{"gene":"ERI1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2013,"finding":"Crystal structure of the ternary complex of human SLBP RNA binding domain, human 3'hExo (ERI1), and a 26-nucleotide histone mRNA stem-loop RNA revealed that SLBP and 3'hExo have no direct protein-protein contact with each other; instead, induced structural changes in the loop of the stem-loop RNA mediate their cooperative binding. The 3' flanking sequence is positioned in the 3'hExo active site, but the ternary complex limits the extent of trimming.","method":"X-ray crystallography (crystal structure of ternary complex)","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at atomic resolution with direct functional implications for cooperative binding mechanism","pmids":["23329046"],"is_preprint":false},{"year":2012,"finding":"Eri1 trims mature histone mRNAs by two unpaired nucleotides at the 3' end but stalls at the double-stranded stem. Upon oligouridylation of histone mRNA, the Lsm1-7 heteroheptamer recognizes the oligo(U) tail and interacts with Eri1, enabling Eri1's catalytic activity to degrade the stem-loop in a stepwise manner, initiating replication-dependent histone mRNA decay.","method":"Mouse cell genetic knockout (Eri1-deficient cells), biochemical analysis of mRNA intermediates, co-immunoprecipitation of Lsm1-7 with Eri1","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, genetic KO with defined molecular phenotype, multiple orthogonal methods in single study","pmids":["23202588"],"is_preprint":false},{"year":2008,"finding":"Mouse Eri1 associates with ribosomes and ribosomal RNA, and catalyzes the final 3' end trimming step of 5.8S rRNA processing. Ribosomes from Eri1-deficient mice contain aberrantly extended 5.8S rRNA, and catalytically active Eri1 (but not a catalytically inactive mutant) restores wild-type 5.8S rRNA in vitro and in cells. Eri1 localizes to the cytoplasm and nucleus, with enrichment in the nucleolus. RNA binding residues in the SAP and linker domains promote stable association with rRNA.","method":"Genetic knockout (Eri1-deficient mice), in vitro reconstitution with catalytic mutant, subcellular fractionation/localization, mutagenesis of SAP and linker domains","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis, genetic KO, and localization, replicated in both mouse and C. elegans by parallel paper","pmids":["18438418"],"is_preprint":false},{"year":2008,"finding":"C. elegans ERI-1 and S. pombe Eri1 perform 3' end processing of 5.8S rRNA. Two protein isoforms of C. elegans ERI-1 are localized to the cytoplasm, and each isoform has distinct functions in rRNA processing versus negative regulation of RNA interference.","method":"Genetic analysis in C. elegans and S. pombe, isoform-specific functional assays, subcellular localization","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic analysis across two organisms, isoform-specific functional dissection, replicates mammalian findings","pmids":["18438419"],"is_preprint":false},{"year":2006,"finding":"3'hExo (ERI1) is a DEDDh family 3' exonuclease. Specific RNA binding requires the SAP domain and two lysines C-terminal to it. 3'hExo binds with highest affinity to the wild-type 3' end of histone mRNA. It has negligible exonuclease activity on DNA substrates. It removes 3' overhangs of siRNAs but cannot degrade the double-stranded region. The protein localizes mostly to the cytoplasm. Efficient degradation requires 2' and 3' hydroxyl groups at the last nucleotide.","method":"Mutagenesis of catalytic and RNA-binding residues, in vitro RNA/DNA degradation assays, RNA binding assays, subcellular localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis, in vitro reconstitution with multiple substrates, and localization in single rigorous study","pmids":["16912046"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of the nuclease domain of 3'hExo complexed with rAMP and Mg2+ at 1.6 Å resolution. The active site contains four acidic residues (D134, E136, D234, D298) coordinating a binuclear Mg2+ cluster, and H293 as a potential general base, consistent with DEDDh exonuclease family mechanism for 3'→5' hydrolytic cleavage of RNA.","method":"X-ray crystallography (1.6 Å resolution), metal coordination analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with active-site metal coordination directly revealing catalytic mechanism","pmids":["15451662"],"is_preprint":false},{"year":2006,"finding":"S. pombe Eri1 specifically degrades double-stranded siRNAs through two functional domains and represses accumulation of cellular siRNAs in vivo. Deletion of eri1+ causes increased siRNAs associated with the RITS complex, enhanced heterochromatic silencing, increased histone H3-K9 methylation, and elevated Swi6 protein levels, demonstrating that Eri1 negatively regulates RNAi-mediated heterochromatin assembly.","method":"Genetic deletion in S. pombe, chromatin immunoprecipitation (H3-K9 methylation), siRNA quantification, RITS complex co-immunoprecipitation","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple molecular readouts (siRNA levels, histone marks, protein levels, RITS association)","pmids":["16797182"],"is_preprint":false},{"year":2012,"finding":"Eri1 regulates microRNA homeostasis in mouse lymphocytes in a sequence-independent manner. Both NK and T cells deficient in Eri1 display a global increase in miRNA abundance. Ectopic Eri1 expression rescues defective miRNA expression in mature Eri1-deficient T cells. Eri1 deficiency causes cell-intrinsic defects in NK cell development, delayed Ly49 receptor acquisition, and impaired virus-specific expansion during MCMV infection.","method":"Genetic knockout (Eri1-/- mice), small RNA sequencing, ectopic Eri1 reconstitution in T cells, in vivo viral infection assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with rescue experiment, multiple cell types and readouts, in vivo functional assay","pmids":["22613798"],"is_preprint":false},{"year":2022,"finding":"3'hExo (ERI1) is essential for initiating histone mRNA degradation on polyribosomes by degrading into the 3' side of the stem-loop. Knockout of 3'hExo prevents initiation of 3'→5' degradation and stabilizes histone mRNA. 3'hExo cooperates with the specific TUTase TENT3B/TUT7 (ZCCHC6): 3'hExo trims histone mRNA to 3 nt after the stem-loop and maintains mRNA length during S-phase, while TUT7 uridylates degradation intermediates to promote degradation.","method":"CRISPR knockout of 3'hExo and TUT7, synchronized cell cycle experiments, RNA sequencing and Northern blotting of histone mRNA intermediates","journal":"RNA","confidence":"High","confidence_rationale":"Tier 2 / Strong — dual KO genetic epistasis with defined molecular phenotypes and multiple orthogonal readouts","pmids":["36041871"],"is_preprint":false},{"year":2020,"finding":"ERI1 interacts with the PB2, PB1, and NP components of influenza A virus ribonucleoproteins (vRNPs) and is required for viral mRNA transcription. The protein-protein interaction is RNA-dependent. Both the RNA-binding and exonuclease activities of ERI1 are required to promote influenza A virus transcription. During infection, SLBP and histone mRNAs co-purify with vRNPs alongside ERI1, indicating ERI1 is recruited as part of the histone pre-mRNA processing complex in the nucleus.","method":"Stringent interactomics screening, siRNA silencing, co-immunoprecipitation (RNase sensitivity tested), functional viral transcription assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with RNA-dependence test and siRNA knockdown with functional readout, single lab","pmids":["32960265"],"is_preprint":false},{"year":2023,"finding":"ERI1 missense variants causing loss of exoribonuclease activity lead to defective trimming of 5.8S rRNA 3' end and decreased degradation of replication-dependent histone mRNAs. Patient-derived iPSCs showed impaired in vitro chondrogenesis with downregulation of skeletal patterning genes, establishing ERI1 RNA metabolism function as required for human skeletal patterning and chondrogenesis.","method":"Patient-derived iPSC differentiation (chondrogenesis), biochemical assay of 5.8S rRNA processing and histone mRNA levels in patient cells, genotype-phenotype analysis of bi-allelic ERI1 variants","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell functional assays with multiple readouts, single study","pmids":["37352860"],"is_preprint":false},{"year":2023,"finding":"Uridylation of the histone mRNA stem-loop weakens SLBP binding affinity but allows 3'hExo to maintain contact with the stem-loop after partial degradation. Fluorescence polarization and EMSA showed both SLBP and 3'hExo can bind uridylated/partially degraded stem-loop intermediates with lower affinity. Molecular dynamics simulations revealed that uridylation disrupts key base pairs in partially degraded histone mRNA and that SLBP dephosphorylation (TPNK motif) further weakens RNA-protein interactions.","method":"Fluorescence polarization, EMSA, 1-µs molecular dynamics simulations (AMBER/NAMD force field)","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — biochemical binding assays with two orthogonal methods plus computational simulation, single lab","pmids":["37516934"],"is_preprint":false}],"current_model":"ERI1 (3'hExo/THEX1) is a conserved DEDDh-family 3'-to-5' exoribonuclease that acts through a binuclear metal active site to perform at least three major RNA metabolic functions: (1) it trims the 3' end of 5.8S rRNA as the final processing step in ribosome biogenesis, associating with ribosomes via its SAP and linker domains; (2) it binds the histone mRNA 3' stem-loop cooperatively with SLBP (without direct protein-protein contact) to trim histone mRNAs during S-phase and, after TUT7-mediated oligouridylation recruits the Lsm1-7 complex to interact with Eri1, it degrades the stem-loop to initiate cell-cycle-coupled mRNA decay; and (3) it degrades siRNAs and trims miRNAs to negatively regulate RNA interference and maintain global miRNA homeostasis in lymphocytes, with loss of Eri1 globally elevating miRNA levels and impairing NK cell development and antiviral immunity."},"narrative":{"mechanistic_narrative":"ERI1 (3'hExo/THEX1) is a DEDDh-family 3'-to-5' exoribonuclease that catalyzes multiple RNA maturation and decay reactions through a binuclear metal active site in which four acidic residues (D134, E136, D234, D298) coordinate two Mg2+ ions and H293 serves as the catalytic general base [PMID:15451662]. Its catalytic activity depends on 2' and 3' hydroxyls at the terminal nucleotide, is RNA-specific with negligible activity on DNA, and substrate engagement requires the SAP domain and adjacent lysines [PMID:16912046]. In ribosome biogenesis, ERI1 performs the final 3'-end trimming of 5.8S rRNA, associating with ribosomes and rRNA through RNA-binding residues in its SAP and linker domains; loss of catalytic activity produces aberrantly extended 5.8S rRNA [PMID:18438418, PMID:18438419]. In histone mRNA metabolism, ERI1 binds the 3' stem-loop cooperatively with SLBP without direct protein-protein contact, instead being coordinated through RNA loop conformational changes, with the 3' flanking sequence positioned in its active site [PMID:23329046]; it trims histone mRNA to a few nucleotides past the stem-loop and then, following TUT7/TENT3B-mediated uridylation and recruitment of the Lsm1-7 heptamer to the oligo(U) tail, degrades into the stem-loop to initiate replication-dependent histone mRNA decay [PMID:23202588, PMID:36041871]. ERI1 also negatively regulates RNA interference: it degrades siRNA 3' overhangs but not duplex regions and represses siRNA accumulation and RNAi-mediated heterochromatin assembly [PMID:16912046, PMID:16797182], and in mammalian lymphocytes it controls global miRNA homeostasis, with its loss elevating miRNA levels and impairing NK cell development and antiviral immunity [PMID:22613798]. Biallelic loss-of-function ERI1 variants impair 5.8S rRNA processing and histone mRNA decay and cause defective human skeletal patterning and chondrogenesis [PMID:37352860].","teleology":[{"year":2004,"claim":"Established the catalytic chemistry of ERI1 by resolving how its active site organizes metal-dependent RNA hydrolysis, defining it as a DEDDh exonuclease.","evidence":"X-ray crystallography of the nuclease domain with rAMP and Mg2+ at 1.6 Å resolution","pmids":["15451662"],"confidence":"High","gaps":["Structure captured an isolated nuclease domain without bound physiological substrate","Did not address how substrate specificity for histone mRNA versus rRNA is achieved"]},{"year":2006,"claim":"Defined ERI1 substrate preferences and domain requirements, showing it is an RNA-specific exonuclease that engages histone mRNA 3' ends and siRNA overhangs via the SAP domain.","evidence":"Active-site and RNA-binding mutagenesis with in vitro RNA/DNA degradation and binding assays plus localization","pmids":["16912046"],"confidence":"High","gaps":["In vitro substrate binding did not establish in vivo function for each substrate","How activity is restrained on cellular targets not resolved"]},{"year":2006,"claim":"Demonstrated that ERI1 negatively regulates RNAi in vivo by degrading siRNAs and limiting heterochromatin assembly, linking the exonuclease to small-RNA pathway suppression.","evidence":"Genetic deletion in S. pombe with siRNA quantification, ChIP for H3-K9 methylation, and RITS co-IP","pmids":["16797182"],"confidence":"High","gaps":["Mechanism of siRNA selection in vivo not detailed","Generality to mammalian small-RNA regulation not addressed here"]},{"year":2008,"claim":"Identified ERI1's role in ribosome biogenesis as the enzyme performing the terminal 3' trimming of 5.8S rRNA, conserved from yeast to mammals.","evidence":"Eri1-deficient mice and C. elegans/S. pombe genetics, in vitro reconstitution with catalytic mutants, subcellular fractionation, and SAP/linker mutagenesis","pmids":["18438418","18438419"],"confidence":"High","gaps":["How ERI1 is recruited to pre-ribosomes mechanistically unclear","Functional separation of rRNA versus RNAi roles (isoform-specific in C. elegans) not fully resolved in mammals"]},{"year":2012,"claim":"Resolved how cell-cycle-coupled histone mRNA decay is initiated, showing ERI1 stalls at the stem and is licensed to degrade it only after oligouridylation recruits Lsm1-7.","evidence":"Mouse Eri1 knockout cells, biochemical analysis of mRNA intermediates, and Lsm1-7 co-immunoprecipitation","pmids":["23202588"],"confidence":"High","gaps":["Direct contacts between Lsm1-7 and ERI1 not structurally defined","TUTase responsible for uridylation not identified in this study"]},{"year":2012,"claim":"Extended ERI1 function to mammalian miRNA homeostasis and immune development, showing it sets global miRNA abundance in lymphocytes sequence-independently.","evidence":"Eri1-/- mice with small RNA sequencing, ectopic Eri1 rescue in T cells, and in vivo MCMV infection assays","pmids":["22613798"],"confidence":"High","gaps":["Whether ERI1 acts directly on mature miRNAs or via trimming intermediates not fully separated","Molecular basis of NK developmental defect downstream of miRNA changes unclear"]},{"year":2013,"claim":"Explained the structural basis for cooperative histone mRNA recognition, showing SLBP and ERI1 cooperate through RNA conformational changes rather than direct protein contact, which limits trimming.","evidence":"X-ray crystallography of the SLBP–3'hExo–stem-loop ternary complex","pmids":["23329046"],"confidence":"High","gaps":["Static structure does not capture transition to active degradation","Does not show how the complex is destabilized to permit decay"]},{"year":2020,"claim":"Linked ERI1 to viral biology, showing it is recruited via the histone processing machinery to influenza vRNPs and is required for viral mRNA transcription.","evidence":"Interactomics, RNase-sensitive co-IP with PB2/PB1/NP, siRNA silencing, and viral transcription assays","pmids":["32960265"],"confidence":"Medium","gaps":["Single lab and not independently replicated","Whether ERI1 catalysis acts on viral RNA or on host RNA recruited to vRNPs unresolved"]},{"year":2022,"claim":"Established genetic epistasis showing ERI1 initiates polyribosome-associated histone mRNA degradation and cooperates with TUT7/TENT3B, which uridylates intermediates.","evidence":"CRISPR knockout of 3'hExo and TUT7, synchronized cell-cycle experiments, RNA-seq and Northern blot of mRNA intermediates","pmids":["36041871"],"confidence":"High","gaps":["Order and coupling of ERI1 trimming and TUT7 uridylation at single-molecule level not defined","Regulation of the switch from maintenance to degradation during S-phase exit unclear"]},{"year":2023,"claim":"Defined the biophysics of the decay transition, showing uridylation weakens SLBP binding while ERI1 retains contact with partially degraded intermediates.","evidence":"Fluorescence polarization, EMSA, and 1-µs molecular dynamics simulations","pmids":["37516934"],"confidence":"Medium","gaps":["Single lab; affinity measurements not validated by in-cell kinetics","MD predictions of base-pair disruption not structurally confirmed"]},{"year":2023,"claim":"Connected ERI1 RNA metabolism to human disease, showing biallelic loss-of-function variants impair rRNA and histone mRNA processing and cause skeletal patterning defects.","evidence":"Patient-derived iPSC chondrogenesis, biochemical assays of 5.8S rRNA and histone mRNA in patient cells, genotype-phenotype analysis","pmids":["37352860"],"confidence":"Medium","gaps":["Single study; tissue-specificity of skeletal phenotype mechanistically unexplained","Whether rRNA or histone mRNA defect (or both) drives chondrogenesis failure not separated"]},{"year":null,"claim":"How ERI1's distinct substrate roles (5.8S rRNA, histone mRNA, siRNA/miRNA) are partitioned and regulated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ERI1 engaged with rRNA or with the full decay machinery","Recruitment determinants directing ERI1 to each substrate class not defined","Mechanism coupling its activity to cell-cycle and immune signaling unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[4,5,2,1,8]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,4]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,4,3]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,1,8,7]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,8]}],"complexes":[],"partners":["SLBP","LSM1-7","TUT7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IV48","full_name":"3'-5' exoribonuclease 1","aliases":["3'-5' exonuclease ERI1","Eri-1 homolog","Histone mRNA 3'-end-specific exoribonuclease","Histone mRNA 3'-exonuclease 1","Protein 3'hExo","HEXO"],"length_aa":349,"mass_kda":40.1,"function":"RNA exonuclease that binds to the 3'-end of histone mRNAs and degrades them, suggesting that it plays an essential role in histone mRNA decay after replication (PubMed:14536070, PubMed:16912046, PubMed:17135487, PubMed:37352860). A 2' and 3'-hydroxyl groups at the last nucleotide of the histone 3'-end is required for efficient 3'-end histone mRNA exonuclease activity and degradation of RNA substrates (PubMed:14536070, PubMed:16912046, PubMed:17135487). Also able to degrade the 3'-overhangs of short interfering RNAs (siRNAs) in vitro, suggesting a possible role as regulator of RNA interference (RNAi) (PubMed:14961122). Required for binding the 5'-ACCCA-3' sequence present in stem-loop structure (PubMed:14536070, PubMed:16912046). Able to bind other mRNAs (PubMed:14536070, PubMed:16912046). Required for 5.8S rRNA 3'-end processing (PubMed:37352860). Also binds to 5.8s ribosomal RNA (By similarity). Binds with high affinity to the stem-loop structure of replication-dependent histone pre-mRNAs (PubMed:14536070, PubMed:16912046, PubMed:17135487). In vitro, does not have sequence specificity (PubMed:17135487). In vitro, has weak DNA exonuclease activity (PubMed:17135487). In vitro, shows biphasic kinetics such that there is rapid hydrolysis of the last three unpaired RNA nucleotides in the 39 flanking sequence followed by a much slower cleavage through the stem that occurs over a longer incubation period in the order of hours (PubMed:17135487). ERI1-mediated RNA metabolism plays a key role in chondrogenesis (PubMed:37352860)","subcellular_location":"Cytoplasm; Nucleus; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q8IV48/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ERI1","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DRG1","stoichiometry":0.2},{"gene":"EIF3G","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SRP68","stoichiometry":0.2},{"gene":"SSB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ERI1","total_profiled":1310},"omim":[{"mim_id":"620663","title":"SPONDYLOEPIMETAPHYSEAL DYSPLASIA, GUO-CAMPEAU TYPE; SEMDGC","url":"https://www.omim.org/entry/620663"},{"mim_id":"620662","title":"HOXHA-ALIU SYNDROME; HXAL","url":"https://www.omim.org/entry/620662"},{"mim_id":"609917","title":"ERI1 EXORIBONUCLEASE FAMILY MEMBER 3; ERI3","url":"https://www.omim.org/entry/609917"},{"mim_id":"608739","title":"EXORIBONUCLEASE 1; ERI1","url":"https://www.omim.org/entry/608739"},{"mim_id":"602422","title":"STEM-LOOP BINDING PROTEIN; SLBP","url":"https://www.omim.org/entry/602422"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ERI1"},"hgnc":{"alias_symbol":["3'HEXO"],"prev_symbol":["THEX1"]},"alphafold":{"accession":"Q8IV48","domains":[{"cath_id":"1.10.720.30","chopping":"63-116","consensus_level":"high","plddt":95.1144,"start":63,"end":116},{"cath_id":"3.30.420.10","chopping":"128-328","consensus_level":"high","plddt":98.205,"start":128,"end":328}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IV48","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IV48-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IV48-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ERI1","jax_strain_url":"https://www.jax.org/strain/search?query=ERI1"},"sequence":{"accession":"Q8IV48","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IV48.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IV48/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IV48"}},"corpus_meta":[{"pmid":"23329046","id":"PMC_23329046","title":"Structure of histone mRNA stem-loop, human stem-loop binding protein, and 3'hExo ternary complex.","date":"2013","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23329046","citation_count":102,"is_preprint":false},{"pmid":"23202588","id":"PMC_23202588","title":"Eri1 degrades the stem-loop of oligouridylated histone mRNAs to induce replication-dependent decay.","date":"2012","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23202588","citation_count":66,"is_preprint":false},{"pmid":"18438419","id":"PMC_18438419","title":"The exonuclease ERI-1 has a conserved dual role in 5.8S rRNA processing and RNAi.","date":"2008","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18438419","citation_count":60,"is_preprint":false},{"pmid":"22613798","id":"PMC_22613798","title":"Eri1 regulates microRNA homeostasis and mouse lymphocyte development and antiviral function.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22613798","citation_count":57,"is_preprint":false},{"pmid":"18438418","id":"PMC_18438418","title":"Mouse Eri1 interacts with the ribosome and catalyzes 5.8S rRNA processing.","date":"2008","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18438418","citation_count":55,"is_preprint":false},{"pmid":"16912046","id":"PMC_16912046","title":"Characterization of 3'hExo, a 3' exonuclease specifically interacting with the 3' end of histone mRNA.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16912046","citation_count":48,"is_preprint":false},{"pmid":"16797182","id":"PMC_16797182","title":"Conserved ribonuclease, Eri1, negatively regulates heterochromatin assembly in fission yeast.","date":"2006","source":"Current biology : 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characterization of Drosophila Snipper: A promiscuous member of the metazoan 3'hExo/ERI-1 family of 3' to 5' exonucleases.","date":"2006","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/17135487","citation_count":29,"is_preprint":false},{"pmid":"28488351","id":"PMC_28488351","title":"Homozygous microdeletion of the ERI1 and MFHAS1 genes in a patient with intellectual disability, limb abnormalities, and cardiac malformation.","date":"2017","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/28488351","citation_count":10,"is_preprint":false},{"pmid":"32960265","id":"PMC_32960265","title":"Influenza A virus co-opts ERI1 exonuclease bound to histone mRNA to promote viral transcription.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/32960265","citation_count":7,"is_preprint":false},{"pmid":"27966489","id":"PMC_27966489","title":"Reserpine requires the D2-type receptor, dop-3, and the exoribonuclease, eri-1, to extend the lifespan in C. elegans.","date":"2016","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/27966489","citation_count":7,"is_preprint":false},{"pmid":"17658462","id":"PMC_17658462","title":"esiRNA to eri-1 and adar-1 genes improving high doses of c-myc-directed esiRNA effect on mouse melanoma growth inhibition.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17658462","citation_count":6,"is_preprint":false},{"pmid":"27531275","id":"PMC_27531275","title":"ERIL1, the plant homologue of ERI-1, is involved in the processing of chloroplastic rRNAs.","date":"2016","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27531275","citation_count":5,"is_preprint":false},{"pmid":"36041871","id":"PMC_36041871","title":"Knockouts of TUT7 and 3'hExo show that they cooperate in histone mRNA maintenance and degradation.","date":"2022","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/36041871","citation_count":4,"is_preprint":false},{"pmid":"27617966","id":"PMC_27617966","title":"Anti-Ephrin Type-B Receptor 2 (EphB2) and Anti-Three Prime Histone mRNA EXonuclease 1 (THEX1) Autoantibodies in Scleroderma and Lupus.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27617966","citation_count":4,"is_preprint":false},{"pmid":"24475317","id":"PMC_24475317","title":"A pre- and co-knockdown of RNAseT enzyme, Eri-1, enhances the efficiency of RNAi induced gene silencing in Caenorhabditis elegans.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24475317","citation_count":4,"is_preprint":false},{"pmid":"37352860","id":"PMC_37352860","title":"Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.","date":"2023","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37352860","citation_count":3,"is_preprint":false},{"pmid":"36208065","id":"PMC_36208065","title":"ERI1: A case report of an autosomal recessive syndrome associated with developmental delay and distal limb abnormalities.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36208065","citation_count":3,"is_preprint":false},{"pmid":"39119676","id":"PMC_39119676","title":"The ER-Resident Ras Inhibitor 1 (Eri1) of Candida albicans Inhibits Hyphal Morphogenesis via the Ras-Independent cAMP-PKA Pathway.","date":"2024","source":"ACS infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39119676","citation_count":2,"is_preprint":false},{"pmid":"28626879","id":"PMC_28626879","title":"Snipper, an Eri1 homologue, affects histone mRNA abundance and is crucial for normal Drosophila melanogaster development.","date":"2017","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/28626879","citation_count":2,"is_preprint":false},{"pmid":"39945916","id":"PMC_39945916","title":"Congenital Bone Disorders Associated with ERI1-Mediated RNA Metabolism Dysfunction: Spondylo-Epi-Metaphyseal Dysplasia Guo-Campeau Type and Beyond.","date":"2025","source":"Current osteoporosis reports","url":"https://pubmed.ncbi.nlm.nih.gov/39945916","citation_count":0,"is_preprint":false},{"pmid":"37516934","id":"PMC_37516934","title":"Uridylation of the histone mRNA stem-loop weakens binding interactions with SLBP while maintaining interactions with 3'hExo.","date":"2023","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/37516934","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.29.24318222","title":"Genetic Evidence for Soluble VEGFR2 as a Protective Factor Against Macular Pucker","date":"2024-11-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.29.24318222","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.11.25325582","title":"Genome-wide association study and multi-ancestry meta-analysis identify common variants associated with carotid artery intima-media thickness","date":"2025-04-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.11.25325582","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14661,"output_tokens":3467,"usd":0.047994,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10989,"output_tokens":3914,"usd":0.076397,"stage2_stop_reason":"end_turn"},"total_usd":0.124391,"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\": 2013,\n      \"finding\": \"Crystal structure of the ternary complex of human SLBP RNA binding domain, human 3'hExo (ERI1), and a 26-nucleotide histone mRNA stem-loop RNA revealed that SLBP and 3'hExo have no direct protein-protein contact with each other; instead, induced structural changes in the loop of the stem-loop RNA mediate their cooperative binding. The 3' flanking sequence is positioned in the 3'hExo active site, but the ternary complex limits the extent of trimming.\",\n      \"method\": \"X-ray crystallography (crystal structure of ternary complex)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at atomic resolution with direct functional implications for cooperative binding mechanism\",\n      \"pmids\": [\"23329046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Eri1 trims mature histone mRNAs by two unpaired nucleotides at the 3' end but stalls at the double-stranded stem. Upon oligouridylation of histone mRNA, the Lsm1-7 heteroheptamer recognizes the oligo(U) tail and interacts with Eri1, enabling Eri1's catalytic activity to degrade the stem-loop in a stepwise manner, initiating replication-dependent histone mRNA decay.\",\n      \"method\": \"Mouse cell genetic knockout (Eri1-deficient cells), biochemical analysis of mRNA intermediates, co-immunoprecipitation of Lsm1-7 with Eri1\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, genetic KO with defined molecular phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"23202588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mouse Eri1 associates with ribosomes and ribosomal RNA, and catalyzes the final 3' end trimming step of 5.8S rRNA processing. Ribosomes from Eri1-deficient mice contain aberrantly extended 5.8S rRNA, and catalytically active Eri1 (but not a catalytically inactive mutant) restores wild-type 5.8S rRNA in vitro and in cells. Eri1 localizes to the cytoplasm and nucleus, with enrichment in the nucleolus. RNA binding residues in the SAP and linker domains promote stable association with rRNA.\",\n      \"method\": \"Genetic knockout (Eri1-deficient mice), in vitro reconstitution with catalytic mutant, subcellular fractionation/localization, mutagenesis of SAP and linker domains\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis, genetic KO, and localization, replicated in both mouse and C. elegans by parallel paper\",\n      \"pmids\": [\"18438418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"C. elegans ERI-1 and S. pombe Eri1 perform 3' end processing of 5.8S rRNA. Two protein isoforms of C. elegans ERI-1 are localized to the cytoplasm, and each isoform has distinct functions in rRNA processing versus negative regulation of RNA interference.\",\n      \"method\": \"Genetic analysis in C. elegans and S. pombe, isoform-specific functional assays, subcellular localization\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic analysis across two organisms, isoform-specific functional dissection, replicates mammalian findings\",\n      \"pmids\": [\"18438419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"3'hExo (ERI1) is a DEDDh family 3' exonuclease. Specific RNA binding requires the SAP domain and two lysines C-terminal to it. 3'hExo binds with highest affinity to the wild-type 3' end of histone mRNA. It has negligible exonuclease activity on DNA substrates. It removes 3' overhangs of siRNAs but cannot degrade the double-stranded region. The protein localizes mostly to the cytoplasm. Efficient degradation requires 2' and 3' hydroxyl groups at the last nucleotide.\",\n      \"method\": \"Mutagenesis of catalytic and RNA-binding residues, in vitro RNA/DNA degradation assays, RNA binding assays, subcellular localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis, in vitro reconstitution with multiple substrates, and localization in single rigorous study\",\n      \"pmids\": [\"16912046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of the nuclease domain of 3'hExo complexed with rAMP and Mg2+ at 1.6 Å resolution. The active site contains four acidic residues (D134, E136, D234, D298) coordinating a binuclear Mg2+ cluster, and H293 as a potential general base, consistent with DEDDh exonuclease family mechanism for 3'→5' hydrolytic cleavage of RNA.\",\n      \"method\": \"X-ray crystallography (1.6 Å resolution), metal coordination analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with active-site metal coordination directly revealing catalytic mechanism\",\n      \"pmids\": [\"15451662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"S. pombe Eri1 specifically degrades double-stranded siRNAs through two functional domains and represses accumulation of cellular siRNAs in vivo. Deletion of eri1+ causes increased siRNAs associated with the RITS complex, enhanced heterochromatic silencing, increased histone H3-K9 methylation, and elevated Swi6 protein levels, demonstrating that Eri1 negatively regulates RNAi-mediated heterochromatin assembly.\",\n      \"method\": \"Genetic deletion in S. pombe, chromatin immunoprecipitation (H3-K9 methylation), siRNA quantification, RITS complex co-immunoprecipitation\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple molecular readouts (siRNA levels, histone marks, protein levels, RITS association)\",\n      \"pmids\": [\"16797182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Eri1 regulates microRNA homeostasis in mouse lymphocytes in a sequence-independent manner. Both NK and T cells deficient in Eri1 display a global increase in miRNA abundance. Ectopic Eri1 expression rescues defective miRNA expression in mature Eri1-deficient T cells. Eri1 deficiency causes cell-intrinsic defects in NK cell development, delayed Ly49 receptor acquisition, and impaired virus-specific expansion during MCMV infection.\",\n      \"method\": \"Genetic knockout (Eri1-/- mice), small RNA sequencing, ectopic Eri1 reconstitution in T cells, in vivo viral infection assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with rescue experiment, multiple cell types and readouts, in vivo functional assay\",\n      \"pmids\": [\"22613798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"3'hExo (ERI1) is essential for initiating histone mRNA degradation on polyribosomes by degrading into the 3' side of the stem-loop. Knockout of 3'hExo prevents initiation of 3'→5' degradation and stabilizes histone mRNA. 3'hExo cooperates with the specific TUTase TENT3B/TUT7 (ZCCHC6): 3'hExo trims histone mRNA to 3 nt after the stem-loop and maintains mRNA length during S-phase, while TUT7 uridylates degradation intermediates to promote degradation.\",\n      \"method\": \"CRISPR knockout of 3'hExo and TUT7, synchronized cell cycle experiments, RNA sequencing and Northern blotting of histone mRNA intermediates\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dual KO genetic epistasis with defined molecular phenotypes and multiple orthogonal readouts\",\n      \"pmids\": [\"36041871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERI1 interacts with the PB2, PB1, and NP components of influenza A virus ribonucleoproteins (vRNPs) and is required for viral mRNA transcription. The protein-protein interaction is RNA-dependent. Both the RNA-binding and exonuclease activities of ERI1 are required to promote influenza A virus transcription. During infection, SLBP and histone mRNAs co-purify with vRNPs alongside ERI1, indicating ERI1 is recruited as part of the histone pre-mRNA processing complex in the nucleus.\",\n      \"method\": \"Stringent interactomics screening, siRNA silencing, co-immunoprecipitation (RNase sensitivity tested), functional viral transcription assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with RNA-dependence test and siRNA knockdown with functional readout, single lab\",\n      \"pmids\": [\"32960265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERI1 missense variants causing loss of exoribonuclease activity lead to defective trimming of 5.8S rRNA 3' end and decreased degradation of replication-dependent histone mRNAs. Patient-derived iPSCs showed impaired in vitro chondrogenesis with downregulation of skeletal patterning genes, establishing ERI1 RNA metabolism function as required for human skeletal patterning and chondrogenesis.\",\n      \"method\": \"Patient-derived iPSC differentiation (chondrogenesis), biochemical assay of 5.8S rRNA processing and histone mRNA levels in patient cells, genotype-phenotype analysis of bi-allelic ERI1 variants\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell functional assays with multiple readouts, single study\",\n      \"pmids\": [\"37352860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Uridylation of the histone mRNA stem-loop weakens SLBP binding affinity but allows 3'hExo to maintain contact with the stem-loop after partial degradation. Fluorescence polarization and EMSA showed both SLBP and 3'hExo can bind uridylated/partially degraded stem-loop intermediates with lower affinity. Molecular dynamics simulations revealed that uridylation disrupts key base pairs in partially degraded histone mRNA and that SLBP dephosphorylation (TPNK motif) further weakens RNA-protein interactions.\",\n      \"method\": \"Fluorescence polarization, EMSA, 1-µs molecular dynamics simulations (AMBER/NAMD force field)\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — biochemical binding assays with two orthogonal methods plus computational simulation, single lab\",\n      \"pmids\": [\"37516934\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERI1 (3'hExo/THEX1) is a conserved DEDDh-family 3'-to-5' exoribonuclease that acts through a binuclear metal active site to perform at least three major RNA metabolic functions: (1) it trims the 3' end of 5.8S rRNA as the final processing step in ribosome biogenesis, associating with ribosomes via its SAP and linker domains; (2) it binds the histone mRNA 3' stem-loop cooperatively with SLBP (without direct protein-protein contact) to trim histone mRNAs during S-phase and, after TUT7-mediated oligouridylation recruits the Lsm1-7 complex to interact with Eri1, it degrades the stem-loop to initiate cell-cycle-coupled mRNA decay; and (3) it degrades siRNAs and trims miRNAs to negatively regulate RNA interference and maintain global miRNA homeostasis in lymphocytes, with loss of Eri1 globally elevating miRNA levels and impairing NK cell development and antiviral immunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ERI1 (3'hExo/THEX1) is a DEDDh-family 3'-to-5' exoribonuclease that catalyzes multiple RNA maturation and decay reactions through a binuclear metal active site in which four acidic residues (D134, E136, D234, D298) coordinate two Mg2+ ions and H293 serves as the catalytic general base [#5]. Its catalytic activity depends on 2' and 3' hydroxyls at the terminal nucleotide, is RNA-specific with negligible activity on DNA, and substrate engagement requires the SAP domain and adjacent lysines [#4]. In ribosome biogenesis, ERI1 performs the final 3'-end trimming of 5.8S rRNA, associating with ribosomes and rRNA through RNA-binding residues in its SAP and linker domains; loss of catalytic activity produces aberrantly extended 5.8S rRNA [#2, #3]. In histone mRNA metabolism, ERI1 binds the 3' stem-loop cooperatively with SLBP without direct protein-protein contact, instead being coordinated through RNA loop conformational changes, with the 3' flanking sequence positioned in its active site [#0]; it trims histone mRNA to a few nucleotides past the stem-loop and then, following TUT7/TENT3B-mediated uridylation and recruitment of the Lsm1-7 heptamer to the oligo(U) tail, degrades into the stem-loop to initiate replication-dependent histone mRNA decay [#1, #8]. ERI1 also negatively regulates RNA interference: it degrades siRNA 3' overhangs but not duplex regions and represses siRNA accumulation and RNAi-mediated heterochromatin assembly [#4, #6], and in mammalian lymphocytes it controls global miRNA homeostasis, with its loss elevating miRNA levels and impairing NK cell development and antiviral immunity [#7]. Biallelic loss-of-function ERI1 variants impair 5.8S rRNA processing and histone mRNA decay and cause defective human skeletal patterning and chondrogenesis [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the catalytic chemistry of ERI1 by resolving how its active site organizes metal-dependent RNA hydrolysis, defining it as a DEDDh exonuclease.\",\n      \"evidence\": \"X-ray crystallography of the nuclease domain with rAMP and Mg2+ at 1.6 Å resolution\",\n      \"pmids\": [\"15451662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure captured an isolated nuclease domain without bound physiological substrate\", \"Did not address how substrate specificity for histone mRNA versus rRNA is achieved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined ERI1 substrate preferences and domain requirements, showing it is an RNA-specific exonuclease that engages histone mRNA 3' ends and siRNA overhangs via the SAP domain.\",\n      \"evidence\": \"Active-site and RNA-binding mutagenesis with in vitro RNA/DNA degradation and binding assays plus localization\",\n      \"pmids\": [\"16912046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro substrate binding did not establish in vivo function for each substrate\", \"How activity is restrained on cellular targets not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that ERI1 negatively regulates RNAi in vivo by degrading siRNAs and limiting heterochromatin assembly, linking the exonuclease to small-RNA pathway suppression.\",\n      \"evidence\": \"Genetic deletion in S. pombe with siRNA quantification, ChIP for H3-K9 methylation, and RITS co-IP\",\n      \"pmids\": [\"16797182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of siRNA selection in vivo not detailed\", \"Generality to mammalian small-RNA regulation not addressed here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified ERI1's role in ribosome biogenesis as the enzyme performing the terminal 3' trimming of 5.8S rRNA, conserved from yeast to mammals.\",\n      \"evidence\": \"Eri1-deficient mice and C. elegans/S. pombe genetics, in vitro reconstitution with catalytic mutants, subcellular fractionation, and SAP/linker mutagenesis\",\n      \"pmids\": [\"18438418\", \"18438419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ERI1 is recruited to pre-ribosomes mechanistically unclear\", \"Functional separation of rRNA versus RNAi roles (isoform-specific in C. elegans) not fully resolved in mammals\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how cell-cycle-coupled histone mRNA decay is initiated, showing ERI1 stalls at the stem and is licensed to degrade it only after oligouridylation recruits Lsm1-7.\",\n      \"evidence\": \"Mouse Eri1 knockout cells, biochemical analysis of mRNA intermediates, and Lsm1-7 co-immunoprecipitation\",\n      \"pmids\": [\"23202588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contacts between Lsm1-7 and ERI1 not structurally defined\", \"TUTase responsible for uridylation not identified in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended ERI1 function to mammalian miRNA homeostasis and immune development, showing it sets global miRNA abundance in lymphocytes sequence-independently.\",\n      \"evidence\": \"Eri1-/- mice with small RNA sequencing, ectopic Eri1 rescue in T cells, and in vivo MCMV infection assays\",\n      \"pmids\": [\"22613798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERI1 acts directly on mature miRNAs or via trimming intermediates not fully separated\", \"Molecular basis of NK developmental defect downstream of miRNA changes unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Explained the structural basis for cooperative histone mRNA recognition, showing SLBP and ERI1 cooperate through RNA conformational changes rather than direct protein contact, which limits trimming.\",\n      \"evidence\": \"X-ray crystallography of the SLBP–3'hExo–stem-loop ternary complex\",\n      \"pmids\": [\"23329046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structure does not capture transition to active degradation\", \"Does not show how the complex is destabilized to permit decay\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked ERI1 to viral biology, showing it is recruited via the histone processing machinery to influenza vRNPs and is required for viral mRNA transcription.\",\n      \"evidence\": \"Interactomics, RNase-sensitive co-IP with PB2/PB1/NP, siRNA silencing, and viral transcription assays\",\n      \"pmids\": [\"32960265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and not independently replicated\", \"Whether ERI1 catalysis acts on viral RNA or on host RNA recruited to vRNPs unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established genetic epistasis showing ERI1 initiates polyribosome-associated histone mRNA degradation and cooperates with TUT7/TENT3B, which uridylates intermediates.\",\n      \"evidence\": \"CRISPR knockout of 3'hExo and TUT7, synchronized cell-cycle experiments, RNA-seq and Northern blot of mRNA intermediates\",\n      \"pmids\": [\"36041871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order and coupling of ERI1 trimming and TUT7 uridylation at single-molecule level not defined\", \"Regulation of the switch from maintenance to degradation during S-phase exit unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the biophysics of the decay transition, showing uridylation weakens SLBP binding while ERI1 retains contact with partially degraded intermediates.\",\n      \"evidence\": \"Fluorescence polarization, EMSA, and 1-µs molecular dynamics simulations\",\n      \"pmids\": [\"37516934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; affinity measurements not validated by in-cell kinetics\", \"MD predictions of base-pair disruption not structurally confirmed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected ERI1 RNA metabolism to human disease, showing biallelic loss-of-function variants impair rRNA and histone mRNA processing and cause skeletal patterning defects.\",\n      \"evidence\": \"Patient-derived iPSC chondrogenesis, biochemical assays of 5.8S rRNA and histone mRNA in patient cells, genotype-phenotype analysis\",\n      \"pmids\": [\"37352860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study; tissue-specificity of skeletal phenotype mechanistically unexplained\", \"Whether rRNA or histone mRNA defect (or both) drives chondrogenesis failure not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ERI1's distinct substrate roles (5.8S rRNA, histone mRNA, siRNA/miRNA) are partitioned and regulated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ERI1 engaged with rRNA or with the full decay machinery\", \"Recruitment determinants directing ERI1 to each substrate class not defined\", \"Mechanism coupling its activity to cell-cycle and immune signaling unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [4, 5, 2, 1, 8]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 4]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 4, 3]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 1, 8, 7]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SLBP\", \"Lsm1-7\", \"TUT7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}