{"gene":"EDC4","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2005,"finding":"Ge-1 (EDC4) is a central component of mammalian cytoplasmic P-bodies. Its C-terminal domain (containing repeating psi(X(2-3)) motifs) is necessary and sufficient for P-body targeting. siRNA-mediated knockdown of Ge-1 results in loss of P-bodies containing Ge-1, DCP1a, and DCP2, but Ge-1-containing P-bodies persist despite knockdown of DCP2, placing Ge-1 upstream of DCP2 in P-body assembly.","method":"siRNA knockdown, immunofluorescence colocalization, deletion mapping, autoimmune serum identification","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal colocalization, deletion domain mapping, and knockdown epistasis; replicated across multiple P-body components in a single rigorous study","pmids":["16314453"],"is_preprint":false},{"year":2008,"finding":"The crystal structure of the Drosophila Ge-1 (EDC4) C-terminal domain reveals an all alpha-helical fold related to ARM/HEAT-repeat proteins. Structure-based mutagenesis identified an invariant surface residue required for P-body localization, and conservation of critical residues suggests this fold and function are shared across the Ge-1 family.","method":"X-ray crystallography, structure-based mutagenesis, P-body localization assay","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation by mutagenesis in a single study with multiple orthogonal methods","pmids":["18755833"],"is_preprint":false},{"year":2014,"finding":"EDC4 serves as a scaffold for assembly of the human mRNA decapping complex, providing distinct binding sites for DCP1, DCP2, and XRN1 on its C-terminal domain. DCP2 and XRN1 bind simultaneously via short linear motifs (SLiMs). DCP1 and DCP2 form direct but weak interactions that are facilitated by EDC4. The DCP1 EVH1 domain NR-loop is critical for DCP2 activation, and this activation occurs preferentially on the EDC4 scaffold, coupling decapping with 5'-to-3' decay by XRN1.","method":"Mutational analysis, co-immunoprecipitation, in vivo decapping assays, binding studies","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding studies, multiple mutants, in vivo functional assays, and mechanistic model validated by multiple orthogonal approaches in one study","pmids":["24510189"],"is_preprint":false},{"year":2011,"finding":"Drosophila Ge-1 (dGe-1) is an essential P-body component required for P-body formation in the germline. dGe-1 partially colocalizes with oskar mRNA and is required for oskar RNP integrity. While not essential for oskar mRNA localization under normal conditions, dGe-1 becomes critical when other components (staufen, DCP1, barentsz) are limiting.","method":"Genetic knockouts, immunohistochemistry, biochemical fractionation, genetic epistasis with other localization factors","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical approaches in a single lab studying Drosophila ortholog","pmids":["21655181"],"is_preprint":false},{"year":2012,"finding":"EDC4 forms a complex with Coenzyme A synthase (CoAsy) and strongly inhibits the dephospho-CoA kinase activity of CoAsy in vitro. CoAsy/EDC4 complex formation is regulated by growth factors and cellular stresses. Transient overexpression of EDC4 decreases cell proliferation, and co-expression of CoAsy diminishes this effect.","method":"Co-immunoprecipitation, in vitro kinase activity assay, overexpression/proliferation assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro enzymatic assay plus Co-IP, but single lab with limited mechanistic follow-up","pmids":["22982864"],"is_preprint":false},{"year":2014,"finding":"CCHCR1 interacts with EDC4 (identified as the major interacting partner by co-immunoprecipitation coupled with LC-MS/MS), and this interaction targets CCHCR1 to P-bodies; the N-terminus of CCHCR1 is required for its P-body localization.","method":"Co-immunoprecipitation with EGFP-tagged CCHCR1, LC-MS/MS, confocal imaging, deletion mapping","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS identification in one lab, no reciprocal validation or functional mechanistic follow-up for EDC4 itself","pmids":["24858563"],"is_preprint":false},{"year":2014,"finding":"EDC4 (Edc4) interacts with the mTORC1 complex (identified via co-immunoprecipitation). Rapamycin treatment increases total Edc4 protein expression but decreases Edc4 interaction with mTORC1 and decreases serine phosphorylation of Edc4, suggesting mTORC1 regulates Edc4 phosphorylation and activity in mRNA decapping.","method":"Co-immunoprecipitation, immunoblotting, confocal colocalization, rapamycin treatment","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up, no identification of specific phosphorylation site or functional consequence of phosphorylation","pmids":["25514416"],"is_preprint":false},{"year":2016,"finding":"A naturally occurring 26 amino acid deletion in the serine-rich linker region of Drosophila Ge-1 confers resistance to sigma virus infection. Knockdown of the susceptible allele decreases viral titre. DCP1, which interacts with Ge-1, also protects against sigma virus. Ge-1-based resistance is not dependent on the siRNA pathway.","method":"Transgenic fly generation with sequence modification, viral titre assay, siRNA pathway epistasis test, knockdown experiments","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic allele replacement, functional viral resistance assay, and pathway epistasis in single study","pmids":["26799957"],"is_preprint":false},{"year":2018,"finding":"EDC4 is a member of the BRCA1-BRIP1-TOPBP1 complex and plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors.","method":"Co-immunoprecipitation (complex membership), HR assay, DNA end resection assay, drug sensitivity assay, genome instability measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (HR, resection, drug sensitivity, genome instability) plus complex identification by Co-IP in a single rigorous study","pmids":["29511213"],"is_preprint":false},{"year":2020,"finding":"EDC4 interacts with MARF1 endoribonuclease and impairs MARF1 activity by preventing its LOTUS domains from binding target mRNAs. This represents a non-canonical role for EDC4 as a repressor of MARF1-mediated mRNA decay, distinct from its role as an enhancer of DCP2-mediated decapping.","method":"Co-immunoprecipitation, transcriptome-wide MARF1 target identification, LOTUS domain RNA binding assay, mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic interaction validated biochemically with transcriptome-wide analysis and functional domain mutagenesis in one study","pmids":["32510323"],"is_preprint":false},{"year":2020,"finding":"EDC4 interacts with replication protein A (RPA) by immunoprecipitation and promotes RPA phosphorylation. EDC4 knockdown enhances cisplatin-induced DNA damage and sensitivity, while EDC4 overexpression reduces DNA damage. RPA knockdown reverses the inhibitory effect of EDC4 on cisplatin-induced DNA damage, placing RPA downstream of EDC4 in this pathway.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, γH2AX immunofluorescence, MTT/colony assays, epistasis by double knockdown","journal":"Hereditas","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus functional epistasis but single lab, and mechanism of RPA phosphorylation promotion is not directly established","pmids":["33054858"],"is_preprint":false},{"year":2023,"finding":"Disrupting the EDC4-XRN1 interaction or altering their stoichiometry inhibits mRNA decapping and stabilizes microRNA-targeted mRNAs in a translationally repressed state. This concomitantly leads to larger P-bodies that are responsible for preventing mRNA decapping. P-bodies support cell viability and prevent stress granule formation when XRN1 is limiting.","method":"Interaction disruption mutants, mRNA stability assays, P-body size measurements, microRNA reporter assays, cell viability assays, stress granule imaging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (interaction mutants, mRNA stability, P-body dynamics, stress granule assays) in single rigorous study establishing causal mechanism","pmids":["37621215"],"is_preprint":false},{"year":2024,"finding":"In C. elegans, EDC-4 counteracts EDC-3 and promotes assembly of DCAP-2 (DCP2) with the GID/CTLH complex (a ubiquitin ligase involved in maternal-to-zygotic transition), linking the mRNA decapping scaffold to the ubiquitin-proteasome system during embryonic development.","method":"Genetic interaction studies, co-immunoprecipitation, mRNA stability assays, fluorescence microscopy in C. elegans","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and biochemical complex identification in C. elegans ortholog, single lab","pmids":["39331503"],"is_preprint":false},{"year":2025,"finding":"The EDC4 C-terminal domain (residues 1266-1401) is the minimal region required for P-body formation, driving phase separation and EDC4 condensation. The microprotein Nobody (NBDY) 22-41 peptide directly binds the EDC4 C-terminal domain and inhibits its self-association, selectively dissolving P-bodies without affecting the canonical mRNA decay pathway. P-body disruption activates the p53 pathway and enhances stability of associated transcripts.","method":"Deletion mapping, phase separation assay, direct binding assay (NBDY peptide to EDC4 CTD), P-body dissolution assay, transcriptome profiling, p53 pathway reporter","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstitution of phase separation, direct peptide binding, transcriptome profiling, and functional pathway readout in single study with multiple orthogonal methods","pmids":["40360209"],"is_preprint":false},{"year":2025,"finding":"Ebola virus VP35 protein binds the EDC4 scaffold protein through the EDC4 C-terminal subdomain, with both proteins colocalizing in EBOV-infected cells. siRNA depletion of EDC4 reduces EBOV replication by inhibiting early viral RNA synthesis.","method":"Proximity-dependent biotinylation (BioID), co-immunoprecipitation, colocalization imaging in infected cells, siRNA knockdown with viral RNA synthesis assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity ligation plus colocalization plus functional knockdown in infected cells, single lab","pmids":["41006235"],"is_preprint":false}],"current_model":"EDC4 (Ge-1/HEDLS) functions as a large scaffold protein central to cytoplasmic P-body assembly and mRNA decapping: its C-terminal domain (residues 1266–1401, adopting an ARM/HEAT-repeat fold) drives phase separation and P-body formation, provides simultaneous binding sites for DCP1, DCP2, and XRN1 via short linear motifs, and facilitates DCP1-mediated activation of the DCP2 decapping enzyme; the EDC4–XRN1 interaction controls P-body dynamics to couple decapping with 5'–3' decay, while EDC4 also acts as a repressor of MARF1 endonuclease activity, a member of the BRCA1-BRIP1-TOPBP1 complex that stimulates homologous recombination end resection, an inhibitor of CoA synthase dephospho-CoA kinase activity, and an interaction partner of RPA that promotes DNA repair and contributes to chemoresistance."},"narrative":{"mechanistic_narrative":"EDC4 (Ge-1/HEDLS) is a large scaffold protein that nucleates cytoplasmic processing bodies (P-bodies) and organizes the 5'-to-3' mRNA decapping machinery [PMID:16314453, PMID:24510189]. Its C-terminal domain is necessary and sufficient for P-body targeting and adopts an all-α-helical ARM/HEAT-repeat fold, with conserved surface residues required for localization [PMID:16314453, PMID:18755833]; the minimal region (residues 1266-1401) drives phase separation and self-association to build the P-body condensate [PMID:40360209]. On this scaffold EDC4 provides simultaneous binding sites for DCP1, DCP2, and XRN1 via short linear motifs, facilitating the weak DCP1-DCP2 interaction and promoting DCP1-mediated activation of the DCP2 decapping enzyme, thereby coupling decapping to XRN1 5'-to-3' decay [PMID:24510189]. The EDC4-XRN1 interaction and stoichiometry govern P-body dynamics: disrupting it inhibits decapping, enlarges P-bodies, and stabilizes microRNA-targeted mRNAs in a translationally repressed state, with P-bodies supporting cell viability and suppressing stress granule formation [PMID:37621215]. Beyond canonical decapping enhancement, EDC4 acts as a repressor of the MARF1 endoribonuclease by preventing its LOTUS domains from binding target mRNAs [PMID:32510323]. EDC4 additionally functions in genome maintenance as a member of the BRCA1-BRIP1-TOPBP1 complex that stimulates double-strand-break end resection during homologous recombination, with its loss causing genome instability and hypersensitivity to interstrand cross-linkers and PARP inhibitors [PMID:29511213].","teleology":[{"year":2005,"claim":"Established EDC4 as a core architectural component of P-bodies acting upstream of the decapping enzyme, answering whether it is structural or merely a passenger.","evidence":"siRNA knockdown, deletion mapping, and colocalization epistasis with DCP1a/DCP2 in mammalian cells","pmids":["16314453"],"confidence":"High","gaps":["Did not define the structural basis of C-terminal targeting","Did not establish molecular partners on the C-terminal domain"]},{"year":2008,"claim":"Defined the fold of the P-body-targeting C-terminal domain as an ARM/HEAT-repeat structure and pinpointed a conserved residue essential for localization.","evidence":"X-ray crystallography and structure-based mutagenesis of the Drosophila Ge-1 C-terminal domain","pmids":["18755833"],"confidence":"High","gaps":["Did not map binding sites for specific decapping factors","Did not address phase separation"]},{"year":2014,"claim":"Resolved how EDC4 organizes the decapping reaction by showing it scaffolds DCP1, DCP2, and XRN1 simultaneously and promotes DCP1-dependent DCP2 activation, coupling decapping to 5'-to-3' decay.","evidence":"Co-immunoprecipitation, SLiM/mutational mapping, and in vivo decapping assays in human cells","pmids":["24510189"],"confidence":"High","gaps":["Did not establish the in vivo stoichiometry controlling P-body dynamics","Structural detail of the scaffold-bound complex not resolved"]},{"year":2012,"claim":"Identified a non-decapping activity in which EDC4 binds and inhibits CoA synthase dephospho-CoA kinase activity, coupling EDC4 to growth-factor/stress signalling and proliferation.","evidence":"Co-immunoprecipitation, in vitro kinase assay, and overexpression proliferation assay","pmids":["22982864"],"confidence":"Medium","gaps":["Cellular significance of CoAsy inhibition not established in vivo","Single lab without mechanistic follow-up"]},{"year":2011,"claim":"Showed the EDC4 ortholog is essential for germline P-body formation and contributes to mRNP integrity, addressing its developmental requirement.","evidence":"Genetic knockouts, immunohistochemistry, and epistasis in Drosophila germline","pmids":["21655181"],"confidence":"Medium","gaps":["Direct molecular role in oskar RNP integrity unresolved","Findings in ortholog, not mammalian system"]},{"year":2016,"claim":"Linked an EDC4 linker-region polymorphism to antiviral resistance, implicating the decapping scaffold in host defence independent of the siRNA pathway.","evidence":"Transgenic allele replacement, viral titre assays, and pathway epistasis in Drosophila","pmids":["26799957"],"confidence":"Medium","gaps":["Mechanism by which the serine-rich linker confers resistance unknown","Not tested in mammalian antiviral contexts"]},{"year":2018,"claim":"Revealed an unexpected nuclear genome-maintenance role: EDC4 is a BRCA1-BRIP1-TOPBP1 complex member that stimulates end resection in homologous recombination.","evidence":"Co-IP complex identification, HR and end-resection assays, drug sensitivity, and genome instability measurement","pmids":["29511213"],"confidence":"High","gaps":["Molecular activity of EDC4 within the resection step not defined","Relationship between cytoplasmic decapping and HR roles unresolved"]},{"year":2020,"claim":"Defined a repressive RNA role distinct from decapping enhancement: EDC4 inhibits MARF1 endoribonuclease by blocking LOTUS-domain mRNA binding.","evidence":"Co-IP, transcriptome-wide MARF1 target mapping, LOTUS RNA-binding assay, and mutagenesis","pmids":["32510323"],"confidence":"High","gaps":["Physiological balance between MARF1 repression and DCP2 enhancement unknown","Regulation of the EDC4-MARF1 switch undefined"]},{"year":2020,"claim":"Connected EDC4 to the DNA-damage response through RPA, showing it promotes RPA phosphorylation and limits cisplatin damage, contributing to chemoresistance.","evidence":"Co-IP, knockdown/overexpression, γH2AX imaging, and double-knockdown epistasis placing RPA downstream","pmids":["33054858"],"confidence":"Medium","gaps":["Mechanism by which EDC4 promotes RPA phosphorylation not established","Single lab, not reciprocally validated"]},{"year":2023,"claim":"Established that EDC4-XRN1 interaction and stoichiometry control P-body size and decay flux, defining P-bodies as regulators of mRNA fate, viability, and stress-granule suppression.","evidence":"Interaction-disruption mutants, mRNA stability and miRNA reporter assays, P-body sizing, and stress granule imaging","pmids":["37621215"],"confidence":"High","gaps":["Quantitative rules governing condensate growth versus decay incompletely defined","Upstream signals tuning stoichiometry unknown"]},{"year":2024,"claim":"Tied the decapping scaffold to the ubiquitin-proteasome system, showing EDC4 promotes DCP2 assembly with the GID/CTLH ligase during the maternal-to-zygotic transition.","evidence":"Genetic interaction, Co-IP, and mRNA stability assays in C. elegans","pmids":["39331503"],"confidence":"Medium","gaps":["Conservation of the EDC4-GID/CTLH link in mammals untested","Direct versus indirect bridging not resolved"]},{"year":2025,"claim":"Identified the minimal phase-separating domain and a microprotein inhibitor (NBDY) that selectively dissolves P-bodies, showing condensate disruption activates the p53 pathway and stabilizes transcripts.","evidence":"Deletion mapping, phase separation reconstitution, direct NBDY-peptide binding, transcriptome profiling, and p53 reporter","pmids":["40360209"],"confidence":"High","gaps":["Mechanism linking P-body dissolution to p53 activation not defined","Endogenous regulation of NBDY-mediated dissolution unknown"]},{"year":2025,"claim":"Showed Ebola virus VP35 hijacks the EDC4 scaffold to support early viral RNA synthesis, implicating the P-body scaffold in viral replication.","evidence":"BioID, Co-IP, colocalization in infected cells, and siRNA knockdown with viral RNA synthesis assay","pmids":["41006235"],"confidence":"Medium","gaps":["Mechanism by which EDC4 supports viral RNA synthesis undefined","Whether decapping activity is required not established"]},{"year":null,"claim":"How EDC4's cytoplasmic decapping/scaffolding function is mechanistically integrated with its nuclear HR and DNA-damage-response roles, and how cells partition EDC4 between these activities, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking the decapping scaffold to the BRCA1-BRIP1-TOPBP1 complex","Signals controlling EDC4 subcellular partitioning unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,9,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,11]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8,10]}],"complexes":["mRNA decapping complex (DCP1-DCP2-XRN1 scaffold)","P-body","BRCA1-BRIP1-TOPBP1 complex"],"partners":["DCP1","DCP2","XRN1","MARF1","RPA","COASY","BRCA1","TOPBP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6P2E9","full_name":"Enhancer of mRNA-decapping protein 4","aliases":["Autoantigen Ge-1","Autoantigen RCD-8","Human enhancer of decapping large subunit","Hedls"],"length_aa":1401,"mass_kda":151.7,"function":"In the process of mRNA degradation, seems to play a role in mRNA decapping. Component of a complex containing DCP2 and DCP1A which functions in decapping of ARE-containing mRNAs. Promotes complex formation between DCP1A and DCP2. Enhances the catalytic activity of DCP2 (in vitro)","subcellular_location":"Cytoplasm, P-body; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6P2E9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EDC4","classification":"Common Essential","n_dependent_lines":438,"n_total_lines":1208,"dependency_fraction":0.36258278145695366},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000038358","cell_line_id":"CID000830","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"DCP1A","stoichiometry":10.0},{"gene":"CLTA","stoichiometry":4.0},{"gene":"EDC3","stoichiometry":4.0},{"gene":"ARHGAP15","stoichiometry":0.2},{"gene":"ARHGAP18","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2},{"gene":"DCP2","stoichiometry":0.2},{"gene":"XRN1","stoichiometry":0.2},{"gene":"ALDH18A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000830","total_profiled":1310},"omim":[{"mim_id":"615231","title":"RING FINGER AND CCCH-TYPE ZINC FINGER DOMAINS-CONTAINING PROTEIN 2; RC3H2","url":"https://www.omim.org/entry/615231"},{"mim_id":"609842","title":"ENHANCER OF mRNA DECAPPING 3; EDC3","url":"https://www.omim.org/entry/609842"},{"mim_id":"609424","title":"RING FINGER AND CCCH-TYPE ZINC FINGER DOMAINS-CONTAINING 1; RC3H1","url":"https://www.omim.org/entry/609424"},{"mim_id":"606030","title":"ENHANCER OF mRNA DECAPPING 4; EDC4","url":"https://www.omim.org/entry/606030"},{"mim_id":"300992","title":"NEGATIVE REGULATOR OF P-BODY ASSOCIATION; NBDY","url":"https://www.omim.org/entry/300992"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytoplasmic bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EDC4"},"hgnc":{"alias_symbol":["RCD-8","Ge-1","HEDLS"],"prev_symbol":[]},"alphafold":{"accession":"Q6P2E9","domains":[{"cath_id":"-","chopping":"80-133_377-473_502-528","consensus_level":"medium","plddt":89.9642,"start":80,"end":528},{"cath_id":"2.130.10.10","chopping":"136-244_252-357","consensus_level":"medium","plddt":90.9255,"start":136,"end":357},{"cath_id":"1.10.220.100","chopping":"1271-1396","consensus_level":"high","plddt":81.9647,"start":1271,"end":1396}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P2E9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P2E9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P2E9-F1-predicted_aligned_error_v6.png","plddt_mean":62.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EDC4","jax_strain_url":"https://www.jax.org/strain/search?query=EDC4"},"sequence":{"accession":"Q6P2E9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P2E9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P2E9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P2E9"}},"corpus_meta":[{"pmid":"16314453","id":"PMC_16314453","title":"Ge-1 is a central component of the mammalian cytoplasmic mRNA processing body.","date":"2005","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/16314453","citation_count":157,"is_preprint":false},{"pmid":"24510189","id":"PMC_24510189","title":"The activation of the decapping enzyme DCP2 by DCP1 occurs on the EDC4 scaffold and involves a conserved loop in DCP1.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/24510189","citation_count":102,"is_preprint":false},{"pmid":"3595602","id":"PMC_3595602","title":"Gerbich blood group deficiency of the Ge:-1,-2,-3 and Ge:-1,-2,3 types. Immunochemical study and genomic analysis with cDNA probes.","date":"1987","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3595602","citation_count":50,"is_preprint":false},{"pmid":"18665315","id":"PMC_18665315","title":"Electrodeposition of Ge, Si and Si x Ge 1-x from an air- and water-stable ionic liquid.","date":"2008","source":"Physical chemistry chemical physics : PCCP","url":"https://pubmed.ncbi.nlm.nih.gov/18665315","citation_count":38,"is_preprint":false},{"pmid":"29511213","id":"PMC_29511213","title":"Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29511213","citation_count":36,"is_preprint":false},{"pmid":"37621215","id":"PMC_37621215","title":"The EDC4-XRN1 interaction controls P-body dynamics to link mRNA decapping with decay.","date":"2023","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/37621215","citation_count":34,"is_preprint":false},{"pmid":"18755833","id":"PMC_18755833","title":"The C-terminal region of Ge-1 presents conserved structural features required for P-body localization.","date":"2008","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18755833","citation_count":32,"is_preprint":false},{"pmid":"21655181","id":"PMC_21655181","title":"Drosophila Ge-1 promotes P body formation and oskar mRNA localization.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21655181","citation_count":24,"is_preprint":false},{"pmid":"26799957","id":"PMC_26799957","title":"A Polymorphism in the Processing Body Component Ge-1 Controls Resistance to a Naturally Occurring Rhabdovirus in Drosophila.","date":"2016","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/26799957","citation_count":22,"is_preprint":false},{"pmid":"24858563","id":"PMC_24858563","title":"CCHCR1 interacts with EDC4, suggesting its localization in P-bodies.","date":"2014","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/24858563","citation_count":21,"is_preprint":false},{"pmid":"22982864","id":"PMC_22982864","title":"EDC4 interacts with and regulates the dephospho-CoA kinase activity of CoA synthase.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22982864","citation_count":18,"is_preprint":false},{"pmid":"33827207","id":"PMC_33827207","title":"Photocatalytic and Photoelectrochemical Hydrogen Evolution from Water over Cu2SnGe1-S3 Particles.","date":"2021","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/33827207","citation_count":18,"is_preprint":false},{"pmid":"32510323","id":"PMC_32510323","title":"A non-canonical role for the EDC4 decapping factor in regulating MARF1-mediated mRNA decay.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32510323","citation_count":13,"is_preprint":false},{"pmid":"33054858","id":"PMC_33054858","title":"Enhancer of mRNA Decapping protein 4 (EDC4) interacts with replication protein a (RPA) and contributes to Cisplatin resistance in cervical Cancer by alleviating DNA damage.","date":"2020","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/33054858","citation_count":12,"is_preprint":false},{"pmid":"35498566","id":"PMC_35498566","title":"Reducing interfacial resistance of a Li1.5Al0.5Ge1.5(PO4)3 solid electrolyte/electrode interface by polymer interlayer protection.","date":"2020","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/35498566","citation_count":9,"is_preprint":false},{"pmid":"25514416","id":"PMC_25514416","title":"Crosstalk between Edc4 and mammalian target of rapamycin complex 1 (mTORC1) signaling in mRNA decapping.","date":"2014","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25514416","citation_count":6,"is_preprint":false},{"pmid":"39331503","id":"PMC_39331503","title":"EDC-3 and EDC-4 regulate embryonic mRNA clearance and biomolecular condensate specialization.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39331503","citation_count":5,"is_preprint":false},{"pmid":"40360209","id":"PMC_40360209","title":"EDC4 C-terminal domain scaffolds P-body assembly and links P-body dynamics to p53-mediated tumor suppression.","date":"2025","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/40360209","citation_count":5,"is_preprint":false},{"pmid":"38394818","id":"PMC_38394818","title":"Construction of SnO2 buffer layer and analysis of its interface modification for Li and Li1.5Al0.5Ge1.5(PO4)3 in solid-state batteries.","date":"2024","source":"Journal of colloid and interface science","url":"https://pubmed.ncbi.nlm.nih.gov/38394818","citation_count":4,"is_preprint":false},{"pmid":"41006235","id":"PMC_41006235","title":"A protein-proximity screen reveals Ebola virus co-opts the mRNA decapping complex through the scaffold protein EDC4.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41006235","citation_count":3,"is_preprint":false},{"pmid":"37750488","id":"PMC_37750488","title":"Dynamic \"Cap\"-abilities of P-bodies and the XRN1-EDC4 axis.","date":"2023","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/37750488","citation_count":3,"is_preprint":false},{"pmid":"40640337","id":"PMC_40640337","title":"The molecular axis hnRNPU/circKCNK2/EDC4/IL-11 aggravates osteolytic bone metastasis of RCC.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40640337","citation_count":2,"is_preprint":false},{"pmid":"38352529","id":"PMC_38352529","title":"A protein-proximity screen reveals Ebola virus co-opts the mRNA decapping complex through the scaffold protein EDC4.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/38352529","citation_count":2,"is_preprint":false},{"pmid":"28174620","id":"PMC_28174620","title":"Complete genome sequence of Thermus brockianus GE-1 reveals key enzymes of xylan/xylose metabolism.","date":"2017","source":"Standards in genomic sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28174620","citation_count":2,"is_preprint":false},{"pmid":"35665754","id":"PMC_35665754","title":"Magnetic phase diagram of the solid solution LaMn2(Ge1-xSix)2 (0 ≤ x ≤ 1) unraveled by powder neutron diffraction.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35665754","citation_count":1,"is_preprint":false},{"pmid":"41073999","id":"PMC_41073999","title":"EDC4 enhances multi-drug chemosensitivity in pancreatic cancer via GR50-based profiling.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/41073999","citation_count":0,"is_preprint":false},{"pmid":"27845925","id":"PMC_27845925","title":"2D Tl-Pb compounds on Ge(1 1 1) surface: atomic arrangement and electronic band structure.","date":"2016","source":"Journal of physics. Condensed matter : an Institute of Physics journal","url":"https://pubmed.ncbi.nlm.nih.gov/27845925","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.09.632073","title":"A single pathogen-secreted protein reprograms plants for drought resilience","date":"2025-01-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.09.632073","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.16.681898","title":"Calcium: Modulator of Post-transcriptional and post-translational process in mESCs","date":"2025-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.16.681898","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.09.669463","title":"Ancestral P-body proteins rewired for autophagic recycling in the early land plant  <i>Marchantia polymorpha</i>","date":"2025-08-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.09.669463","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15603,"output_tokens":3851,"usd":0.052287,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11623,"output_tokens":4025,"usd":0.07937,"stage2_stop_reason":"end_turn"},"total_usd":0.131657,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Ge-1 (EDC4) is a central component of mammalian cytoplasmic P-bodies. Its C-terminal domain (containing repeating psi(X(2-3)) motifs) is necessary and sufficient for P-body targeting. siRNA-mediated knockdown of Ge-1 results in loss of P-bodies containing Ge-1, DCP1a, and DCP2, but Ge-1-containing P-bodies persist despite knockdown of DCP2, placing Ge-1 upstream of DCP2 in P-body assembly.\",\n      \"method\": \"siRNA knockdown, immunofluorescence colocalization, deletion mapping, autoimmune serum identification\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal colocalization, deletion domain mapping, and knockdown epistasis; replicated across multiple P-body components in a single rigorous study\",\n      \"pmids\": [\"16314453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The crystal structure of the Drosophila Ge-1 (EDC4) C-terminal domain reveals an all alpha-helical fold related to ARM/HEAT-repeat proteins. Structure-based mutagenesis identified an invariant surface residue required for P-body localization, and conservation of critical residues suggests this fold and function are shared across the Ge-1 family.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, P-body localization assay\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation by mutagenesis in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"18755833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EDC4 serves as a scaffold for assembly of the human mRNA decapping complex, providing distinct binding sites for DCP1, DCP2, and XRN1 on its C-terminal domain. DCP2 and XRN1 bind simultaneously via short linear motifs (SLiMs). DCP1 and DCP2 form direct but weak interactions that are facilitated by EDC4. The DCP1 EVH1 domain NR-loop is critical for DCP2 activation, and this activation occurs preferentially on the EDC4 scaffold, coupling decapping with 5'-to-3' decay by XRN1.\",\n      \"method\": \"Mutational analysis, co-immunoprecipitation, in vivo decapping assays, binding studies\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding studies, multiple mutants, in vivo functional assays, and mechanistic model validated by multiple orthogonal approaches in one study\",\n      \"pmids\": [\"24510189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Drosophila Ge-1 (dGe-1) is an essential P-body component required for P-body formation in the germline. dGe-1 partially colocalizes with oskar mRNA and is required for oskar RNP integrity. While not essential for oskar mRNA localization under normal conditions, dGe-1 becomes critical when other components (staufen, DCP1, barentsz) are limiting.\",\n      \"method\": \"Genetic knockouts, immunohistochemistry, biochemical fractionation, genetic epistasis with other localization factors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical approaches in a single lab studying Drosophila ortholog\",\n      \"pmids\": [\"21655181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EDC4 forms a complex with Coenzyme A synthase (CoAsy) and strongly inhibits the dephospho-CoA kinase activity of CoAsy in vitro. CoAsy/EDC4 complex formation is regulated by growth factors and cellular stresses. Transient overexpression of EDC4 decreases cell proliferation, and co-expression of CoAsy diminishes this effect.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase activity assay, overexpression/proliferation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro enzymatic assay plus Co-IP, but single lab with limited mechanistic follow-up\",\n      \"pmids\": [\"22982864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CCHCR1 interacts with EDC4 (identified as the major interacting partner by co-immunoprecipitation coupled with LC-MS/MS), and this interaction targets CCHCR1 to P-bodies; the N-terminus of CCHCR1 is required for its P-body localization.\",\n      \"method\": \"Co-immunoprecipitation with EGFP-tagged CCHCR1, LC-MS/MS, confocal imaging, deletion mapping\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS identification in one lab, no reciprocal validation or functional mechanistic follow-up for EDC4 itself\",\n      \"pmids\": [\"24858563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EDC4 (Edc4) interacts with the mTORC1 complex (identified via co-immunoprecipitation). Rapamycin treatment increases total Edc4 protein expression but decreases Edc4 interaction with mTORC1 and decreases serine phosphorylation of Edc4, suggesting mTORC1 regulates Edc4 phosphorylation and activity in mRNA decapping.\",\n      \"method\": \"Co-immunoprecipitation, immunoblotting, confocal colocalization, rapamycin treatment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up, no identification of specific phosphorylation site or functional consequence of phosphorylation\",\n      \"pmids\": [\"25514416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A naturally occurring 26 amino acid deletion in the serine-rich linker region of Drosophila Ge-1 confers resistance to sigma virus infection. Knockdown of the susceptible allele decreases viral titre. DCP1, which interacts with Ge-1, also protects against sigma virus. Ge-1-based resistance is not dependent on the siRNA pathway.\",\n      \"method\": \"Transgenic fly generation with sequence modification, viral titre assay, siRNA pathway epistasis test, knockdown experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic allele replacement, functional viral resistance assay, and pathway epistasis in single study\",\n      \"pmids\": [\"26799957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EDC4 is a member of the BRCA1-BRIP1-TOPBP1 complex and plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors.\",\n      \"method\": \"Co-immunoprecipitation (complex membership), HR assay, DNA end resection assay, drug sensitivity assay, genome instability measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (HR, resection, drug sensitivity, genome instability) plus complex identification by Co-IP in a single rigorous study\",\n      \"pmids\": [\"29511213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EDC4 interacts with MARF1 endoribonuclease and impairs MARF1 activity by preventing its LOTUS domains from binding target mRNAs. This represents a non-canonical role for EDC4 as a repressor of MARF1-mediated mRNA decay, distinct from its role as an enhancer of DCP2-mediated decapping.\",\n      \"method\": \"Co-immunoprecipitation, transcriptome-wide MARF1 target identification, LOTUS domain RNA binding assay, mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic interaction validated biochemically with transcriptome-wide analysis and functional domain mutagenesis in one study\",\n      \"pmids\": [\"32510323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EDC4 interacts with replication protein A (RPA) by immunoprecipitation and promotes RPA phosphorylation. EDC4 knockdown enhances cisplatin-induced DNA damage and sensitivity, while EDC4 overexpression reduces DNA damage. RPA knockdown reverses the inhibitory effect of EDC4 on cisplatin-induced DNA damage, placing RPA downstream of EDC4 in this pathway.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, γH2AX immunofluorescence, MTT/colony assays, epistasis by double knockdown\",\n      \"journal\": \"Hereditas\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus functional epistasis but single lab, and mechanism of RPA phosphorylation promotion is not directly established\",\n      \"pmids\": [\"33054858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Disrupting the EDC4-XRN1 interaction or altering their stoichiometry inhibits mRNA decapping and stabilizes microRNA-targeted mRNAs in a translationally repressed state. This concomitantly leads to larger P-bodies that are responsible for preventing mRNA decapping. P-bodies support cell viability and prevent stress granule formation when XRN1 is limiting.\",\n      \"method\": \"Interaction disruption mutants, mRNA stability assays, P-body size measurements, microRNA reporter assays, cell viability assays, stress granule imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (interaction mutants, mRNA stability, P-body dynamics, stress granule assays) in single rigorous study establishing causal mechanism\",\n      \"pmids\": [\"37621215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In C. elegans, EDC-4 counteracts EDC-3 and promotes assembly of DCAP-2 (DCP2) with the GID/CTLH complex (a ubiquitin ligase involved in maternal-to-zygotic transition), linking the mRNA decapping scaffold to the ubiquitin-proteasome system during embryonic development.\",\n      \"method\": \"Genetic interaction studies, co-immunoprecipitation, mRNA stability assays, fluorescence microscopy in C. elegans\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and biochemical complex identification in C. elegans ortholog, single lab\",\n      \"pmids\": [\"39331503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The EDC4 C-terminal domain (residues 1266-1401) is the minimal region required for P-body formation, driving phase separation and EDC4 condensation. The microprotein Nobody (NBDY) 22-41 peptide directly binds the EDC4 C-terminal domain and inhibits its self-association, selectively dissolving P-bodies without affecting the canonical mRNA decay pathway. P-body disruption activates the p53 pathway and enhances stability of associated transcripts.\",\n      \"method\": \"Deletion mapping, phase separation assay, direct binding assay (NBDY peptide to EDC4 CTD), P-body dissolution assay, transcriptome profiling, p53 pathway reporter\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstitution of phase separation, direct peptide binding, transcriptome profiling, and functional pathway readout in single study with multiple orthogonal methods\",\n      \"pmids\": [\"40360209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ebola virus VP35 protein binds the EDC4 scaffold protein through the EDC4 C-terminal subdomain, with both proteins colocalizing in EBOV-infected cells. siRNA depletion of EDC4 reduces EBOV replication by inhibiting early viral RNA synthesis.\",\n      \"method\": \"Proximity-dependent biotinylation (BioID), co-immunoprecipitation, colocalization imaging in infected cells, siRNA knockdown with viral RNA synthesis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity ligation plus colocalization plus functional knockdown in infected cells, single lab\",\n      \"pmids\": [\"41006235\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EDC4 (Ge-1/HEDLS) functions as a large scaffold protein central to cytoplasmic P-body assembly and mRNA decapping: its C-terminal domain (residues 1266–1401, adopting an ARM/HEAT-repeat fold) drives phase separation and P-body formation, provides simultaneous binding sites for DCP1, DCP2, and XRN1 via short linear motifs, and facilitates DCP1-mediated activation of the DCP2 decapping enzyme; the EDC4–XRN1 interaction controls P-body dynamics to couple decapping with 5'–3' decay, while EDC4 also acts as a repressor of MARF1 endonuclease activity, a member of the BRCA1-BRIP1-TOPBP1 complex that stimulates homologous recombination end resection, an inhibitor of CoA synthase dephospho-CoA kinase activity, and an interaction partner of RPA that promotes DNA repair and contributes to chemoresistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EDC4 (Ge-1/HEDLS) is a large scaffold protein that nucleates cytoplasmic processing bodies (P-bodies) and organizes the 5'-to-3' mRNA decapping machinery [#0, #2]. Its C-terminal domain is necessary and sufficient for P-body targeting and adopts an all-α-helical ARM/HEAT-repeat fold, with conserved surface residues required for localization [#0, #1]; the minimal region (residues 1266-1401) drives phase separation and self-association to build the P-body condensate [#13]. On this scaffold EDC4 provides simultaneous binding sites for DCP1, DCP2, and XRN1 via short linear motifs, facilitating the weak DCP1-DCP2 interaction and promoting DCP1-mediated activation of the DCP2 decapping enzyme, thereby coupling decapping to XRN1 5'-to-3' decay [#2]. The EDC4-XRN1 interaction and stoichiometry govern P-body dynamics: disrupting it inhibits decapping, enlarges P-bodies, and stabilizes microRNA-targeted mRNAs in a translationally repressed state, with P-bodies supporting cell viability and suppressing stress granule formation [#11]. Beyond canonical decapping enhancement, EDC4 acts as a repressor of the MARF1 endoribonuclease by preventing its LOTUS domains from binding target mRNAs [#9]. EDC4 additionally functions in genome maintenance as a member of the BRCA1-BRIP1-TOPBP1 complex that stimulates double-strand-break end resection during homologous recombination, with its loss causing genome instability and hypersensitivity to interstrand cross-linkers and PARP inhibitors [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established EDC4 as a core architectural component of P-bodies acting upstream of the decapping enzyme, answering whether it is structural or merely a passenger.\",\n      \"evidence\": \"siRNA knockdown, deletion mapping, and colocalization epistasis with DCP1a/DCP2 in mammalian cells\",\n      \"pmids\": [\"16314453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of C-terminal targeting\", \"Did not establish molecular partners on the C-terminal domain\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the fold of the P-body-targeting C-terminal domain as an ARM/HEAT-repeat structure and pinpointed a conserved residue essential for localization.\",\n      \"evidence\": \"X-ray crystallography and structure-based mutagenesis of the Drosophila Ge-1 C-terminal domain\",\n      \"pmids\": [\"18755833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map binding sites for specific decapping factors\", \"Did not address phase separation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how EDC4 organizes the decapping reaction by showing it scaffolds DCP1, DCP2, and XRN1 simultaneously and promotes DCP1-dependent DCP2 activation, coupling decapping to 5'-to-3' decay.\",\n      \"evidence\": \"Co-immunoprecipitation, SLiM/mutational mapping, and in vivo decapping assays in human cells\",\n      \"pmids\": [\"24510189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the in vivo stoichiometry controlling P-body dynamics\", \"Structural detail of the scaffold-bound complex not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a non-decapping activity in which EDC4 binds and inhibits CoA synthase dephospho-CoA kinase activity, coupling EDC4 to growth-factor/stress signalling and proliferation.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro kinase assay, and overexpression proliferation assay\",\n      \"pmids\": [\"22982864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular significance of CoAsy inhibition not established in vivo\", \"Single lab without mechanistic follow-up\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed the EDC4 ortholog is essential for germline P-body formation and contributes to mRNP integrity, addressing its developmental requirement.\",\n      \"evidence\": \"Genetic knockouts, immunohistochemistry, and epistasis in Drosophila germline\",\n      \"pmids\": [\"21655181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular role in oskar RNP integrity unresolved\", \"Findings in ortholog, not mammalian system\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked an EDC4 linker-region polymorphism to antiviral resistance, implicating the decapping scaffold in host defence independent of the siRNA pathway.\",\n      \"evidence\": \"Transgenic allele replacement, viral titre assays, and pathway epistasis in Drosophila\",\n      \"pmids\": [\"26799957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the serine-rich linker confers resistance unknown\", \"Not tested in mammalian antiviral contexts\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed an unexpected nuclear genome-maintenance role: EDC4 is a BRCA1-BRIP1-TOPBP1 complex member that stimulates end resection in homologous recombination.\",\n      \"evidence\": \"Co-IP complex identification, HR and end-resection assays, drug sensitivity, and genome instability measurement\",\n      \"pmids\": [\"29511213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular activity of EDC4 within the resection step not defined\", \"Relationship between cytoplasmic decapping and HR roles unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a repressive RNA role distinct from decapping enhancement: EDC4 inhibits MARF1 endoribonuclease by blocking LOTUS-domain mRNA binding.\",\n      \"evidence\": \"Co-IP, transcriptome-wide MARF1 target mapping, LOTUS RNA-binding assay, and mutagenesis\",\n      \"pmids\": [\"32510323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological balance between MARF1 repression and DCP2 enhancement unknown\", \"Regulation of the EDC4-MARF1 switch undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected EDC4 to the DNA-damage response through RPA, showing it promotes RPA phosphorylation and limits cisplatin damage, contributing to chemoresistance.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, γH2AX imaging, and double-knockdown epistasis placing RPA downstream\",\n      \"pmids\": [\"33054858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which EDC4 promotes RPA phosphorylation not established\", \"Single lab, not reciprocally validated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that EDC4-XRN1 interaction and stoichiometry control P-body size and decay flux, defining P-bodies as regulators of mRNA fate, viability, and stress-granule suppression.\",\n      \"evidence\": \"Interaction-disruption mutants, mRNA stability and miRNA reporter assays, P-body sizing, and stress granule imaging\",\n      \"pmids\": [\"37621215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative rules governing condensate growth versus decay incompletely defined\", \"Upstream signals tuning stoichiometry unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tied the decapping scaffold to the ubiquitin-proteasome system, showing EDC4 promotes DCP2 assembly with the GID/CTLH ligase during the maternal-to-zygotic transition.\",\n      \"evidence\": \"Genetic interaction, Co-IP, and mRNA stability assays in C. elegans\",\n      \"pmids\": [\"39331503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of the EDC4-GID/CTLH link in mammals untested\", \"Direct versus indirect bridging not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the minimal phase-separating domain and a microprotein inhibitor (NBDY) that selectively dissolves P-bodies, showing condensate disruption activates the p53 pathway and stabilizes transcripts.\",\n      \"evidence\": \"Deletion mapping, phase separation reconstitution, direct NBDY-peptide binding, transcriptome profiling, and p53 reporter\",\n      \"pmids\": [\"40360209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking P-body dissolution to p53 activation not defined\", \"Endogenous regulation of NBDY-mediated dissolution unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed Ebola virus VP35 hijacks the EDC4 scaffold to support early viral RNA synthesis, implicating the P-body scaffold in viral replication.\",\n      \"evidence\": \"BioID, Co-IP, colocalization in infected cells, and siRNA knockdown with viral RNA synthesis assay\",\n      \"pmids\": [\"41006235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which EDC4 supports viral RNA synthesis undefined\", \"Whether decapping activity is required not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EDC4's cytoplasmic decapping/scaffolding function is mechanistically integrated with its nuclear HR and DNA-damage-response roles, and how cells partition EDC4 between these activities, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking the decapping scaffold to the BRCA1-BRIP1-TOPBP1 complex\", \"Signals controlling EDC4 subcellular partitioning unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 9, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"complexes\": [\n      \"mRNA decapping complex (DCP1-DCP2-XRN1 scaffold)\",\n      \"P-body\",\n      \"BRCA1-BRIP1-TOPBP1 complex\"\n    ],\n    \"partners\": [\n      \"DCP1\",\n      \"DCP2\",\n      \"XRN1\",\n      \"MARF1\",\n      \"RPA\",\n      \"CoAsy\",\n      \"BRCA1\",\n      \"TOPBP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}