{"gene":"ERH","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2005,"finding":"Crystal structure of murine ERH determined at 2.1 Å resolution, revealing a novel alpha+beta fold comprising three alpha-helices and four beta-strands. ERH forms a homodimer through interactions between beta-sheet regions, confirmed by analytical ultracentrifugation. Conserved residues at the core and dimer interface suggest conservation of both monomer fold and dimer formation. Putative phosphorylation sites were identified at Thr18 and Ser24.","method":"X-ray crystallography (MAD phasing), analytical ultracentrifugation","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.1 Å with orthogonal solution-phase validation of dimerization; replicated by subsequent structures from other labs","pmids":["15937287"],"is_preprint":false},{"year":2007,"finding":"Human ERH (HEF2/ERH) crystal structure determined at 1.55 Å, confirming the novel alpha+beta fold with a four-strand antiparallel beta-sheet and three alpha-helices. The physiological dimer forms a pseudo-beta-barrel at the interface with a cavity channel. Docking analysis suggests ERH may regulate the oligomeric state of its partner DCOH/PCD.","method":"X-ray crystallography, in silico protein-protein docking","journal":"Proteins","confidence":"High","confidence_rationale":"Tier 1 / Strong — 1.55 Å crystal structure of human ERH, independent replication of dimeric architecture","pmids":["17444515"],"is_preprint":false},{"year":2001,"finding":"Xenopus ERH (XERH), which is identical in amino acid sequence to mammalian ERH, was identified as a binding partner of DCoH/PCD (dimerization cofactor of HNF1) by yeast two-hybrid assay. When fused to the GAL4 DNA-binding domain, XERH represses a GAL4-responsive reporter in HeLa cells (but not NIH3T3 cells), and inhibits DCoH/PCD coactivation of an HNF1-responsive reporter, establishing ERH as a cell-type-specific transcriptional repressor that interferes with HNF1-dependent gene regulation via DCoH/PCD.","method":"Yeast two-hybrid, GAL4-fusion transcriptional reporter assay, HNF1-responsive reporter assay","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus two orthogonal reporter assays in a single lab; cell-type specificity documented","pmids":["11688721"],"is_preprint":false},{"year":2012,"finding":"ERH interacts with the spliceosome protein SNRPD3 (an Sm complex component) and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E protein and chromosome congression defects. ERH depletion also broadly alters expression of cell cycle genes. KRAS-mutant cancer cells show greater sensitivity to ERH depletion than KRAS wild-type cells.","method":"Co-immunoprecipitation, RNAi knockdown, gene expression profiling, chromosome congression assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP of ERH–SNRPD3, RNAi phenotype with defined molecular readout (CENP-E splicing), replicated across multiple cell lines and supported by gene expression data","pmids":["23236152"],"is_preprint":false},{"year":2012,"finding":"ERH depletion causes severe chromosome misalignment and weakened kinetochore-microtubule attachment during mitosis. ERH depletion causes dissociation of CENP-E (a mitotic kinesin involved in stabilizing kinetochore-microtubule attachment) from kinetochores, establishing that ERH contributes to chromosome alignment at the metaphase plate by maintaining CENP-E at kinetochores.","method":"RNAi knockdown, immunofluorescence microscopy of mitotic chromosomes and kinetochores","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with clear kinetochore localization phenotype and CENP-E mislocalization, single lab but two orthogonal readouts (chromosome alignment, CENP-E IF)","pmids":["22704934"],"is_preprint":false},{"year":2019,"finding":"In fission yeast, the ERH ortholog Erh1 forms the Erh1-Mmi1 complex (EMC) with the YTH-family RNA-binding protein Mmi1 in a 2:2 stoichiometry, mediated by a conserved hydrophobic dimer interface. Co-crystal structure of the EMC was determined. Structure-guided mutation of Mmi1 Trp112, required for Erh1 binding, causes defects in facultative heterochromatin assembly and gene silencing while leaving Mmi1-mediated transcription termination intact, demonstrating that the ERH–YTH interaction is specifically required for gene silencing.","method":"Co-crystal structure, structure-guided mutagenesis, ChIP, RNA-seq, genetic analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-crystal structure plus structure-guided mutagenesis with functional genetic readouts (heterochromatin assembly, gene silencing); multiple orthogonal methods in one study","pmids":["30651569"],"is_preprint":false},{"year":2020,"finding":"ERH is a component of the Microprocessor complex (DROSHA/DGCR8). Crystal structure and biochemical experiments reveal that ERH uses its hydrophobic groove to bind a conserved region in the N-terminus of DGCR8 in a 2:2 stoichiometry. Knockdown of ERH or deletion of the DGCR8 N-terminus reduces processing of suboptimal pri-miRNAs in polycistronic miRNA clusters. ERH increases processing of suboptimal pri-miR-451 in a manner dependent on its neighboring pri-miR-144, suggesting that the ERH dimer mediates 'cluster assistance' by helping load Microprocessor onto poor substrates.","method":"Co-crystal structure, biochemical binding assays, ERH knockdown, pri-miRNA processing assay, Northern blot","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of ERH–DGCR8 complex with stoichiometry determination, corroborated by functional knockdown and processing assays; multiple orthogonal methods","pmids":["33035348"],"is_preprint":false},{"year":2020,"finding":"ERH copurifies with Microprocessor and can dimerize and interact with other proteins that dimerize. ERH is required for the 'cluster assistance' phenomenon in which a helper miRNA hairpin in a polycistronic cluster augments processing of an otherwise defective neighboring hairpin (e.g., miR-451 with miR-144 as helper). This effect requires Microprocessor recognition of the helper hairpin, physical linkage of the two hairpins, and ERH, suggesting ERH bridges two Microprocessor complexes.","method":"Biochemical copurification, miRNA processing reporter assays, ERH knockdown/complementation, RNA-seq","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — copurification with Microprocessor, systematic dissection of cluster assistance requirements with multiple hairpin/linker variants and ERH knockdown; replicated by independent lab (Kwon et al. 2020)","pmids":["32302541"],"is_preprint":false},{"year":2013,"finding":"ERH is localized to nuclear speckles when coexpressed with PDIP46/SKAR in HeLa cells, and to replication foci when coexpressed with Ciz1. Mutagenesis identified specific ERH residues: H3A Q9A mutations diminish recruitment to nuclear speckles but not to replication foci; E37A T51A mutations impair replication foci recruitment while preserving nuclear speckle accumulation. These mutants show loss of interaction with PDIP46/SKAR and/or Ciz1 in GST pull-down assays. The beta-sheet surface of ERH (monomer form) mediates interaction with PDIP46/SKAR, while the loop between alpha1 and alpha2 helices mediates Ciz1 interaction.","method":"Site-directed mutagenesis, fluorescence microscopy, GST pull-down assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with pull-down and live-cell localization; single lab, two orthogonal methods","pmids":["24015320"],"is_preprint":false},{"year":2016,"finding":"Drosophila ERH nuclear localization requires the first 24 amino acids (which contain no canonical NLS). Three new ERH binding partners were identified by yeast two-hybrid: RPS3, RPL19, and DDIT4. RPS3 was identified in both human and Drosophila screens. The ERH sequences required for RPS3 and RPL19 interactions map to the same 24-amino-acid N-terminal region required for nuclear localization, suggesting ERH enters the nucleus through association with one of these DNA/RNA-binding partners.","method":"Yeast two-hybrid, deletion/truncation mutagenesis, nuclear localization assay","journal":"Molecular biology international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid identification of partners and localization mapping; single lab, replicated across human and Drosophila screens for RPS3","pmids":["27830090"],"is_preprint":false},{"year":2015,"finding":"RNA-binding protein Musashi-1 (MSI1) directly targets Erh mRNA in mouse spermatogonia, as identified through crosslinking and immunoprecipitation (CLIP) and validated in a transgenic Msi1 overexpression model, establishing Erh as a posttranscriptional target of MSI1 during early spermatogenesis.","method":"CLIP-seq, transgenic overexpression model, expression studies","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP identification of ERH mRNA as MSI1 target with transgenic model validation; single lab","pmids":["25782991"],"is_preprint":false},{"year":2019,"finding":"ERH knockdown in bladder cancer T24 and 5637 cells significantly inhibits cell migration and invasion in vitro and metastasis in vivo (nude mouse tail vein assay). Gene expression profiling revealed MYC as an important downstream target of ERH, and functional experiments confirmed MYC as a functional target mediating ERH's effect on metastasis in T24 cells.","method":"shRNA knockdown, wound healing assay, transwell migration/invasion assay, nude mouse metastasis assay, gene expression profiling, functional rescue experiments","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype (migration/invasion) plus in vivo assay and pathway placement via MYC; single lab","pmids":["30866868"],"is_preprint":false},{"year":2022,"finding":"ERH interacts with EIF2α (encoded by EIF2S1) in human T24 bladder cancer cells, as demonstrated by co-immunoprecipitation/shotgun mass spectrometry and immunofluorescence colocalization, with binding sites predicted by ZDOCK docking. ERH overexpression upregulates mRNA levels of ATF4 and CHOP, placing ERH upstream of the EIF2α/ATF4/CHOP integrated stress response pathway.","method":"Co-immunoprecipitation, shotgun mass spectrometry, immunofluorescence colocalization, ZDOCK computational docking, RT-PCR","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP/MS identification of interaction with orthogonal IF colocalization; pathway downstream effects confirmed by PCR; single lab","pmids":["35774124"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of the human ERH–CIZ1 complex was determined, showing that a CIZ1 fragment upstream of its first zinc finger is sufficient for ERH binding (confirmed by GST pull-down). The ERH dimer binds two CIZ1 fragments in a 2:2 heterotetramer. CIZ1 forms intermolecular antiparallel beta-strands with ERH, and its binding surface on ERH is distinct from those of other known ERH ligands (DGCR8, Mmi1). Interface validated by mutagenesis and binding experiments.","method":"X-ray crystallography, GST pull-down, mutagenesis, binding assays","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of complex with stoichiometry determination, validated by GST pull-down and mutagenesis; multiple orthogonal methods in one study","pmids":["36047590"],"is_preprint":false},{"year":1996,"finding":"Human ERH cDNA was cloned, encoding a 104 amino acid protein with 80% amino acid identity to Drosophila DROER (enhancer of rudimentary). The ERH gene was mapped to chromosomal band 7q34 by fluorescence in situ hybridization (FISH). ERH mRNA is expressed in all normal human tissues examined.","method":"cDNA cloning, sequence analysis, FISH chromosomal mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and chromosomal localization by FISH; foundational gene characterization","pmids":["8786099"],"is_preprint":false}],"current_model":"ERH is a small, highly conserved homodimeric nuclear protein (2:2 stoichiometry established by crystal structures) that functions as a scaffold for multiple RNA-processing complexes: it associates with the spliceosome Sm protein SNRPD3 to enable mRNA splicing of CENP-E (required for mitotic chromosome alignment), binds the N-terminus of DGCR8 to act as a Microprocessor component that facilitates processing of suboptimal miRNA hairpins in polycistronic clusters via a 'cluster assistance' mechanism, interacts with CIZ1 (via a distinct surface) to localize to replication foci, binds PDIP46/SKAR to accumulate in nuclear speckles, and in fission yeast its ortholog Erh1 forms a 2:2 complex with the YTH-protein Mmi1 to mediate facultative heterochromatin assembly and gene silencing—collectively indicating that ERH homodimerizes to present multiple ligand-binding surfaces that recruit different RNA-processing and chromatin-regulatory factors to maintain genome integrity."},"narrative":{"mechanistic_narrative":"ERH is a small, highly conserved nuclear protein that functions as an obligate homodimer to serve as a scaffold presenting multiple distinct ligand-binding surfaces that recruit RNA-processing and chromatin-regulatory factors to maintain genome integrity [PMID:15937287, PMID:17444515]. Crystal structures established that ERH adopts a novel alpha+beta fold and dimerizes through its beta-sheet regions to form a pseudo-beta-barrel interface [PMID:15937287, PMID:17444515]. Through this architecture ERH engages partners using surfaces that are biochemically separable: it binds the N-terminus of DGCR8 in a 2:2 stoichiometry as a Microprocessor component, where the ERH dimer bridges two Microprocessor complexes to mediate 'cluster assistance' processing of suboptimal pri-miRNAs in polycistronic clusters such as pri-miR-451 helped by pri-miR-144 [PMID:33035348, PMID:32302541]; it associates with the Sm spliceosome component SNRPD3 and is required for splicing of the mitotic kinesin CENP-E, with ERH loss causing CENP-E depletion, kinetochore-microtubule attachment defects, and chromosome misalignment [PMID:23236152, PMID:22704934]; and it binds a CIZ1 fragment via a surface distinct from that used for DGCR8, forming a 2:2 heterotetramer through intermolecular antiparallel beta-strand pairing [PMID:36047590, PMID:24015320]. The same scaffolding logic is conserved in fission yeast, where the Erh1 ortholog forms a 2:2 complex with the YTH RNA-binding protein Mmi1 that is specifically required for facultative heterochromatin assembly and gene silencing [PMID:30651569]. ERH depletion broadly perturbs cell-cycle gene expression, and KRAS-mutant cancer cells are preferentially sensitive to its loss [PMID:23236152]; in bladder cancer it promotes migration, invasion, and metastasis via the downstream target MYC [PMID:30866868].","teleology":[{"year":1996,"claim":"Establishing ERH as a discrete, ubiquitously expressed human gene conserved with Drosophila enhancer of rudimentary provided the molecular entry point for all subsequent mechanistic work.","evidence":"cDNA cloning, sequence analysis, and FISH chromosomal mapping","pmids":["8786099"],"confidence":"Medium","gaps":["No biochemical function assigned","No interacting partners identified"]},{"year":2001,"claim":"The first functional partner assignment came from linking ERH to DCoH/PCD-dependent HNF1 transcription, raising the possibility of a transcriptional regulatory role.","evidence":"Yeast two-hybrid and GAL4/HNF1-responsive reporter assays in cell lines","pmids":["11688721"],"confidence":"Medium","gaps":["Cell-type-specific repression mechanism unresolved","No structural basis for the DCoH interaction","Direct DNA binding not demonstrated"]},{"year":2005,"claim":"Determining the ERH fold and demonstrating homodimerization defined the structural platform that underlies its scaffolding function.","evidence":"Murine ERH X-ray crystallography at 2.1 A with analytical ultracentrifugation","pmids":["15937287"],"confidence":"High","gaps":["No partner-bound structure","Functional consequence of putative Thr18/Ser24 phosphorylation untested"]},{"year":2007,"claim":"An independent high-resolution human ERH structure confirmed the dimeric pseudo-beta-barrel architecture and mapped a candidate interface cavity for partner binding.","evidence":"Human ERH X-ray crystallography at 1.55 A with in silico docking","pmids":["17444515"],"confidence":"High","gaps":["Docking-predicted DCOH regulation not experimentally validated","No co-complex structure"]},{"year":2012,"claim":"Connecting ERH to SNRPD3 and CENP-E splicing established a concrete RNA-processing function with a mitotic readout, and tied ERH dependency to KRAS-mutant cancers.","evidence":"Reciprocal co-IP, RNAi, gene expression profiling, and chromosome congression/kinetochore imaging across cell lines","pmids":["23236152","22704934"],"confidence":"High","gaps":["Mechanism by which ERH selects CENP-E pre-mRNA unknown","Direct role within the spliceosome not structurally defined","Basis of KRAS-mutant selective vulnerability unexplained"]},{"year":2013,"claim":"Mutagenesis showed ERH uses biochemically separable surfaces to recruit distinct partners to distinct nuclear compartments, formalizing the multi-surface scaffold model.","evidence":"Site-directed mutagenesis, GST pull-down, and fluorescence microscopy of PDIP46/SKAR and Ciz1 recruitment","pmids":["24015320"],"confidence":"Medium","gaps":["Functional output of speckle vs replication-foci localization unresolved","No co-complex structures at this stage"]},{"year":2015,"claim":"Identifying Erh mRNA as a CLIP target of MSI1 placed ERH within a posttranscriptional regulatory circuit during spermatogenesis.","evidence":"CLIP-seq and transgenic Msi1 overexpression model in mouse spermatogonia","pmids":["25782991"],"confidence":"Medium","gaps":["Functional consequence of MSI1-mediated ERH regulation not established","Single lab"]},{"year":2016,"claim":"Mapping nuclear import to the ERH N-terminus and identifying ribosomal-protein partners suggested ERH reaches the nucleus by piggybacking on a nucleic-acid-binding partner rather than via a canonical NLS.","evidence":"Yeast two-hybrid, truncation mutagenesis, and nuclear localization assays in Drosophila and human cells","pmids":["27830090"],"confidence":"Medium","gaps":["Direct import partner not confirmed in cells","Y2H interactions lack orthogonal validation"]},{"year":2019,"claim":"The Erh1-Mmi1 co-crystal structure with structure-guided mutagenesis demonstrated that a 2:2 ERH-YTH complex is specifically required for heterochromatin assembly and gene silencing, separable from transcription termination.","evidence":"Co-crystal structure, structure-guided mutagenesis, ChIP, RNA-seq, and genetics in fission yeast","pmids":["30651569"],"confidence":"High","gaps":["Conservation of an analogous chromatin-silencing role in mammals not shown","Downstream silencing machinery recruited by EMC not fully defined"]},{"year":2020,"claim":"Structural and biochemical work defined ERH as a Microprocessor component that uses its hydrophobic groove to bind the DGCR8 N-terminus and bridge two Microprocessor complexes, enabling 'cluster assistance' processing of suboptimal pri-miRNAs.","evidence":"Co-crystal structure with stoichiometry, ERH knockdown, pri-miRNA processing/reporter assays, Northern blot, and RNA-seq (two independent labs)","pmids":["33035348","32302541"],"confidence":"High","gaps":["In vivo extent of cluster assistance across the miRNA repertoire not mapped","How ERH dimer geometry constrains hairpin spacing not fully resolved"]},{"year":2022,"claim":"The ERH-CIZ1 co-crystal structure showed CIZ1 binds via an intermolecular beta-strand on a surface distinct from the DGCR8 and Mmi1 sites, structurally confirming that the ERH dimer presents multiple non-overlapping ligand surfaces; separately, ERH was linked to EIF2alpha and the integrated stress response.","evidence":"X-ray crystallography, GST pull-down, mutagenesis (CIZ1); co-IP/MS, IF colocalization, docking, and RT-PCR (EIF2alpha) in bladder cancer cells","pmids":["36047590","35774124"],"confidence":"High","gaps":["Cellular function of the ERH-CIZ1 complex at replication foci not mechanistically defined","EIF2alpha interaction is single-lab co-IP/MS with predicted rather than validated interface"]},{"year":null,"claim":"How a single small dimer coordinates its many partner surfaces in a single cell, and whether its splicing, miRNA, replication-foci, and stress-response roles operate independently or are co-regulated, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model integrating ERH's distinct partner complexes","Regulation of partner selection (e.g., by phosphorylation) untested","Mammalian counterpart of the yeast heterochromatin-silencing role unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,7,13,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,9]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,6,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5]}],"complexes":["Microprocessor (DROSHA/DGCR8)","Erh1-Mmi1 complex (EMC)","ERH homodimer"],"partners":["DGCR8","SNRPD3","CIZ1","MMI1","PDIP46/SKAR","RPS3","EIF2S1","DCOH/PCD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P84090","full_name":"Enhancer of rudimentary homolog","aliases":[],"length_aa":104,"mass_kda":12.3,"function":"May have a role in the cell cycle","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P84090/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ERH","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBM39","stoichiometry":10.0},{"gene":"RTCB","stoichiometry":10.0},{"gene":"SF3A2","stoichiometry":10.0},{"gene":"SF3B1","stoichiometry":10.0},{"gene":"SNRPB","stoichiometry":10.0},{"gene":"SNRPC","stoichiometry":10.0},{"gene":"SSRP1","stoichiometry":10.0},{"gene":"TOP1","stoichiometry":10.0},{"gene":"CPSF6","stoichiometry":4.0},{"gene":"DDX21","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/ERH","total_profiled":1310},"omim":[{"mim_id":"601191","title":"ERH mRNA SPLICING AND MITOSIS FACTOR; ERH","url":"https://www.omim.org/entry/601191"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ERH"},"hgnc":{"alias_symbol":["DROER"],"prev_symbol":[]},"alphafold":{"accession":"P84090","domains":[{"cath_id":"3.30.2260.10","chopping":"2-102","consensus_level":"high","plddt":96.4238,"start":2,"end":102}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P84090","model_url":"https://alphafold.ebi.ac.uk/files/AF-P84090-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P84090-F1-predicted_aligned_error_v6.png","plddt_mean":95.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ERH","jax_strain_url":"https://www.jax.org/strain/search?query=ERH"},"sequence":{"accession":"P84090","fasta_url":"https://rest.uniprot.org/uniprotkb/P84090.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P84090/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P84090"}},"corpus_meta":[{"pmid":"31672964","id":"PMC_31672964","title":"Theabrownin from Pu-erh tea attenuates 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Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/16511088","citation_count":6,"is_preprint":false},{"pmid":"39638201","id":"PMC_39638201","title":"Theabrownin from Pu-erh tea attenuated high-fat diet-induced metabolic syndrome in rat by regulating microRNA and affecting gut microbiota.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39638201","citation_count":6,"is_preprint":false},{"pmid":"36047590","id":"PMC_36047590","title":"Molecular basis for the recognition of CIZ1 by ERH.","date":"2022","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/36047590","citation_count":5,"is_preprint":false},{"pmid":"34499597","id":"PMC_34499597","title":"Massilia puerhi sp. nov., isolated from soil of Pu-erh tea cellar.","date":"2021","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34499597","citation_count":5,"is_preprint":false},{"pmid":"39521187","id":"PMC_39521187","title":"High lead-tolerant mutant Bacillus tropicus AT31-1 from rhizosphere soil of Pu-erh and its remediation mechanism.","date":"2024","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/39521187","citation_count":5,"is_preprint":false},{"pmid":"7330047","id":"PMC_7330047","title":"Defective packing of an unusual DNA in a virulent Erwinia phage, Erh 1.","date":"1981","source":"Progress in clinical and biological research","url":"https://pubmed.ncbi.nlm.nih.gov/7330047","citation_count":5,"is_preprint":false},{"pmid":"22715783","id":"PMC_22715783","title":"[Spectroscopic and structural characteristics of the main components of Theabrownin in Pu-erh tea].","date":"2012","source":"Guang pu xue yu guang pu fen xi = Guang pu","url":"https://pubmed.ncbi.nlm.nih.gov/22715783","citation_count":5,"is_preprint":false},{"pmid":"36334004","id":"PMC_36334004","title":"ERH: a plug-and-play protein important for gene silencing and cell cycle progression.","date":"2022","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/36334004","citation_count":4,"is_preprint":false},{"pmid":"37266757","id":"PMC_37266757","title":"Effects of Pu-erh and Dian Hong tea polyphenols on the gut-liver axis in mice.","date":"2023","source":"AMB Express","url":"https://pubmed.ncbi.nlm.nih.gov/37266757","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47806,"output_tokens":4237,"usd":0.103486,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12236,"output_tokens":3831,"usd":0.078478,"stage2_stop_reason":"end_turn"},"total_usd":0.181964,"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\": \"Crystal structure of murine ERH determined at 2.1 Å resolution, revealing a novel alpha+beta fold comprising three alpha-helices and four beta-strands. ERH forms a homodimer through interactions between beta-sheet regions, confirmed by analytical ultracentrifugation. Conserved residues at the core and dimer interface suggest conservation of both monomer fold and dimer formation. Putative phosphorylation sites were identified at Thr18 and Ser24.\",\n      \"method\": \"X-ray crystallography (MAD phasing), analytical ultracentrifugation\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.1 Å with orthogonal solution-phase validation of dimerization; replicated by subsequent structures from other labs\",\n      \"pmids\": [\"15937287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human ERH (HEF2/ERH) crystal structure determined at 1.55 Å, confirming the novel alpha+beta fold with a four-strand antiparallel beta-sheet and three alpha-helices. The physiological dimer forms a pseudo-beta-barrel at the interface with a cavity channel. Docking analysis suggests ERH may regulate the oligomeric state of its partner DCOH/PCD.\",\n      \"method\": \"X-ray crystallography, in silico protein-protein docking\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — 1.55 Å crystal structure of human ERH, independent replication of dimeric architecture\",\n      \"pmids\": [\"17444515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Xenopus ERH (XERH), which is identical in amino acid sequence to mammalian ERH, was identified as a binding partner of DCoH/PCD (dimerization cofactor of HNF1) by yeast two-hybrid assay. When fused to the GAL4 DNA-binding domain, XERH represses a GAL4-responsive reporter in HeLa cells (but not NIH3T3 cells), and inhibits DCoH/PCD coactivation of an HNF1-responsive reporter, establishing ERH as a cell-type-specific transcriptional repressor that interferes with HNF1-dependent gene regulation via DCoH/PCD.\",\n      \"method\": \"Yeast two-hybrid, GAL4-fusion transcriptional reporter assay, HNF1-responsive reporter assay\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus two orthogonal reporter assays in a single lab; cell-type specificity documented\",\n      \"pmids\": [\"11688721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERH interacts with the spliceosome protein SNRPD3 (an Sm complex component) and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E protein and chromosome congression defects. ERH depletion also broadly alters expression of cell cycle genes. KRAS-mutant cancer cells show greater sensitivity to ERH depletion than KRAS wild-type cells.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, gene expression profiling, chromosome congression assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP of ERH–SNRPD3, RNAi phenotype with defined molecular readout (CENP-E splicing), replicated across multiple cell lines and supported by gene expression data\",\n      \"pmids\": [\"23236152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERH depletion causes severe chromosome misalignment and weakened kinetochore-microtubule attachment during mitosis. ERH depletion causes dissociation of CENP-E (a mitotic kinesin involved in stabilizing kinetochore-microtubule attachment) from kinetochores, establishing that ERH contributes to chromosome alignment at the metaphase plate by maintaining CENP-E at kinetochores.\",\n      \"method\": \"RNAi knockdown, immunofluorescence microscopy of mitotic chromosomes and kinetochores\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with clear kinetochore localization phenotype and CENP-E mislocalization, single lab but two orthogonal readouts (chromosome alignment, CENP-E IF)\",\n      \"pmids\": [\"22704934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In fission yeast, the ERH ortholog Erh1 forms the Erh1-Mmi1 complex (EMC) with the YTH-family RNA-binding protein Mmi1 in a 2:2 stoichiometry, mediated by a conserved hydrophobic dimer interface. Co-crystal structure of the EMC was determined. Structure-guided mutation of Mmi1 Trp112, required for Erh1 binding, causes defects in facultative heterochromatin assembly and gene silencing while leaving Mmi1-mediated transcription termination intact, demonstrating that the ERH–YTH interaction is specifically required for gene silencing.\",\n      \"method\": \"Co-crystal structure, structure-guided mutagenesis, ChIP, RNA-seq, genetic analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-crystal structure plus structure-guided mutagenesis with functional genetic readouts (heterochromatin assembly, gene silencing); multiple orthogonal methods in one study\",\n      \"pmids\": [\"30651569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERH is a component of the Microprocessor complex (DROSHA/DGCR8). Crystal structure and biochemical experiments reveal that ERH uses its hydrophobic groove to bind a conserved region in the N-terminus of DGCR8 in a 2:2 stoichiometry. Knockdown of ERH or deletion of the DGCR8 N-terminus reduces processing of suboptimal pri-miRNAs in polycistronic miRNA clusters. ERH increases processing of suboptimal pri-miR-451 in a manner dependent on its neighboring pri-miR-144, suggesting that the ERH dimer mediates 'cluster assistance' by helping load Microprocessor onto poor substrates.\",\n      \"method\": \"Co-crystal structure, biochemical binding assays, ERH knockdown, pri-miRNA processing assay, Northern blot\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of ERH–DGCR8 complex with stoichiometry determination, corroborated by functional knockdown and processing assays; multiple orthogonal methods\",\n      \"pmids\": [\"33035348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERH copurifies with Microprocessor and can dimerize and interact with other proteins that dimerize. ERH is required for the 'cluster assistance' phenomenon in which a helper miRNA hairpin in a polycistronic cluster augments processing of an otherwise defective neighboring hairpin (e.g., miR-451 with miR-144 as helper). This effect requires Microprocessor recognition of the helper hairpin, physical linkage of the two hairpins, and ERH, suggesting ERH bridges two Microprocessor complexes.\",\n      \"method\": \"Biochemical copurification, miRNA processing reporter assays, ERH knockdown/complementation, RNA-seq\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — copurification with Microprocessor, systematic dissection of cluster assistance requirements with multiple hairpin/linker variants and ERH knockdown; replicated by independent lab (Kwon et al. 2020)\",\n      \"pmids\": [\"32302541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERH is localized to nuclear speckles when coexpressed with PDIP46/SKAR in HeLa cells, and to replication foci when coexpressed with Ciz1. Mutagenesis identified specific ERH residues: H3A Q9A mutations diminish recruitment to nuclear speckles but not to replication foci; E37A T51A mutations impair replication foci recruitment while preserving nuclear speckle accumulation. These mutants show loss of interaction with PDIP46/SKAR and/or Ciz1 in GST pull-down assays. The beta-sheet surface of ERH (monomer form) mediates interaction with PDIP46/SKAR, while the loop between alpha1 and alpha2 helices mediates Ciz1 interaction.\",\n      \"method\": \"Site-directed mutagenesis, fluorescence microscopy, GST pull-down assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with pull-down and live-cell localization; single lab, two orthogonal methods\",\n      \"pmids\": [\"24015320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Drosophila ERH nuclear localization requires the first 24 amino acids (which contain no canonical NLS). Three new ERH binding partners were identified by yeast two-hybrid: RPS3, RPL19, and DDIT4. RPS3 was identified in both human and Drosophila screens. The ERH sequences required for RPS3 and RPL19 interactions map to the same 24-amino-acid N-terminal region required for nuclear localization, suggesting ERH enters the nucleus through association with one of these DNA/RNA-binding partners.\",\n      \"method\": \"Yeast two-hybrid, deletion/truncation mutagenesis, nuclear localization assay\",\n      \"journal\": \"Molecular biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid identification of partners and localization mapping; single lab, replicated across human and Drosophila screens for RPS3\",\n      \"pmids\": [\"27830090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RNA-binding protein Musashi-1 (MSI1) directly targets Erh mRNA in mouse spermatogonia, as identified through crosslinking and immunoprecipitation (CLIP) and validated in a transgenic Msi1 overexpression model, establishing Erh as a posttranscriptional target of MSI1 during early spermatogenesis.\",\n      \"method\": \"CLIP-seq, transgenic overexpression model, expression studies\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP identification of ERH mRNA as MSI1 target with transgenic model validation; single lab\",\n      \"pmids\": [\"25782991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERH knockdown in bladder cancer T24 and 5637 cells significantly inhibits cell migration and invasion in vitro and metastasis in vivo (nude mouse tail vein assay). Gene expression profiling revealed MYC as an important downstream target of ERH, and functional experiments confirmed MYC as a functional target mediating ERH's effect on metastasis in T24 cells.\",\n      \"method\": \"shRNA knockdown, wound healing assay, transwell migration/invasion assay, nude mouse metastasis assay, gene expression profiling, functional rescue experiments\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype (migration/invasion) plus in vivo assay and pathway placement via MYC; single lab\",\n      \"pmids\": [\"30866868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERH interacts with EIF2α (encoded by EIF2S1) in human T24 bladder cancer cells, as demonstrated by co-immunoprecipitation/shotgun mass spectrometry and immunofluorescence colocalization, with binding sites predicted by ZDOCK docking. ERH overexpression upregulates mRNA levels of ATF4 and CHOP, placing ERH upstream of the EIF2α/ATF4/CHOP integrated stress response pathway.\",\n      \"method\": \"Co-immunoprecipitation, shotgun mass spectrometry, immunofluorescence colocalization, ZDOCK computational docking, RT-PCR\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP/MS identification of interaction with orthogonal IF colocalization; pathway downstream effects confirmed by PCR; single lab\",\n      \"pmids\": [\"35774124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of the human ERH–CIZ1 complex was determined, showing that a CIZ1 fragment upstream of its first zinc finger is sufficient for ERH binding (confirmed by GST pull-down). The ERH dimer binds two CIZ1 fragments in a 2:2 heterotetramer. CIZ1 forms intermolecular antiparallel beta-strands with ERH, and its binding surface on ERH is distinct from those of other known ERH ligands (DGCR8, Mmi1). Interface validated by mutagenesis and binding experiments.\",\n      \"method\": \"X-ray crystallography, GST pull-down, mutagenesis, binding assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of complex with stoichiometry determination, validated by GST pull-down and mutagenesis; multiple orthogonal methods in one study\",\n      \"pmids\": [\"36047590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Human ERH cDNA was cloned, encoding a 104 amino acid protein with 80% amino acid identity to Drosophila DROER (enhancer of rudimentary). The ERH gene was mapped to chromosomal band 7q34 by fluorescence in situ hybridization (FISH). ERH mRNA is expressed in all normal human tissues examined.\",\n      \"method\": \"cDNA cloning, sequence analysis, FISH chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and chromosomal localization by FISH; foundational gene characterization\",\n      \"pmids\": [\"8786099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERH is a small, highly conserved homodimeric nuclear protein (2:2 stoichiometry established by crystal structures) that functions as a scaffold for multiple RNA-processing complexes: it associates with the spliceosome Sm protein SNRPD3 to enable mRNA splicing of CENP-E (required for mitotic chromosome alignment), binds the N-terminus of DGCR8 to act as a Microprocessor component that facilitates processing of suboptimal miRNA hairpins in polycistronic clusters via a 'cluster assistance' mechanism, interacts with CIZ1 (via a distinct surface) to localize to replication foci, binds PDIP46/SKAR to accumulate in nuclear speckles, and in fission yeast its ortholog Erh1 forms a 2:2 complex with the YTH-protein Mmi1 to mediate facultative heterochromatin assembly and gene silencing—collectively indicating that ERH homodimerizes to present multiple ligand-binding surfaces that recruit different RNA-processing and chromatin-regulatory factors to maintain genome integrity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ERH is a small, highly conserved nuclear protein that functions as an obligate homodimer to serve as a scaffold presenting multiple distinct ligand-binding surfaces that recruit RNA-processing and chromatin-regulatory factors to maintain genome integrity [#0, #1]. Crystal structures established that ERH adopts a novel alpha+beta fold and dimerizes through its beta-sheet regions to form a pseudo-beta-barrel interface [#0, #1]. Through this architecture ERH engages partners using surfaces that are biochemically separable: it binds the N-terminus of DGCR8 in a 2:2 stoichiometry as a Microprocessor component, where the ERH dimer bridges two Microprocessor complexes to mediate 'cluster assistance' processing of suboptimal pri-miRNAs in polycistronic clusters such as pri-miR-451 helped by pri-miR-144 [#6, #7]; it associates with the Sm spliceosome component SNRPD3 and is required for splicing of the mitotic kinesin CENP-E, with ERH loss causing CENP-E depletion, kinetochore-microtubule attachment defects, and chromosome misalignment [#3, #4]; and it binds a CIZ1 fragment via a surface distinct from that used for DGCR8, forming a 2:2 heterotetramer through intermolecular antiparallel beta-strand pairing [#13, #8]. The same scaffolding logic is conserved in fission yeast, where the Erh1 ortholog forms a 2:2 complex with the YTH RNA-binding protein Mmi1 that is specifically required for facultative heterochromatin assembly and gene silencing [#5]. ERH depletion broadly perturbs cell-cycle gene expression, and KRAS-mutant cancer cells are preferentially sensitive to its loss [#3]; in bladder cancer it promotes migration, invasion, and metastasis via the downstream target MYC [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing ERH as a discrete, ubiquitously expressed human gene conserved with Drosophila enhancer of rudimentary provided the molecular entry point for all subsequent mechanistic work.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and FISH chromosomal mapping\",\n      \"pmids\": [\"8786099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical function assigned\", \"No interacting partners identified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The first functional partner assignment came from linking ERH to DCoH/PCD-dependent HNF1 transcription, raising the possibility of a transcriptional regulatory role.\",\n      \"evidence\": \"Yeast two-hybrid and GAL4/HNF1-responsive reporter assays in cell lines\",\n      \"pmids\": [\"11688721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type-specific repression mechanism unresolved\", \"No structural basis for the DCoH interaction\", \"Direct DNA binding not demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Determining the ERH fold and demonstrating homodimerization defined the structural platform that underlies its scaffolding function.\",\n      \"evidence\": \"Murine ERH X-ray crystallography at 2.1 A with analytical ultracentrifugation\",\n      \"pmids\": [\"15937287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No partner-bound structure\", \"Functional consequence of putative Thr18/Ser24 phosphorylation untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"An independent high-resolution human ERH structure confirmed the dimeric pseudo-beta-barrel architecture and mapped a candidate interface cavity for partner binding.\",\n      \"evidence\": \"Human ERH X-ray crystallography at 1.55 A with in silico docking\",\n      \"pmids\": [\"17444515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Docking-predicted DCOH regulation not experimentally validated\", \"No co-complex structure\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connecting ERH to SNRPD3 and CENP-E splicing established a concrete RNA-processing function with a mitotic readout, and tied ERH dependency to KRAS-mutant cancers.\",\n      \"evidence\": \"Reciprocal co-IP, RNAi, gene expression profiling, and chromosome congression/kinetochore imaging across cell lines\",\n      \"pmids\": [\"23236152\", \"22704934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ERH selects CENP-E pre-mRNA unknown\", \"Direct role within the spliceosome not structurally defined\", \"Basis of KRAS-mutant selective vulnerability unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mutagenesis showed ERH uses biochemically separable surfaces to recruit distinct partners to distinct nuclear compartments, formalizing the multi-surface scaffold model.\",\n      \"evidence\": \"Site-directed mutagenesis, GST pull-down, and fluorescence microscopy of PDIP46/SKAR and Ciz1 recruitment\",\n      \"pmids\": [\"24015320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of speckle vs replication-foci localization unresolved\", \"No co-complex structures at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying Erh mRNA as a CLIP target of MSI1 placed ERH within a posttranscriptional regulatory circuit during spermatogenesis.\",\n      \"evidence\": \"CLIP-seq and transgenic Msi1 overexpression model in mouse spermatogonia\",\n      \"pmids\": [\"25782991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of MSI1-mediated ERH regulation not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapping nuclear import to the ERH N-terminus and identifying ribosomal-protein partners suggested ERH reaches the nucleus by piggybacking on a nucleic-acid-binding partner rather than via a canonical NLS.\",\n      \"evidence\": \"Yeast two-hybrid, truncation mutagenesis, and nuclear localization assays in Drosophila and human cells\",\n      \"pmids\": [\"27830090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct import partner not confirmed in cells\", \"Y2H interactions lack orthogonal validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The Erh1-Mmi1 co-crystal structure with structure-guided mutagenesis demonstrated that a 2:2 ERH-YTH complex is specifically required for heterochromatin assembly and gene silencing, separable from transcription termination.\",\n      \"evidence\": \"Co-crystal structure, structure-guided mutagenesis, ChIP, RNA-seq, and genetics in fission yeast\",\n      \"pmids\": [\"30651569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of an analogous chromatin-silencing role in mammals not shown\", \"Downstream silencing machinery recruited by EMC not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Structural and biochemical work defined ERH as a Microprocessor component that uses its hydrophobic groove to bind the DGCR8 N-terminus and bridge two Microprocessor complexes, enabling 'cluster assistance' processing of suboptimal pri-miRNAs.\",\n      \"evidence\": \"Co-crystal structure with stoichiometry, ERH knockdown, pri-miRNA processing/reporter assays, Northern blot, and RNA-seq (two independent labs)\",\n      \"pmids\": [\"33035348\", \"32302541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo extent of cluster assistance across the miRNA repertoire not mapped\", \"How ERH dimer geometry constrains hairpin spacing not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The ERH-CIZ1 co-crystal structure showed CIZ1 binds via an intermolecular beta-strand on a surface distinct from the DGCR8 and Mmi1 sites, structurally confirming that the ERH dimer presents multiple non-overlapping ligand surfaces; separately, ERH was linked to EIF2alpha and the integrated stress response.\",\n      \"evidence\": \"X-ray crystallography, GST pull-down, mutagenesis (CIZ1); co-IP/MS, IF colocalization, docking, and RT-PCR (EIF2alpha) in bladder cancer cells\",\n      \"pmids\": [\"36047590\", \"35774124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular function of the ERH-CIZ1 complex at replication foci not mechanistically defined\", \"EIF2alpha interaction is single-lab co-IP/MS with predicted rather than validated interface\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single small dimer coordinates its many partner surfaces in a single cell, and whether its splicing, miRNA, replication-foci, and stress-response roles operate independently or are co-regulated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model integrating ERH's distinct partner complexes\", \"Regulation of partner selection (e.g., by phosphorylation) untested\", \"Mammalian counterpart of the yeast heterochromatin-silencing role unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 7, 13, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"Microprocessor (DROSHA/DGCR8)\", \"Erh1-Mmi1 complex (EMC)\", \"ERH homodimer\"],\n    \"partners\": [\"DGCR8\", \"SNRPD3\", \"CIZ1\", \"Mmi1\", \"PDIP46/SKAR\", \"RPS3\", \"EIF2S1\", \"DCoH/PCD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}