{"gene":"ZC3H4","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2021,"finding":"ZC3H4 depletion causes upregulation and extension of hundreds of unstable non-coding transcripts (particularly antisense RNAs and enhancer RNAs from super-enhancers), and ZC3H4 occupies these loci, indicating a direct role in restricting non-coding transcription. Engineered tethering of ZC3H4 to reporter RNA promotes its degradation by the nuclear exosome. ZC3H4 loss also causes a substantial reduction in cell proliferation.","method":"siRNA knockdown with nascent RNA sequencing, ChIP/occupancy analysis, reporter tethering assay, cell proliferation assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD + genome-wide RNA-seq + ChIP + tethering assay) in a single rigorous study establishing direct occupancy and function","pmids":["33913806"],"is_preprint":false},{"year":2023,"finding":"ZC3H4 forms a 'Restrictor' complex with WDR82 and ARS2, and additionally associates with the nuclear exosome targeting (NEXT) complex. The domains of ZC3H4 that contact ARS2 and WDR82 are required for ncRNA restriction. Restrictor co-transcriptionally controls an overlapping population of ncRNAs, and its function is enabled by PNUTS. U1 snRNA shields protein-coding transcripts from Restrictor and PNUTS at hundreds of genes.","method":"Co-immunoprecipitation, domain mutagenesis, nascent RNA sequencing, genetic depletion experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, genome-wide nascent RNA-seq, multiple orthogonal methods in one study replicated across two concurrent papers","pmids":["37329883"],"is_preprint":false},{"year":2023,"finding":"A conserved basic domain of ARS2 binds a conserved acidic-rich short linear motif (SLiM) in ZC3H4. This interaction recruits ZC3H4 to chromatin to elicit RNAPII termination, independent of CPA and Integrator pathways. ZC3H4 in turn forms a direct connection to the NEXT complex to facilitate rapid degradation of the nascent RNA, coupling transcription termination to RNA decay.","method":"Biochemical binding assays, domain mapping, chromatin immunoprecipitation, nascent RNA sequencing upon depletion","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding mapped to specific SLiM/domain, multiple orthogonal methods, replicated concurrently with PMID 37329883","pmids":["37329882"],"is_preprint":false},{"year":2024,"finding":"ZC3H4/WDR82 (Restrictor) co-purifies with PP1 phosphatase and its nuclear targeting subunit PNUTS, which binds directly to WDR82. AlphaFold predicts a quaternary PPWZ complex. A dominant-negative PP1 H66K-PNUTS substrate trap inhibits antisense transcription termination and CTD Ser5 dephosphorylation, and these activities require the PNUTS-WDR82 binding domain. CTD Ser5 hyperphosphorylation is associated with higher RNAPII processivity, suggesting PP1-mediated Ser5 dephosphorylation by PPWZ is coupled to termination.","method":"Co-purification/mass spectrometry, AlphaFold structural prediction, dominant-negative PP1 substrate trap, nascent RNA sequencing, CTD phosphorylation analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical co-purification, structural modelling, dominant-negative functional assay; preprint, single lab","pmids":["bio_10.1101_2024.07.12.603302"],"is_preprint":true},{"year":2025,"finding":"ZC3H4 deficiency leads to increased replication stress, R-loop formation, and transcription-replication conflicts (TRCs) at ncRNA loci, causing DNA damage, abnormal mitosis, and cellular senescence. ZC3H4 preferentially binds genomic regions prone to TRCs and R loops, where it suppresses ncRNA bursts, thereby safeguarding genome integrity.","method":"ZC3H4 knockout/depletion, super-resolution microscopy, biochemical analysis, bioinformatic analysis of binding sites, DNA damage and senescence assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with multiple defined phenotypic readouts (DNA damage, RS, R-loops, TRCs, mitosis, senescence) combined with genome-wide binding analysis and microscopy","pmids":["40531993"],"is_preprint":false},{"year":2025,"finding":"The Restrictor complex (ZC3H4/WDR82) promiscuously suppresses early RNAPII elongation genome-wide, but this activity is blocked at most mRNAs by the presence of a 5′ splice site. Restrictor reduces the rate of transcription elongation rather than directly terminating RNAPII, rendering it susceptible to termination by other machineries. Restrictor is a critical determinant of transcription directionality at divergent promoters and prevents transcriptional interference.","method":"Unbiased sequence screens, rapid protein degradation (degron), nascent RNA sequencing (TT-seq/PRO-seq), splicing mutant analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rapid degron depletion with genome-wide nascent RNA-seq and mechanistic dissection; preprint, single lab","pmids":["bio_10.1101_2025.01.08.631787"],"is_preprint":true},{"year":2021,"finding":"ZC3H4 is essential for early mouse embryogenesis: homozygous mutant embryos are lost by E7.5, fail to hatch or form inner cell mass colonies, display severe DNA breaks, reduced cell proliferation, and compromised epiblast and primitive endoderm specification.","method":"In vivo mouse knockout, blastocyst outgrowth assay, immunofluorescence for lineage markers, DNA damage assay (γH2AX), ROS measurement","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with multiple orthogonal cellular and developmental phenotypic readouts","pmids":["33246328"],"is_preprint":false},{"year":2025,"finding":"ZC3H4 ablation in prostate stromal cells phenocopies mitochondrial Complex I inhibition, causing elevated mitochondrial superoxide (mtROS), altered mitochondrial membrane potential, abnormal mitochondrial morphology, altered NAD+/NADH ratio, and reduced Complex I function, in addition to altered cell-matrix adhesion, fibronectin upregulation, anoikis resistance, and stress-induced premature senescence.","method":"CRISPR/Cas9 ablation, mitochondrial function assays (mtROS, membrane potential, NAD+/NADH, CI activity), cell adhesion/anoikis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with multiple phenotypic readouts in a single lab study; mechanistic link to Complex I is correlative","pmids":["41120279"],"is_preprint":false},{"year":2025,"finding":"HPV16 E2 protein recruits ZC3H4 in a BRD4-dependent manner to specifically activate the HPV16 late promoter P670. ZC3H4 and E2 co-localize in cells with high P670 activity, and ZC3H4 knockdown in differentiated HPV16- or HPV31-positive cells reduces late viral transcripts in an E2-BRD4-dependent manner. Knockdown of ZC3H4 does not increase viral antisense (uaRNA) transcripts, indicating ZC3H4 enhances late transcription independently of antisense suppression.","method":"Biotin proximity ligation screen, reporter assay, co-localization (immunofluorescence), siRNA knockdown, RT-qPCR","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proximity ligation + reporter assay + co-localization + KD, multiple methods but no direct biochemical reconstitution","pmids":["40801544"],"is_preprint":false},{"year":2020,"finding":"The transcription factor ELK-1 acts at the ZC3H4 promoter to transcriptionally upregulate ZC3H4 expression in response to SiO2-induced oxidative stress, placing ELK-1 upstream of ZC3H4 in the silica-EMT signaling axis.","method":"Promoter reporter assay, ChIP, siRNA knockdown, Western blotting","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — promoter reporter and ChIP demonstrating direct ELK-1 binding to ZC3H4 promoter, single lab","pmids":["32218530"],"is_preprint":false},{"year":2022,"finding":"ZC3H4 activates fibroblasts via the sigmar1/ER stress pathway; specific knockdown of ZC3H4 attenuates SiO2-induced fibroblast activation (COL1A1, COL3A1, ACTA1 expression) and migration. ER stress blockade also inhibits ZC3H4 expression, demonstrating a positive feedback loop between ER stress and ZC3H4.","method":"CRISPR/Cas9 knockdown, ER stress inhibitor treatment, Western blotting, scratch/3D migration assay","journal":"Toxicology and applied pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, CRISPR KD plus pharmacological inhibition but no direct molecular interaction demonstrated","pmids":["34979141"],"is_preprint":false},{"year":2022,"finding":"ZC3H4 knockdown in SiO2-exposed monocytes reduces ZC3H4-induced autophagy, which in turn reverses ZC3H4-mediated downregulation of IL-10 secretion. IL-10 from infiltrating monocytes inhibits fibroblast activation and migration, attenuating pulmonary fibrosis.","method":"CRISPR/Cas9 knockdown, ELISA, Western blotting, cell functional assays","journal":"Respiratory research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional assays without direct biochemical mechanism for ZC3H4-autophagy link","pmids":["35962397"],"is_preprint":false},{"year":2023,"finding":"ZC3H4 governs SiO2-induced epithelial cell migration through the ROCK/p-PYK2/p-MLC2 signaling pathway, as demonstrated by CRISPR/Cas9 knockdown of ZC3H4 and pathway inhibitor experiments.","method":"CRISPR/Cas9 knockdown, pathway inhibitors (ROCK, PYK2, MLC2), 2D migration assay, Western blotting","journal":"Environmental toxicology and pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological inhibitors combined with KD but no direct molecular interaction established","pmids":["37866415"],"is_preprint":false}],"current_model":"ZC3H4 is an RNA-binding CCCH zinc finger protein that forms the core of the 'Restrictor' complex (with WDR82 and ARS2), which is recruited co-transcriptionally to chromatin to suppress early RNAPII elongation and promote premature termination at non-coding RNA loci genome-wide; it does so by slowing elongation rate (rendering RNAPII susceptible to termination by other factors), coupling to NEXT complex-mediated nuclear exosome degradation of the nascent RNA, and working together with PP1-PNUTS to dephosphorylate CTD Ser5—while mRNA-coding genes are protected from Restrictor activity by 5′ splice sites; loss of ZC3H4 causes R-loop accumulation, transcription-replication conflicts, DNA damage, and genome instability, and is essential for early mammalian embryogenesis."},"narrative":{"mechanistic_narrative":"ZC3H4 is an RNA-binding CCCH zinc finger protein that suppresses pervasive non-coding transcription genome-wide, restricting unstable antisense and enhancer-derived RNAs while coupling premature transcription termination to RNA decay [PMID:33913806, PMID:37329883]. It forms the core of the 'Restrictor' complex with WDR82 and ARS2, where a conserved acidic short linear motif in ZC3H4 is engaged by a basic domain of ARS2 to recruit ZC3H4 to chromatin and elicit RNAPII termination independently of the CPA and Integrator pathways; ZC3H4 in turn connects directly to the NEXT complex to drive rapid nuclear-exosome degradation of the nascent transcript [PMID:37329883, PMID:37329882]. Mechanistically, Restrictor reduces the rate of RNAPII elongation rather than terminating polymerase itself, rendering it susceptible to termination by other machineries, and acts together with PP1 phosphatase and its nuclear targeting subunit PNUTS (which binds WDR82) to dephosphorylate the RNAPII CTD at Ser5 [PMID:bio_10.1101_2024.07.12.603302, PMID:bio_10.1101_2025.01.08.631787]. Protein-coding genes are shielded from this activity by the presence of a 5' splice site / U1 snRNA, so Restrictor enforces transcription directionality at divergent promoters and prevents transcriptional interference [PMID:37329883, PMID:bio_10.1101_2025.01.08.631787]. By suppressing ncRNA bursts at loci prone to transcription-replication conflicts, ZC3H4 limits R-loop formation, replication stress, and DNA damage, and its loss causes abnormal mitosis, senescence, and genome instability [PMID:40531993]; ZC3H4 is essential for early mouse embryogenesis, with knockouts displaying severe DNA breaks and failed lineage specification [PMID:33246328].","teleology":[{"year":2021,"claim":"Established that ZC3H4 is a direct, locus-occupying restrictor of pervasive non-coding transcription, answering whether it acts on RNA at chromatin or post-transcriptionally elsewhere.","evidence":"siRNA knockdown with nascent RNA-seq, ChIP occupancy, and reporter tethering coupling ZC3H4 to nuclear-exosome degradation in human cells","pmids":["33913806"],"confidence":"High","gaps":["Did not define ZC3H4's protein partners or how it is recruited to chromatin","Mechanism of termination versus elongation control not resolved"]},{"year":2021,"claim":"Demonstrated the physiological essentiality of ZC3H4, showing its ncRNA-restriction function is required for viable early development.","evidence":"in vivo mouse knockout with blastocyst outgrowth, lineage-marker immunofluorescence, and γH2AX DNA-damage readouts","pmids":["33246328"],"confidence":"High","gaps":["Did not connect embryonic DNA damage mechanistically to transcription restriction","No molecular partners assayed in the embryo"]},{"year":2023,"claim":"Defined the Restrictor complex and its recruitment logic, answering how ZC3H4 is targeted to chromatin and links termination to decay.","evidence":"reciprocal Co-IP, domain mutagenesis and SLiM/domain mapping (ZC3H4 acidic motif to ARS2 basic domain), plus nascent RNA-seq, across two concurrent studies; U1 snRNA shown to shield mRNAs","pmids":["37329883","37329882"],"confidence":"High","gaps":["Did not establish the enzymatic step ZC3H4 itself catalyzes","How U1/5' splice site mechanistically antagonizes Restrictor not fully resolved"]},{"year":2024,"claim":"Linked Restrictor to CTD dephosphorylation, addressing how slowed elongation/termination is enforced biochemically.","evidence":"co-purification/MS, AlphaFold prediction of a PP1-PNUTS-WDR82-ZC3H4 (PPWZ) complex, and a dominant-negative PP1 substrate trap with CTD Ser5 phosphorylation analysis (preprint)","pmids":["bio_10.1101_2024.07.12.603302"],"confidence":"Medium","gaps":["Preprint, single lab","Causal ordering of Ser5 dephosphorylation versus termination not fully resolved","Structural model is predicted, not experimentally determined"]},{"year":2025,"claim":"Resolved the kinetic mechanism, showing Restrictor slows elongation rather than directly terminating RNAPII and governs promoter directionality.","evidence":"rapid degron depletion with TT-seq/PRO-seq, unbiased sequence screens, and splicing-mutant analysis (preprint)","pmids":["bio_10.1101_2025.01.08.631787"],"confidence":"Medium","gaps":["Preprint, single lab","Identity of the downstream termination machinery acting on slowed RNAPII not defined"]},{"year":2025,"claim":"Connected ZC3H4 ncRNA restriction to genome stability, explaining the DNA-damage phenotypes via transcription-replication conflicts.","evidence":"knockout/depletion with super-resolution microscopy, genome-wide binding analysis, and DNA-damage/senescence assays","pmids":["40531993"],"confidence":"High","gaps":["Does not establish whether R-loop accumulation is a direct or indirect consequence of ncRNA bursts","Relationship between mitotic abnormalities and specific TRC sites not mapped"]},{"year":2025,"claim":"Reported context-specific, possibly non-canonical ZC3H4 roles in mitochondrial function and viral transcription that diverge from antisense suppression.","evidence":"CRISPR ablation with mitochondrial assays in prostate stromal cells, and proximity ligation/reporter/co-localization/KD showing HPV16 E2-BRD4-dependent recruitment to activate the late promoter P670","pmids":["41120279","40801544"],"confidence":"Medium","gaps":["Mitochondrial Complex I link is correlative, not mechanistic","Viral late-promoter activation lacks biochemical reconstitution","How these roles relate to canonical Restrictor activity is unknown"]},{"year":null,"claim":"How ZC3H4/Restrictor mechanistically distinguishes coding from non-coding nascent RNA in real time, and the precise enzymatic contribution of ZC3H4 itself, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the assembled Restrictor/PPWZ complex on RNAPII","ZC3H4's own catalytic activity, if any, undefined","Quantitative model coupling elongation slowing, Ser5 dephosphorylation, and exosome handoff not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,2,4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]}],"complexes":["Restrictor (ZC3H4-WDR82-ARS2)","NEXT complex (association)","PPWZ (PP1-PNUTS-WDR82-ZC3H4)"],"partners":["WDR82","ARS2","PNUTS","PP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UPT8","full_name":"Zinc finger CCCH domain-containing protein 4","aliases":[],"length_aa":1303,"mass_kda":140.3,"function":"RNA-binding protein that suppresses transcription of long non-coding RNAs (lncRNAs) (PubMed:33767452, PubMed:33913806). LncRNAs are defined as transcripts more than 200 nucleotides that are not translated into protein (PubMed:33767452, PubMed:33913806). Together with WDR82, part of a transcription termination checkpoint that promotes transcription termination of lncRNAs and their subsequent degradation by the exosome (PubMed:33767452, PubMed:33913806). The transcription termination checkpoint is activated by the inefficiently spliced first exon of lncRNAs (PubMed:33767452)","subcellular_location":"Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9UPT8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZC3H4","classification":"Not Classified","n_dependent_lines":111,"n_total_lines":1208,"dependency_fraction":0.09188741721854304},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CFAP298","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"HNRNPL","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"SUPT5H","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZC3H4","total_profiled":1310},"omim":[{"mim_id":"619498","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 4; ZC3H4","url":"https://www.omim.org/entry/619498"},{"mim_id":"611059","title":"WD REPEAT-CONTAINING PROTEIN 82; WDR82","url":"https://www.omim.org/entry/611059"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZC3H4"},"hgnc":{"alias_symbol":["KIAA1064"],"prev_symbol":["C19orf7"]},"alphafold":{"accession":"Q9UPT8","domains":[{"cath_id":"-","chopping":"445-503","consensus_level":"high","plddt":84.0788,"start":445,"end":503}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPT8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPT8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPT8-F1-predicted_aligned_error_v6.png","plddt_mean":50.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZC3H4","jax_strain_url":"https://www.jax.org/strain/search?query=ZC3H4"},"sequence":{"accession":"Q9UPT8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPT8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPT8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPT8"}},"corpus_meta":[{"pmid":"29401612","id":"PMC_29401612","title":"Silica-induced initiation of circular ZC3H4 RNA/ZC3H4 pathway promotes the pulmonary macrophage activation.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29401612","citation_count":83,"is_preprint":false},{"pmid":"33913806","id":"PMC_33913806","title":"ZC3H4 restricts non-coding transcription in human cells.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33913806","citation_count":53,"is_preprint":false},{"pmid":"37329883","id":"PMC_37329883","title":"A restrictor complex of ZC3H4, WDR82, and ARS2 integrates with PNUTS to control unproductive transcription.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/37329883","citation_count":39,"is_preprint":false},{"pmid":"37329882","id":"PMC_37329882","title":"ARS2 instructs early transcription termination-coupled RNA decay by recruiting ZC3H4 to nascent transcripts.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/37329882","citation_count":38,"is_preprint":false},{"pmid":"30826420","id":"PMC_30826420","title":"The emerging roles of a novel CCCH-type zinc finger protein, ZC3H4, in silica-induced epithelial to mesenchymal transition.","date":"2019","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30826420","citation_count":31,"is_preprint":false},{"pmid":"35962397","id":"PMC_35962397","title":"ZC3H4 regulates infiltrating monocytes, attenuating pulmonary fibrosis through IL-10.","date":"2022","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/35962397","citation_count":22,"is_preprint":false},{"pmid":"37944732","id":"PMC_37944732","title":"CircDYM attenuates microglial apoptosis via CEBPB/ZC3H4 axis in LPS-induced mouse model of depression.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37944732","citation_count":16,"is_preprint":false},{"pmid":"33246328","id":"PMC_33246328","title":"ZC3H4-a novel Cys-Cys-Cys-His-type zinc finger protein-is essential for early embryogenesis in mice†.","date":"2021","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/33246328","citation_count":15,"is_preprint":false},{"pmid":"33545378","id":"PMC_33545378","title":"ZC3H4 mediates silica-induced EndoMT via ER stress and autophagy.","date":"2021","source":"Environmental toxicology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33545378","citation_count":13,"is_preprint":false},{"pmid":"32218530","id":"PMC_32218530","title":"Elk-1 transcriptionally regulates ZC3H4 expression to promote silica-induced epithelial-mesenchymal transition.","date":"2020","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32218530","citation_count":10,"is_preprint":false},{"pmid":"34979141","id":"PMC_34979141","title":"ZC3H4 promotes pulmonary fibrosis via an ER stress-related positive feedback loop.","date":"2022","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34979141","citation_count":10,"is_preprint":false},{"pmid":"39002716","id":"PMC_39002716","title":"ZC3H4/Restrictor Exerts a Stranglehold on Pervasive Transcription.","date":"2024","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39002716","citation_count":8,"is_preprint":false},{"pmid":"40531993","id":"PMC_40531993","title":"ZC3H4 safeguards genome integrity by preventing transcription-replication conflicts at noncoding RNA loci.","date":"2025","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/40531993","citation_count":3,"is_preprint":false},{"pmid":"37866415","id":"PMC_37866415","title":"ZC3H4 governs epithelial cell migration through ROCK/p-PYK2/p-MLC2 pathway in silica-induced pulmonary fibrosis.","date":"2023","source":"Environmental toxicology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37866415","citation_count":1,"is_preprint":false},{"pmid":"40801544","id":"PMC_40801544","title":"Activation of the HPV16 late promoter by viral E2 and cellular BRD4 and ZC3H4 proteins.","date":"2025","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/40801544","citation_count":0,"is_preprint":false},{"pmid":"41120279","id":"PMC_41120279","title":"ZC3H4, a novel regulator of mitochondrial complex I, impacts prostate stromal cell senescence, attachment, adhesion and anoikis resistance.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41120279","citation_count":0,"is_preprint":false},{"pmid":"41110293","id":"PMC_41110293","title":"Possible involvement of a ZC3H4 gene splicing defect in the etiology of pre-eclampsia.","date":"2025","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/41110293","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.30.635704","title":"Modelling transcription with explainable AI uncovers context-specific epigenetic gene regulation at promoters and gene bodies","date":"2025-02-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.30.635704","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.08.631787","title":"Restrictor slows early transcription elongation to render RNA polymerase II susceptible to termination at non-coding RNA loci","date":"2025-01-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.08.631787","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.12.603302","title":"PP1 PNUTS binds the “restrictor” and dephosphorylates RNA pol II CTD Ser5 to stimulate transcription termination","date":"2024-07-13","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.12.603302","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11751,"output_tokens":3529,"usd":0.044094,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11165,"output_tokens":3042,"usd":0.065937,"stage2_stop_reason":"end_turn"},"total_usd":0.110031,"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\": 2021,\n      \"finding\": \"ZC3H4 depletion causes upregulation and extension of hundreds of unstable non-coding transcripts (particularly antisense RNAs and enhancer RNAs from super-enhancers), and ZC3H4 occupies these loci, indicating a direct role in restricting non-coding transcription. Engineered tethering of ZC3H4 to reporter RNA promotes its degradation by the nuclear exosome. ZC3H4 loss also causes a substantial reduction in cell proliferation.\",\n      \"method\": \"siRNA knockdown with nascent RNA sequencing, ChIP/occupancy analysis, reporter tethering assay, cell proliferation assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD + genome-wide RNA-seq + ChIP + tethering assay) in a single rigorous study establishing direct occupancy and function\",\n      \"pmids\": [\"33913806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZC3H4 forms a 'Restrictor' complex with WDR82 and ARS2, and additionally associates with the nuclear exosome targeting (NEXT) complex. The domains of ZC3H4 that contact ARS2 and WDR82 are required for ncRNA restriction. Restrictor co-transcriptionally controls an overlapping population of ncRNAs, and its function is enabled by PNUTS. U1 snRNA shields protein-coding transcripts from Restrictor and PNUTS at hundreds of genes.\",\n      \"method\": \"Co-immunoprecipitation, domain mutagenesis, nascent RNA sequencing, genetic depletion experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, genome-wide nascent RNA-seq, multiple orthogonal methods in one study replicated across two concurrent papers\",\n      \"pmids\": [\"37329883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A conserved basic domain of ARS2 binds a conserved acidic-rich short linear motif (SLiM) in ZC3H4. This interaction recruits ZC3H4 to chromatin to elicit RNAPII termination, independent of CPA and Integrator pathways. ZC3H4 in turn forms a direct connection to the NEXT complex to facilitate rapid degradation of the nascent RNA, coupling transcription termination to RNA decay.\",\n      \"method\": \"Biochemical binding assays, domain mapping, chromatin immunoprecipitation, nascent RNA sequencing upon depletion\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding mapped to specific SLiM/domain, multiple orthogonal methods, replicated concurrently with PMID 37329883\",\n      \"pmids\": [\"37329882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZC3H4/WDR82 (Restrictor) co-purifies with PP1 phosphatase and its nuclear targeting subunit PNUTS, which binds directly to WDR82. AlphaFold predicts a quaternary PPWZ complex. A dominant-negative PP1 H66K-PNUTS substrate trap inhibits antisense transcription termination and CTD Ser5 dephosphorylation, and these activities require the PNUTS-WDR82 binding domain. CTD Ser5 hyperphosphorylation is associated with higher RNAPII processivity, suggesting PP1-mediated Ser5 dephosphorylation by PPWZ is coupled to termination.\",\n      \"method\": \"Co-purification/mass spectrometry, AlphaFold structural prediction, dominant-negative PP1 substrate trap, nascent RNA sequencing, CTD phosphorylation analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical co-purification, structural modelling, dominant-negative functional assay; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.07.12.603302\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H4 deficiency leads to increased replication stress, R-loop formation, and transcription-replication conflicts (TRCs) at ncRNA loci, causing DNA damage, abnormal mitosis, and cellular senescence. ZC3H4 preferentially binds genomic regions prone to TRCs and R loops, where it suppresses ncRNA bursts, thereby safeguarding genome integrity.\",\n      \"method\": \"ZC3H4 knockout/depletion, super-resolution microscopy, biochemical analysis, bioinformatic analysis of binding sites, DNA damage and senescence assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with multiple defined phenotypic readouts (DNA damage, RS, R-loops, TRCs, mitosis, senescence) combined with genome-wide binding analysis and microscopy\",\n      \"pmids\": [\"40531993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The Restrictor complex (ZC3H4/WDR82) promiscuously suppresses early RNAPII elongation genome-wide, but this activity is blocked at most mRNAs by the presence of a 5′ splice site. Restrictor reduces the rate of transcription elongation rather than directly terminating RNAPII, rendering it susceptible to termination by other machineries. Restrictor is a critical determinant of transcription directionality at divergent promoters and prevents transcriptional interference.\",\n      \"method\": \"Unbiased sequence screens, rapid protein degradation (degron), nascent RNA sequencing (TT-seq/PRO-seq), splicing mutant analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rapid degron depletion with genome-wide nascent RNA-seq and mechanistic dissection; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.01.08.631787\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZC3H4 is essential for early mouse embryogenesis: homozygous mutant embryos are lost by E7.5, fail to hatch or form inner cell mass colonies, display severe DNA breaks, reduced cell proliferation, and compromised epiblast and primitive endoderm specification.\",\n      \"method\": \"In vivo mouse knockout, blastocyst outgrowth assay, immunofluorescence for lineage markers, DNA damage assay (γH2AX), ROS measurement\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with multiple orthogonal cellular and developmental phenotypic readouts\",\n      \"pmids\": [\"33246328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H4 ablation in prostate stromal cells phenocopies mitochondrial Complex I inhibition, causing elevated mitochondrial superoxide (mtROS), altered mitochondrial membrane potential, abnormal mitochondrial morphology, altered NAD+/NADH ratio, and reduced Complex I function, in addition to altered cell-matrix adhesion, fibronectin upregulation, anoikis resistance, and stress-induced premature senescence.\",\n      \"method\": \"CRISPR/Cas9 ablation, mitochondrial function assays (mtROS, membrane potential, NAD+/NADH, CI activity), cell adhesion/anoikis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with multiple phenotypic readouts in a single lab study; mechanistic link to Complex I is correlative\",\n      \"pmids\": [\"41120279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HPV16 E2 protein recruits ZC3H4 in a BRD4-dependent manner to specifically activate the HPV16 late promoter P670. ZC3H4 and E2 co-localize in cells with high P670 activity, and ZC3H4 knockdown in differentiated HPV16- or HPV31-positive cells reduces late viral transcripts in an E2-BRD4-dependent manner. Knockdown of ZC3H4 does not increase viral antisense (uaRNA) transcripts, indicating ZC3H4 enhances late transcription independently of antisense suppression.\",\n      \"method\": \"Biotin proximity ligation screen, reporter assay, co-localization (immunofluorescence), siRNA knockdown, RT-qPCR\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proximity ligation + reporter assay + co-localization + KD, multiple methods but no direct biochemical reconstitution\",\n      \"pmids\": [\"40801544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The transcription factor ELK-1 acts at the ZC3H4 promoter to transcriptionally upregulate ZC3H4 expression in response to SiO2-induced oxidative stress, placing ELK-1 upstream of ZC3H4 in the silica-EMT signaling axis.\",\n      \"method\": \"Promoter reporter assay, ChIP, siRNA knockdown, Western blotting\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter reporter and ChIP demonstrating direct ELK-1 binding to ZC3H4 promoter, single lab\",\n      \"pmids\": [\"32218530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZC3H4 activates fibroblasts via the sigmar1/ER stress pathway; specific knockdown of ZC3H4 attenuates SiO2-induced fibroblast activation (COL1A1, COL3A1, ACTA1 expression) and migration. ER stress blockade also inhibits ZC3H4 expression, demonstrating a positive feedback loop between ER stress and ZC3H4.\",\n      \"method\": \"CRISPR/Cas9 knockdown, ER stress inhibitor treatment, Western blotting, scratch/3D migration assay\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, CRISPR KD plus pharmacological inhibition but no direct molecular interaction demonstrated\",\n      \"pmids\": [\"34979141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZC3H4 knockdown in SiO2-exposed monocytes reduces ZC3H4-induced autophagy, which in turn reverses ZC3H4-mediated downregulation of IL-10 secretion. IL-10 from infiltrating monocytes inhibits fibroblast activation and migration, attenuating pulmonary fibrosis.\",\n      \"method\": \"CRISPR/Cas9 knockdown, ELISA, Western blotting, cell functional assays\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional assays without direct biochemical mechanism for ZC3H4-autophagy link\",\n      \"pmids\": [\"35962397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZC3H4 governs SiO2-induced epithelial cell migration through the ROCK/p-PYK2/p-MLC2 signaling pathway, as demonstrated by CRISPR/Cas9 knockdown of ZC3H4 and pathway inhibitor experiments.\",\n      \"method\": \"CRISPR/Cas9 knockdown, pathway inhibitors (ROCK, PYK2, MLC2), 2D migration assay, Western blotting\",\n      \"journal\": \"Environmental toxicology and pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological inhibitors combined with KD but no direct molecular interaction established\",\n      \"pmids\": [\"37866415\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZC3H4 is an RNA-binding CCCH zinc finger protein that forms the core of the 'Restrictor' complex (with WDR82 and ARS2), which is recruited co-transcriptionally to chromatin to suppress early RNAPII elongation and promote premature termination at non-coding RNA loci genome-wide; it does so by slowing elongation rate (rendering RNAPII susceptible to termination by other factors), coupling to NEXT complex-mediated nuclear exosome degradation of the nascent RNA, and working together with PP1-PNUTS to dephosphorylate CTD Ser5—while mRNA-coding genes are protected from Restrictor activity by 5′ splice sites; loss of ZC3H4 causes R-loop accumulation, transcription-replication conflicts, DNA damage, and genome instability, and is essential for early mammalian embryogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZC3H4 is an RNA-binding CCCH zinc finger protein that suppresses pervasive non-coding transcription genome-wide, restricting unstable antisense and enhancer-derived RNAs while coupling premature transcription termination to RNA decay [#0, #1]. It forms the core of the 'Restrictor' complex with WDR82 and ARS2, where a conserved acidic short linear motif in ZC3H4 is engaged by a basic domain of ARS2 to recruit ZC3H4 to chromatin and elicit RNAPII termination independently of the CPA and Integrator pathways; ZC3H4 in turn connects directly to the NEXT complex to drive rapid nuclear-exosome degradation of the nascent transcript [#1, #2]. Mechanistically, Restrictor reduces the rate of RNAPII elongation rather than terminating polymerase itself, rendering it susceptible to termination by other machineries, and acts together with PP1 phosphatase and its nuclear targeting subunit PNUTS (which binds WDR82) to dephosphorylate the RNAPII CTD at Ser5 [#3, #5]. Protein-coding genes are shielded from this activity by the presence of a 5' splice site / U1 snRNA, so Restrictor enforces transcription directionality at divergent promoters and prevents transcriptional interference [#1, #5]. By suppressing ncRNA bursts at loci prone to transcription-replication conflicts, ZC3H4 limits R-loop formation, replication stress, and DNA damage, and its loss causes abnormal mitosis, senescence, and genome instability [#4]; ZC3H4 is essential for early mouse embryogenesis, with knockouts displaying severe DNA breaks and failed lineage specification [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that ZC3H4 is a direct, locus-occupying restrictor of pervasive non-coding transcription, answering whether it acts on RNA at chromatin or post-transcriptionally elsewhere.\",\n      \"evidence\": \"siRNA knockdown with nascent RNA-seq, ChIP occupancy, and reporter tethering coupling ZC3H4 to nuclear-exosome degradation in human cells\",\n      \"pmids\": [\"33913806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define ZC3H4's protein partners or how it is recruited to chromatin\", \"Mechanism of termination versus elongation control not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated the physiological essentiality of ZC3H4, showing its ncRNA-restriction function is required for viable early development.\",\n      \"evidence\": \"in vivo mouse knockout with blastocyst outgrowth, lineage-marker immunofluorescence, and γH2AX DNA-damage readouts\",\n      \"pmids\": [\"33246328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect embryonic DNA damage mechanistically to transcription restriction\", \"No molecular partners assayed in the embryo\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the Restrictor complex and its recruitment logic, answering how ZC3H4 is targeted to chromatin and links termination to decay.\",\n      \"evidence\": \"reciprocal Co-IP, domain mutagenesis and SLiM/domain mapping (ZC3H4 acidic motif to ARS2 basic domain), plus nascent RNA-seq, across two concurrent studies; U1 snRNA shown to shield mRNAs\",\n      \"pmids\": [\"37329883\", \"37329882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the enzymatic step ZC3H4 itself catalyzes\", \"How U1/5' splice site mechanistically antagonizes Restrictor not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked Restrictor to CTD dephosphorylation, addressing how slowed elongation/termination is enforced biochemically.\",\n      \"evidence\": \"co-purification/MS, AlphaFold prediction of a PP1-PNUTS-WDR82-ZC3H4 (PPWZ) complex, and a dominant-negative PP1 substrate trap with CTD Ser5 phosphorylation analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.12.603302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Causal ordering of Ser5 dephosphorylation versus termination not fully resolved\", \"Structural model is predicted, not experimentally determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the kinetic mechanism, showing Restrictor slows elongation rather than directly terminating RNAPII and governs promoter directionality.\",\n      \"evidence\": \"rapid degron depletion with TT-seq/PRO-seq, unbiased sequence screens, and splicing-mutant analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.08.631787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Identity of the downstream termination machinery acting on slowed RNAPII not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected ZC3H4 ncRNA restriction to genome stability, explaining the DNA-damage phenotypes via transcription-replication conflicts.\",\n      \"evidence\": \"knockout/depletion with super-resolution microscopy, genome-wide binding analysis, and DNA-damage/senescence assays\",\n      \"pmids\": [\"40531993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish whether R-loop accumulation is a direct or indirect consequence of ncRNA bursts\", \"Relationship between mitotic abnormalities and specific TRC sites not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported context-specific, possibly non-canonical ZC3H4 roles in mitochondrial function and viral transcription that diverge from antisense suppression.\",\n      \"evidence\": \"CRISPR ablation with mitochondrial assays in prostate stromal cells, and proximity ligation/reporter/co-localization/KD showing HPV16 E2-BRD4-dependent recruitment to activate the late promoter P670\",\n      \"pmids\": [\"41120279\", \"40801544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial Complex I link is correlative, not mechanistic\", \"Viral late-promoter activation lacks biochemical reconstitution\", \"How these roles relate to canonical Restrictor activity is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZC3H4/Restrictor mechanistically distinguishes coding from non-coding nascent RNA in real time, and the precise enzymatic contribution of ZC3H4 itself, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the assembled Restrictor/PPWZ complex on RNAPII\", \"ZC3H4's own catalytic activity, if any, undefined\", \"Quantitative model coupling elongation slowing, Ser5 dephosphorylation, and exosome handoff not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"Restrictor (ZC3H4-WDR82-ARS2)\",\n      \"NEXT complex (association)\",\n      \"PPWZ (PP1-PNUTS-WDR82-ZC3H4)\"\n    ],\n    \"partners\": [\n      \"WDR82\",\n      \"ARS2\",\n      \"PNUTS\",\n      \"PP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}