD, placing EIF3C downstream of ZNF280A.","method":"Loss-of-function (siRNA knockdown), overexpression, gene expression profiling, rescue experiment (EIF3C downregulation in ZNF280A-overexpressed cells), in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple functional methods and epistasis rescue experiment, but mechanistic link between ZNF280A and EIF3C transcription not biochemically defined; single lab","pmids":["33414445"],"is_preprint":false},{"year":2019,"finding":"ZNF280A promotes colorectal cancer cell proliferation by inactivating the Hippo signaling pathway; silencing ZNF280A activates Hippo signaling and induces G0/G1 arrest.","method":"siRNA knockdown, Western blot, luciferase reporter assay for Hippo pathway activity, in vitro proliferation assays, in vivo xenograft","journal":"Molecular therapy oncolytics","confidence":"Medium","confidence_rationale":"Tier 2-3 — luciferase and Western blot provide pathway placement, but upstream mechanism of how ZNF280A inactivates Hippo is not defined; single lab","pmids":["30847384"],"is_preprint":false},{"year":2022,"finding":"ZNF280A knockdown promotes ubiquitination and proteasomal degradation of RPS14 in colorectal cancer cells; RPS14 acts downstream of ZNF280A to regulate CRC progression via the PI3K-Akt signaling pathway.","method":"Loss-of-function (shRNA knockdown), ubiquitination assay, Western blot for RPS14 protein levels, in vitro and in vivo functional assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — ubiquitination assay demonstrates post-translational regulation of RPS14 downstream of ZNF280A, but the E3 ligase mediating ubiquitination is not identified; single lab","pmids":["36059657"],"is_preprint":false},{"year":2025,"finding":"ZNF280A enhances ACRV1 transcription by interacting with the transcription factor CUX2 and facilitating its recruitment to the ACRV1 promoter; elevated ZNF280A or ACRV1 activates PI3K/AKT signaling and increases glycolytic enzyme expression (PKM2 and LDHA), glucose uptake, lactate production, and ATP generation in ovarian cancer cells.","method":"Co-immunoprecipitation (ZNF280A-CUX2 interaction), chromatin recruitment assay (CUX2 to ACRV1 promoter), knockdown/overexpression functional assays, pharmacological inhibition of AKT and glycolysis, in vitro and in vivo assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP identifies ZNF280A-CUX2 interaction and promoter recruitment is demonstrated; single lab but multiple orthogonal methods","pmids":["41338461"],"is_preprint":false},{"year":2025,"finding":"ZNF280A knockdown in malignant melanoma cells inhibits proliferation, migration, and invasion, and promotes apoptosis and cell cycle arrest; the mechanism may involve regulation of p53 expression by ZNF280A.","method":"shRNA knockdown, Western blot for p53, in vitro proliferation/apoptosis/migration assays, in vivo xenograft","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 — p53 link is associative (Western blot only); single lab, limited mechanistic depth","pmids":["40251414"],"is_preprint":false},{"year":2023,"finding":"ZNF280A knockdown in bladder cancer inhibits cell proliferation and migration, and promotes apoptosis; ZNF280A may promote bladder cancer through regulation of MAPK9, Cyclin D1, and the Akt pathway.","method":"shRNA lentiviral knockdown, MTT assay, flow cytometry, wound healing, Transwell, Western blotting, Human Apoptosis Antibody Microarray, mouse xenograft","journal":"Histology and histopathology","confidence":"Low","confidence_rationale":"Tier 3 — pathway placement based on Western blot association without mechanistic dissection; single lab","pmids":["37345848"],"is_preprint":false},{"year":2023,"finding":"ZNF280A is identified as a transcriptional target upregulated by the preimplantation transcription factor LEUTX, which acts through cis-regulatory sequences overlapping repetitive elements.","method":"Proteomics, genome-wide sequencing (multiomics), LEUTX overexpression with transcriptome profiling","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 — ZNF280A identified as a downstream target gene of LEUTX; no direct mechanistic characterization of ZNF280A itself","pmids":["36876139"],"is_preprint":false}],"current_model":"ZNF280A is a chromatin-associated zinc finger protein that functions primarily in DNA double-strand break repair by promoting long-range DNA-end resection through recruitment of the BLM-DNA2 helicase-nuclease complex to break sites; in cancer contexts, it also acts as a transcriptional regulator that drives tumor cell proliferation and survival by modulating downstream effectors including EIF3C, RPS14 (via ubiquitination control), ACRV1 (via CUX2 co-recruitment to promoters), and the Hippo and PI3K-AKT signaling pathways."},"narrative":{"teleology":[{"year":2019,"claim":"The first functional characterization of ZNF280A established that it promotes cell proliferation in colorectal cancer by inactivating the Hippo signaling pathway, revealing it as a pro-proliferative factor linked to a defined developmental signaling cascade.","evidence":"siRNA knockdown, Hippo pathway luciferase reporter, Western blot, xenograft assays in CRC cells","pmids":["30847384"],"confidence":"Medium","gaps":["Mechanism by which ZNF280A inactivates Hippo signaling is undefined","Direct binding to Hippo pathway components not tested","Single-lab observation in one cancer type"]},{"year":2021,"claim":"Epistasis experiments placed EIF3C as a functional mediator downstream of ZNF280A in lung adenocarcinoma, suggesting ZNF280A acts as a transcriptional regulator controlling translation machinery components.","evidence":"ZNF280A overexpression and EIF3C knockdown rescue, gene expression profiling, in vitro and in vivo assays in LUAD cells","pmids":["33414445"],"confidence":"Medium","gaps":["Whether ZNF280A directly binds the EIF3C promoter is not determined","Biochemical mechanism linking ZNF280A to EIF3C transcription is missing","Specificity of ZNF280A transcriptional targets not addressed genome-wide"]},{"year":2022,"claim":"ZNF280A was shown to stabilize RPS14 protein by preventing its ubiquitin-dependent proteasomal degradation, connecting ZNF280A to post-translational protein quality control and PI3K-AKT pathway activation in colorectal cancer.","evidence":"shRNA knockdown, ubiquitination assay, Western blot for RPS14 levels, functional assays in CRC cells","pmids":["36059657"],"confidence":"Medium","gaps":["The E3 ubiquitin ligase responsible for RPS14 ubiquitination is not identified","Whether ZNF280A acts directly on ubiquitination machinery or indirectly through transcriptional regulation is unknown","Single-lab finding in CRC"]},{"year":2025,"claim":"A genome-wide screen identified ZNF280A as a DSB-recruited factor that promotes long-range DNA-end resection through recruitment and activation of the BLM-DNA2 complex, establishing its primary molecular function in homologous recombination repair and linking its loss to the 22q11.2 distal deletion syndrome.","evidence":"High-throughput microscopy cDNA screen (chromORFeome), loss-of-function/epistasis with BLM-DNA2, functional rescue in patient-derived cells, multiple orthogonal assays","pmids":["40523937"],"confidence":"High","gaps":["Structural basis of ZNF280A interaction with BLM-DNA2 is not resolved","Whether ZNF280A zinc fingers directly engage DNA or protein interfaces at break sites is unknown","Contribution of ZNF280A loss to the clinical phenotype of 22q11.2 distal deletion syndrome beyond cellular DNA repair defects is not established"]},{"year":2025,"claim":"ZNF280A was shown to physically interact with the transcription factor CUX2 and facilitate its recruitment to the ACRV1 promoter, providing the first direct evidence of ZNF280A acting as a transcriptional co-activator at a specific genomic locus and linking this to PI3K/AKT-driven glycolytic reprogramming.","evidence":"Reciprocal co-immunoprecipitation of ZNF280A-CUX2, chromatin recruitment assay at ACRV1 promoter, AKT inhibition, glycolysis measurements in ovarian cancer cells","pmids":["41338461"],"confidence":"Medium","gaps":["Whether ZNF280A-CUX2 co-regulation extends beyond ACRV1 to other loci is unknown","DNA-binding specificity of ZNF280A itself has not been characterized","Relationship between ZNF280A's DNA repair and transcriptional functions is unexplored"]},{"year":null,"claim":"How ZNF280A coordinates its dual roles in DSB repair (BLM-DNA2 recruitment) and transcriptional regulation (CUX2 co-activation, EIF3C/RPS14 control) remains unresolved, and no structural or genome-wide binding data define its DNA recognition specificity or full target repertoire.","evidence":"","pmids":[],"confidence":"Low","gaps":["No ChIP-seq or structural data for ZNF280A DNA-binding specificity","Separation-of-function between DNA repair and transcriptional roles not tested","No interactome study beyond BLM-DNA2 and CUX2"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,4]}],"complexes":[],"partners":["BLM","DNA2","CUX2","EIF3C","RPS14"],"other_free_text":[]},"mechanistic_narrative":"ZNF280A is a chromatin-associated zinc finger protein that functions in DNA double-strand break (DSB) repair and transcriptional regulation. At DSB sites, ZNF280A promotes long-range DNA-end resection by recruiting the BLM-DNA2 helicase-nuclease complex and enhancing its enzymatic activity, thereby enabling homologous recombination repair [PMID:40523937]. ZNF280A also acts as a transcriptional co-regulator: it interacts with the transcription factor CUX2 to drive ACRV1 promoter activation and PI3K/AKT-dependent glycolytic reprogramming [PMID:41338461], upregulates EIF3C to promote lung adenocarcinoma cell proliferation [PMID:33414445], stabilizes RPS14 protein by suppressing its ubiquitin-dependent degradation to sustain PI3K-AKT signaling in colorectal cancer [PMID:36059657], and inactivates the Hippo signaling pathway to promote colorectal cancer cell cycle progression [PMID:30847384]."},"prefetch_data":{"uniprot":{"accession":"P59817","full_name":"Zinc finger protein 280A","aliases":["3'OY11.1","Suppressor of hairy wing homolog 1","Zinc finger protein 636"],"length_aa":542,"mass_kda":60.6,"function":"May function as a transcription factor","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P59817/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF280A","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZNF280A","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"adrenal gland","ntpm":1.3}],"url":"https://www.proteinatlas.org/search/ZNF280A"},"hgnc":{"alias_symbol":["3'OY11.1","ZNF636"],"prev_symbol":["ZNF280","SUHW1"]},"alphafold":{"accession":"P59817","domains":[{"cath_id":"-","chopping":"283-478","consensus_level":"high","plddt":89.8712,"start":283,"end":478}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P59817","model_url":"https://alphafold.ebi.ac.uk/files/AF-P59817-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P59817-F1-predicted_aligned_error_v6.png","plddt_mean":59.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF280A","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF280A"},"sequence":{"accession":"P59817","fasta_url":"https://rest.uniprot.org/uniprotkb/P59817.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P59817/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P59817"}},"corpus_meta":[{"pmid":"18984860","id":"PMC_18984860","title":"Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18984860","citation_count":137,"is_preprint":false},{"pmid":"19027161","id":"PMC_19027161","title":"Array CGH analysis of chronic lymphocytic leukemia reveals frequent cryptic monoallelic and biallelic deletions of chromosome 22q11 that include the PRAME gene.","date":"2008","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/19027161","citation_count":44,"is_preprint":false},{"pmid":"33414445","id":"PMC_33414445","title":"ZNF280A promotes lung adenocarcinoma development by regulating the expression of EIF3C.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33414445","citation_count":22,"is_preprint":false},{"pmid":"30847384","id":"PMC_30847384","title":"ZNF280A Promotes Proliferation and Tumorigenicity via Inactivating the Hippo-Signaling Pathway in Colorectal Cancer.","date":"2019","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/30847384","citation_count":15,"is_preprint":false},{"pmid":"36876139","id":"PMC_36876139","title":"Comprehensive characterization of the embryonic factor LEUTX.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36876139","citation_count":13,"is_preprint":false},{"pmid":"36059657","id":"PMC_36059657","title":"Downregulation of ZNF280A inhibits proliferation and tumorigenicity of colorectal cancer cells by promoting the ubiquitination and degradation of RPS14.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36059657","citation_count":9,"is_preprint":false},{"pmid":"40523937","id":"PMC_40523937","title":"ZNF280A links DNA double-strand break repair to human 22q11.2 distal deletion syndrome.","date":"2025","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/40523937","citation_count":3,"is_preprint":false},{"pmid":"37345848","id":"PMC_37345848","title":"Knockdown of ZNF280A inhibits cell proliferation and promotes cell apoptosis of bladder cancer.","date":"2023","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/37345848","citation_count":3,"is_preprint":false},{"pmid":"40514799","id":"PMC_40514799","title":"ZNF280AY: a pseudogene on the ovine Y chromosome and its copy number variation associated with testicular size in Hu sheep.","date":"2025","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/40514799","citation_count":1,"is_preprint":false},{"pmid":"40251414","id":"PMC_40251414","title":"ZNF280A promotes malignant melanoma development through regulating cell proliferation, apoptosis, and cell cycle.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40251414","citation_count":0,"is_preprint":false},{"pmid":"41338461","id":"PMC_41338461","title":"ZNF280A and ACRV1 enhance aerobic glycolysis and drive ovarian cancer progression via the PI3K/AKT signaling pathway.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41338461","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6387,"output_tokens":1989,"usd":0.024498},"stage2":{"model":"claude-opus-4-6","input_tokens":5261,"output_tokens":1921,"usd":0.111495},"total_usd":0.135993,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF280A is recruited to DNA double-strand break (DSB) sites and promotes long-range DNA-end resection by facilitating the recruitment of the BLM-DNA2 helicase-nuclease complex to DSB sites, enhancing the enzymatic activity of this complex at DNA damage sites, thereby enabling homologous recombination repair.\",\n      \"method\": \"High-throughput microscopy with cDNA 'chromORFeome' library screen, loss-of-function assays, recruitment/localization experiments, epistasis with BLM-DNA2 complex, functional rescue in patient-derived cells from 22q11.2 distal deletion syndrome\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including genome-wide screen, mechanistic epistasis with BLM-DNA2, functional rescue in human disease cells; single study but rigorous and comprehensive\",\n      \"pmids\": [\"40523937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZNF280A promotes lung adenocarcinoma cell proliferation, survival, and migration by regulating the expression of EIF3C; EIF3C knockdown in ZNF280A-overexpressing cells attenuates ZNF280A-induced promotion of LUAD, placing EIF3C downstream of ZNF280A.\",\n      \"method\": \"Loss-of-function (siRNA knockdown), overexpression, gene expression profiling, rescue experiment (EIF3C downregulation in ZNF280A-overexpressed cells), in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple functional methods and epistasis rescue experiment, but mechanistic link between ZNF280A and EIF3C transcription not biochemically defined; single lab\",\n      \"pmids\": [\"33414445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZNF280A promotes colorectal cancer cell proliferation by inactivating the Hippo signaling pathway; silencing ZNF280A activates Hippo signaling and induces G0/G1 arrest.\",\n      \"method\": \"siRNA knockdown, Western blot, luciferase reporter assay for Hippo pathway activity, in vitro proliferation assays, in vivo xenograft\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — luciferase and Western blot provide pathway placement, but upstream mechanism of how ZNF280A inactivates Hippo is not defined; single lab\",\n      \"pmids\": [\"30847384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZNF280A knockdown promotes ubiquitination and proteasomal degradation of RPS14 in colorectal cancer cells; RPS14 acts downstream of ZNF280A to regulate CRC progression via the PI3K-Akt signaling pathway.\",\n      \"method\": \"Loss-of-function (shRNA knockdown), ubiquitination assay, Western blot for RPS14 protein levels, in vitro and in vivo functional assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ubiquitination assay demonstrates post-translational regulation of RPS14 downstream of ZNF280A, but the E3 ligase mediating ubiquitination is not identified; single lab\",\n      \"pmids\": [\"36059657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF280A enhances ACRV1 transcription by interacting with the transcription factor CUX2 and facilitating its recruitment to the ACRV1 promoter; elevated ZNF280A or ACRV1 activates PI3K/AKT signaling and increases glycolytic enzyme expression (PKM2 and LDHA), glucose uptake, lactate production, and ATP generation in ovarian cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (ZNF280A-CUX2 interaction), chromatin recruitment assay (CUX2 to ACRV1 promoter), knockdown/overexpression functional assays, pharmacological inhibition of AKT and glycolysis, in vitro and in vivo assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP identifies ZNF280A-CUX2 interaction and promoter recruitment is demonstrated; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41338461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF280A knockdown in malignant melanoma cells inhibits proliferation, migration, and invasion, and promotes apoptosis and cell cycle arrest; the mechanism may involve regulation of p53 expression by ZNF280A.\",\n      \"method\": \"shRNA knockdown, Western blot for p53, in vitro proliferation/apoptosis/migration assays, in vivo xenograft\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — p53 link is associative (Western blot only); single lab, limited mechanistic depth\",\n      \"pmids\": [\"40251414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZNF280A knockdown in bladder cancer inhibits cell proliferation and migration, and promotes apoptosis; ZNF280A may promote bladder cancer through regulation of MAPK9, Cyclin D1, and the Akt pathway.\",\n      \"method\": \"shRNA lentiviral knockdown, MTT assay, flow cytometry, wound healing, Transwell, Western blotting, Human Apoptosis Antibody Microarray, mouse xenograft\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement based on Western blot association without mechanistic dissection; single lab\",\n      \"pmids\": [\"37345848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZNF280A is identified as a transcriptional target upregulated by the preimplantation transcription factor LEUTX, which acts through cis-regulatory sequences overlapping repetitive elements.\",\n      \"method\": \"Proteomics, genome-wide sequencing (multiomics), LEUTX overexpression with transcriptome profiling\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ZNF280A identified as a downstream target gene of LEUTX; no direct mechanistic characterization of ZNF280A itself\",\n      \"pmids\": [\"36876139\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF280A is a chromatin-associated zinc finger protein that functions primarily in DNA double-strand break repair by promoting long-range DNA-end resection through recruitment of the BLM-DNA2 helicase-nuclease complex to break sites; in cancer contexts, it also acts as a transcriptional regulator that drives tumor cell proliferation and survival by modulating downstream effectors including EIF3C, RPS14 (via ubiquitination control), ACRV1 (via CUX2 co-recruitment to promoters), and the Hippo and PI3K-AKT signaling pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZNF280A is a chromatin-associated zinc finger protein that functions in DNA double-strand break (DSB) repair and transcriptional regulation. At DSB sites, ZNF280A promotes long-range DNA-end resection by recruiting the BLM-DNA2 helicase-nuclease complex and enhancing its enzymatic activity, thereby enabling homologous recombination repair [PMID:40523937]. ZNF280A also acts as a transcriptional co-regulator: it interacts with the transcription factor CUX2 to drive ACRV1 promoter activation and PI3K/AKT-dependent glycolytic reprogramming [PMID:41338461], upregulates EIF3C to promote lung adenocarcinoma cell proliferation [PMID:33414445], stabilizes RPS14 protein by suppressing its ubiquitin-dependent degradation to sustain PI3K-AKT signaling in colorectal cancer [PMID:36059657], and inactivates the Hippo signaling pathway to promote colorectal cancer cell cycle progression [PMID:30847384].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"The first functional characterization of ZNF280A established that it promotes cell proliferation in colorectal cancer by inactivating the Hippo signaling pathway, revealing it as a pro-proliferative factor linked to a defined developmental signaling cascade.\",\n      \"evidence\": \"siRNA knockdown, Hippo pathway luciferase reporter, Western blot, xenograft assays in CRC cells\",\n      \"pmids\": [\"30847384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which ZNF280A inactivates Hippo signaling is undefined\",\n        \"Direct binding to Hippo pathway components not tested\",\n        \"Single-lab observation in one cancer type\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Epistasis experiments placed EIF3C as a functional mediator downstream of ZNF280A in lung adenocarcinoma, suggesting ZNF280A acts as a transcriptional regulator controlling translation machinery components.\",\n      \"evidence\": \"ZNF280A overexpression and EIF3C knockdown rescue, gene expression profiling, in vitro and in vivo assays in LUAD cells\",\n      \"pmids\": [\"33414445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ZNF280A directly binds the EIF3C promoter is not determined\",\n        \"Biochemical mechanism linking ZNF280A to EIF3C transcription is missing\",\n        \"Specificity of ZNF280A transcriptional targets not addressed genome-wide\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ZNF280A was shown to stabilize RPS14 protein by preventing its ubiquitin-dependent proteasomal degradation, connecting ZNF280A to post-translational protein quality control and PI3K-AKT pathway activation in colorectal cancer.\",\n      \"evidence\": \"shRNA knockdown, ubiquitination assay, Western blot for RPS14 levels, functional assays in CRC cells\",\n      \"pmids\": [\"36059657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The E3 ubiquitin ligase responsible for RPS14 ubiquitination is not identified\",\n        \"Whether ZNF280A acts directly on ubiquitination machinery or indirectly through transcriptional regulation is unknown\",\n        \"Single-lab finding in CRC\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A genome-wide screen identified ZNF280A as a DSB-recruited factor that promotes long-range DNA-end resection through recruitment and activation of the BLM-DNA2 complex, establishing its primary molecular function in homologous recombination repair and linking its loss to the 22q11.2 distal deletion syndrome.\",\n      \"evidence\": \"High-throughput microscopy cDNA screen (chromORFeome), loss-of-function/epistasis with BLM-DNA2, functional rescue in patient-derived cells, multiple orthogonal assays\",\n      \"pmids\": [\"40523937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of ZNF280A interaction with BLM-DNA2 is not resolved\",\n        \"Whether ZNF280A zinc fingers directly engage DNA or protein interfaces at break sites is unknown\",\n        \"Contribution of ZNF280A loss to the clinical phenotype of 22q11.2 distal deletion syndrome beyond cellular DNA repair defects is not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ZNF280A was shown to physically interact with the transcription factor CUX2 and facilitate its recruitment to the ACRV1 promoter, providing the first direct evidence of ZNF280A acting as a transcriptional co-activator at a specific genomic locus and linking this to PI3K/AKT-driven glycolytic reprogramming.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation of ZNF280A-CUX2, chromatin recruitment assay at ACRV1 promoter, AKT inhibition, glycolysis measurements in ovarian cancer cells\",\n      \"pmids\": [\"41338461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ZNF280A-CUX2 co-regulation extends beyond ACRV1 to other loci is unknown\",\n        \"DNA-binding specificity of ZNF280A itself has not been characterized\",\n        \"Relationship between ZNF280A's DNA repair and transcriptional functions is unexplored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZNF280A coordinates its dual roles in DSB repair (BLM-DNA2 recruitment) and transcriptional regulation (CUX2 co-activation, EIF3C/RPS14 control) remains unresolved, and no structural or genome-wide binding data define its DNA recognition specificity or full target repertoire.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No ChIP-seq or structural data for ZNF280A DNA-binding specificity\",\n        \"Separation-of-function between DNA repair and transcriptional roles not tested\",\n        \"No interactome study beyond BLM-DNA2 and CUX2\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"BLM\",\n      \"DNA2\",\n      \"CUX2\",\n      \"EIF3C\",\n      \"RPS14\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}