{"gene":"MEPCE","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2009,"finding":"MePCE caps 7SK snRNA in a LARP7-free state, likely co-transcriptionally. Upon incorporation into the 7SK snRNP, MePCE interacts with LARP7, which occludes MePCE's catalytic center and abolishes its capping activity. Despite loss of capping activity within the snRNP, MePCE retains a capping-independent function that promotes the LARP7–7SK interaction, stabilizing 7SK and facilitating assembly of a stable MePCE–LARP7–7SK subcomplex.","method":"Biochemical fractionation, co-immunoprecipitation, in vitro capping assays, RNAi knockdown with rescue experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vitro enzymatic assay, RNAi knockdown), replicated concept across subsequent papers","pmids":["19906723"],"is_preprint":false},{"year":2013,"finding":"MePCE binds to the short 5'-terminal G1-U4/U106-G111 helix-tail motif of 7SK snRNA; both the overall RNA structure and specific nucleotides provide information for MePCE's specific binding. LARP7 binds the 3'-terminal hairpin and U-rich tail. These interactions direct assembly of the core 7SK/MePCE/LARP7 snRNP in vivo.","method":"In vivo RNA-protein interaction assays (immunoprecipitation of RNA–protein complexes with mutant 7SK constructs)","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo binding assays with systematic RNA mutants, single lab","pmids":["23471002"],"is_preprint":false},{"year":2018,"finding":"X-ray crystal structures (2.0 Å and 2.1 Å) of the human MePCE methyltransferase domain bound to SAH and uncapped or capped 7SK substrates reveal that 7SK recognition is achieved via protein contacts to a 5'-hairpin–single-stranded RNA region, explaining MePCE specificity for 7SK and U6. The structures capture SAH and product RNA in near-transition-state geometry. Binding experiments show MePCE has higher affinity for capped versus uncapped 7SK, and kinetic data support slow product release, providing the mechanism for 7SK retention by MePCE after cap methylation.","method":"X-ray crystallography (2.0 Å / 2.1 Å), binding affinity measurements, kinetic assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structures with kinetic and binding validation, multiple orthogonal methods in one study","pmids":["30559425"],"is_preprint":false},{"year":2018,"finding":"MePCE binds to the histone H4 tail on chromatin and serves as a P-TEFb activator at specific genes controlling cellular identity. This histone-binding activity abolishes MePCE's RNA methyltransferase activity toward 7SK, explaining why chromatin-bound MePCE–P-TEFb complexes are not associated with the full 7SK snRNP and are competent to activate RNAP II. This crosstalk between histone-binding and RNA methylation activities regulates P-TEFb activation on chromatin in a 7SK- and Brd4-independent manner.","method":"ChIP, co-immunoprecipitation, in vitro histone-binding assays, RNA methyltransferase activity assays, RNAi knockdown with gene expression readouts","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, enzymatic assay), single lab","pmids":["29425494"],"is_preprint":false},{"year":2020,"finding":"JMJD6 cleaves MePCE proteolytically in vivo and in vitro. Crystal structure of JMJD6 bound to methyl-arginine and enzymatic assays establish MePCE as a cognate substrate for JMJD6's proteolytic activity. Cleavage of MePCE disrupts the 7SK snRNP complex, releasing P-TEFb, and Jmjd6 knockout/overexpression modulates RNAP II CTD phosphorylation downstream.","method":"X-ray crystallography (JMJD6–methyl-arginine), in vitro and in vivo proteolytic assays, binding assays, Jmjd6 knockout and overexpression with CTD phosphorylation readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro enzymatic assay plus in vivo genetic models with functional readout, multiple orthogonal methods","pmids":["32048991"],"is_preprint":false},{"year":2019,"finding":"A de novo MEPCE nonsense variant (p.Arg518*) causes nonsense-mediated mRNA decay, reducing MEPCE protein levels, which leads to secondary downregulation of LARP7 and 7SK snRNA, upregulation of HEXIM1, reduced HEXIM1–Cyclin-T1 binding, and hyperphosphorylation of the RNAP II CTD — indicating enhanced P-TEFb activation. Ectopic MEPCE expression rescued increased expression of P-TEFb-sensitive genes, establishing MEPCE's repressive role in P-TEFb-dependent transcription.","method":"Patient fibroblast analysis, mRNA/protein quantification, co-immunoprecipitation (HEXIM1–Cyclin-T1), RNAP II CTD phosphorylation assay, ectopic MEPCE rescue experiment, flavopiridol treatment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived loss-of-function model with rescue, multiple molecular readouts, single lab","pmids":["31467394"],"is_preprint":false},{"year":2023,"finding":"In human cells, MePCE is required for stability of both U6 and 7SK snRNAs. A conserved 'Bin3-Box' domain present only in enzymes associated with 7SK regulation is important for Bin3/MePCE function with 7SK but not U6. An Amus–MePCE hybrid bearing the MePCE methyltransferase domain rescues U6 stability in Drosophila lacking Amus, demonstrating the conserved U6-capping function of the methyltransferase domain.","method":"Human cell MePCE depletion (snRNA stability assay), Drosophila genetic rescue with hybrid proteins, targeted mutagenesis of Bin3-Box","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue with domain-swap hybrid plus mutagenesis, single lab","pmids":["38100593"],"is_preprint":false},{"year":2024,"finding":"In Drosophila, a catalytic-dead Bin3 mutant (Bin3Y795A) can still bind and stabilize 7SK snRNA and rescues all bin3 mutant phenotypes (reduced fecundity, neuromuscular defects), demonstrating that the methyltransferase catalytic activity of Bin3/MePCE is dispensable for 7SK snRNP stability and function in vivo. A metazoan-specific motif (MSM) outside the methyltransferase domain is required for a 7SK-independent, tissue-specific function of Bin3.","method":"Drosophila genetics (bin3 null mutants, catalytic point mutant Bin3Y795A, MSM deletion mutant Bin3ΔMSM), genetic epistasis with P-TEFb reduction, 7SK snRNA stability assay","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — catalytic point mutant with full phenotypic rescue plus epistasis genetics, multiple alleles and phenotypes tested","pmids":["37982586"],"is_preprint":false},{"year":2022,"finding":"In fission yeast, the MePCE ortholog Bmc1 (Bin3/MePCE 1) functions together with Pof8 (LARP7 ortholog) and Thc1 in recognizing correctly folded telomerase RNA, promoting recruitment of the Lsm2-8 complex and assembly of functional telomerase holoenzyme; Bmc1 is required for wildtype telomerase activity and telomere length maintenance.","method":"Affinity purification of Pof8, telomerase activity assay, telomere length analysis, genetic knockouts","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification plus functional assays in fission yeast ortholog, single lab","pmids":["35217638"],"is_preprint":false},{"year":2024,"finding":"In human cells, LARP7 and MePCE are involved in early-stage telomerase RNA (hTR) biogenesis: their depletion inhibits conversion of the 3'-extended short (exS) precursor form into mature hTR and causes cytoplasmic accumulation of hTR, resulting in telomere shortening.","method":"Biochemical fractionation, RNA analysis of hTR processing intermediates, LARP7/MePCE depletion, telomere length measurement","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — depletion with specific RNA processing and telomere readouts, multiple methods, single lab","pmids":["39009594"],"is_preprint":false},{"year":2025,"finding":"Chromatin-associated MePCE interacts with R-loop processing and DNA repair factors and is recruited to DNA double-strand breaks (DSBs). MePCE depletion impairs DSB repair by homologous recombination, decreases RAD51 loading, and enhances R-loop levels at AsiSI-induced DSBs. MePCE depletion also increases LARP7 interaction with R-loops; LARP7 is degraded by BRCA1/BARD1 upon DSB, revealing dynamic regulation of the 7SK RNP at DSBs.","method":"Co-immunoprecipitation (MePCE with R-loop/repair factors), ChIP at AsiSI-induced DSBs, HR repair assay, RAD51 foci, R-loop immunofluorescence (S9.6), MePCE depletion","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, functional HR assay, RAD51 loading), single lab","pmids":["40411785"],"is_preprint":false}],"current_model":"MePCE (BCDIN3/FLJ20257) is a multifunctional methyltransferase that co-transcriptionally caps the 5'-γ-phosphate of 7SK (and U6) snRNA, then is retained on capped 7SK through slow product release; within the assembled 7SK snRNP its catalytic activity is suppressed by LARP7 occluding its active site, yet MePCE retains a catalysis-independent scaffolding function that stabilizes LARP7–7SK interactions, maintains the inhibitory P-TEFb-sequestering complex, and—on chromatin—binds the histone H4 tail (abolishing its RNA methyltransferase activity) to activate P-TEFb at specific genes; MePCE is also cleaved by the protease JMJD6 to release P-TEFb, participates in hTR precursor processing and telomerase biogenesis, and at DNA double-strand breaks promotes homologous recombination by coordinating R-loop resolution in a manner involving dynamic remodeling of the 7SK RNP."},"narrative":{"mechanistic_narrative":"MEPCE encodes a SAM-dependent methyltransferase that co-transcriptionally caps the 5'-γ-phosphate of 7SK and U6 snRNAs, an activity central to the assembly and regulation of the P-TEFb-sequestering 7SK snRNP [PMID:19906723, PMID:38100593]. MePCE recognizes 7SK through protein contacts to a 5'-hairpin–single-stranded RNA motif, and crystal structures of its methyltransferase domain bound to SAH and capped/uncapped 7SK capture the reaction in near-transition-state geometry; higher affinity for capped product plus slow product release explain why MePCE remains stably retained on 7SK after capping [PMID:23471002, PMID:30559425]. Within the assembled snRNP, LARP7 binding occludes the MePCE catalytic center and abolishes capping activity, yet MePCE retains a catalysis-independent scaffolding role that stabilizes the LARP7–7SK interaction and the core MePCE–LARP7–7SK subcomplex [PMID:19906723]; consistent with this, a catalytic-dead ortholog still binds and stabilizes 7SK and fully rescues loss-of-function phenotypes in vivo, establishing that catalytic activity is dispensable for 7SK snRNP function [PMID:37982586]. Through this complex MePCE acts as a repressor of P-TEFb-dependent transcription, and reducing MePCE leads to downregulation of LARP7 and 7SK, weakened HEXIM1–Cyclin-T1 binding, and hyperphosphorylation of the RNAP II CTD reflecting de-repressed P-TEFb [PMID:31467394]. On chromatin, MePCE binds the histone H4 tail—which abolishes its RNA methyltransferase activity—and acts as a 7SK- and Brd4-independent P-TEFb activator at genes controlling cellular identity, while proteolytic cleavage of MePCE by JMJD6 disrupts the 7SK snRNP to release active P-TEFb [PMID:29425494, PMID:32048991]. Beyond transcriptional control, MePCE together with LARP7 participates in early hTR precursor processing and telomerase biogenesis [PMID:35217638, PMID:39009594], and chromatin-associated MePCE promotes homologous-recombination repair of DNA double-strand breaks by supporting RAD51 loading and limiting R-loop accumulation through dynamic remodeling of the 7SK RNP [PMID:40411785]. A de novo MEPCE nonsense variant causing protein loss has been directly linked to a neurodevelopmental phenotype via patient fibroblast analysis and ectopic-MEPCE rescue [PMID:31467394].","teleology":[{"year":2009,"claim":"Established that MePCE both caps 7SK and, separately, scaffolds the snRNP, resolving how a capping enzyme becomes a stable structural component after its enzymatic job is done.","evidence":"Biochemical fractionation, Co-IP, in vitro capping assays, and RNAi rescue in human cells","pmids":["19906723"],"confidence":"High","gaps":["Structural basis of LARP7 occlusion of the active site not resolved","Did not define which RNA elements direct specific 7SK binding"]},{"year":2013,"claim":"Mapped the RNA determinants of snRNP assembly, showing MePCE and LARP7 bind opposite ends of 7SK to nucleate the core complex.","evidence":"In vivo RNA-protein interaction assays with systematic 7SK mutants","pmids":["23471002"],"confidence":"Medium","gaps":["Atomic-resolution recognition mechanism not defined","Single lab, in vivo binding only"]},{"year":2018,"claim":"Provided the atomic mechanism for 7SK/U6 specificity and for post-capping retention, explaining why MePCE stays bound to its product.","evidence":"X-ray crystallography of the MePCE MTase domain with SAH and capped/uncapped 7SK, plus binding and kinetic assays","pmids":["30559425"],"confidence":"High","gaps":["Structure of full snRNP with LARP7 occlusion not solved","Catalytic chemistry inferred from near-transition-state geometry"]},{"year":2018,"claim":"Revealed a second, chromatin-based mode in which histone H4 binding switches off MePCE methyltransferase activity and converts it into a P-TEFb activator independent of the full 7SK snRNP.","evidence":"ChIP, Co-IP, in vitro histone-binding and RNA methyltransferase assays, RNAi with expression readouts","pmids":["29425494"],"confidence":"Medium","gaps":["Mechanism of recruitment to specific genes not defined","Single lab"]},{"year":2019,"claim":"Defined the functional consequence of MEPCE loss in vivo, linking it to de-repressed P-TEFb and to a human disease phenotype.","evidence":"Patient fibroblast analysis, mRNA/protein quantification, Co-IP, CTD phosphorylation assay, and ectopic MEPCE rescue","pmids":["31467394"],"confidence":"Medium","gaps":["Single de novo variant; broader genotype-phenotype spectrum unestablished","Secondary downregulation of LARP7/7SK mechanism not dissected"]},{"year":2020,"claim":"Identified a regulated mechanism for releasing P-TEFb by establishing MePCE as a proteolytic substrate of JMJD6.","evidence":"JMJD6–methyl-arginine crystal structure, in vitro/in vivo proteolytic assays, Jmjd6 knockout/overexpression with CTD phosphorylation readout","pmids":["32048991"],"confidence":"High","gaps":["Physiological signals triggering cleavage not defined","Cleavage site fate and product stability unresolved"]},{"year":2022,"claim":"Extended MePCE function beyond 7SK by showing the ortholog assembles functional telomerase via recognition of correctly folded telomerase RNA.","evidence":"Affinity purification of Pof8, telomerase activity and telomere length assays, genetic knockouts in fission yeast","pmids":["35217638"],"confidence":"Medium","gaps":["Ortholog system; direct human telomerase role addressed separately","Structural basis of RNA folding recognition unknown"]},{"year":2023,"claim":"Clarified the conserved versus specialized roles of MePCE by separating its U6-capping function from a 'Bin3-Box' domain dedicated to 7SK regulation.","evidence":"Human MePCE depletion snRNA stability assays plus Drosophila domain-swap hybrid rescue and Bin3-Box mutagenesis","pmids":["38100593"],"confidence":"Medium","gaps":["Molecular basis of Bin3-Box specificity for 7SK not defined","Single lab"]},{"year":2024,"claim":"Demonstrated genetically that MePCE catalytic activity is dispensable for 7SK snRNP stability and function, and identified a separable 7SK-independent tissue role.","evidence":"Drosophila catalytic-dead Bin3Y795A and MSM-deletion mutants, phenotypic rescue, and epistasis with reduced P-TEFb","pmids":["37982586"],"confidence":"High","gaps":["Molecular function of the metazoan-specific motif unknown","Whether human MePCE catalysis is similarly dispensable not directly shown"]},{"year":2024,"claim":"Placed MePCE in human telomerase biogenesis by showing it is required to convert precursor hTR into the mature form and prevent its cytoplasmic mislocalization.","evidence":"Biochemical fractionation, hTR processing-intermediate analysis, LARP7/MePCE depletion, telomere length measurement","pmids":["39009594"],"confidence":"Medium","gaps":["Direct role of MePCE catalysis in hTR processing not isolated","Step at which MePCE acts on the precursor not pinpointed"]},{"year":2025,"claim":"Revealed a chromatin/genome-maintenance role in which MePCE supports homologous-recombination repair through dynamic 7SK RNP remodeling at DNA breaks.","evidence":"Co-IP with R-loop/repair factors, ChIP at AsiSI-induced DSBs, HR assay, RAD51 foci, and S9.6 R-loop immunofluorescence","pmids":["40411785"],"confidence":"Medium","gaps":["Whether MePCE methyltransferase activity is required at DSBs unknown","Direct recruitment mechanism to breaks not defined"]},{"year":null,"claim":"How MePCE's distinct activities—capping, 7SK scaffolding, chromatin H4 binding, telomerase biogenesis, and DSB repair—are coordinated and switched within a cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of MePCE in alternate complexes","Signals partitioning MePCE between 7SK snRNP, chromatin, and DNA-repair functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,10]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,6,9]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10]}],"complexes":["7SK snRNP","MePCE–LARP7–7SK core subcomplex"],"partners":["LARP7","JMJD6","HEXIM1","CCNT1","RAD51"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7L2J0","full_name":"7SK snRNA methylphosphate capping enzyme","aliases":["Bicoid-interacting protein 3 homolog","Bin3 homolog"],"length_aa":689,"mass_kda":74.4,"function":"S-adenosyl-L-methionine-dependent methyltransferase that adds a methylphosphate cap at the 5'-end of 7SK snRNA (7SK RNA), leading to stabilize it (PubMed:17643375, PubMed:19906723, PubMed:30559425). Also has a non-enzymatic function as part of the 7SK RNP complex: the 7SK RNP complex sequesters the positive transcription elongation factor b (P-TEFb) in a large inactive 7SK RNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation (PubMed:17643375). The 7SK RNP complex also promotes snRNA gene transcription by RNA polymerase II via interaction with the little elongation complex (LEC) (PubMed:28254838). In the 7SK RNP complex, MEPCE is required to stabilize 7SK RNA and facilitate the assembly of 7SK RNP complex (PubMed:19906723, PubMed:38100593). MEPCE has a non-enzymatic function in the 7SK RNP complex; interaction with LARP7 within the 7SK RNP complex occluding its catalytic center (PubMed:19906723). Also required for stability of U6 snRNAs (PubMed:38100593)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q7L2J0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MEPCE","classification":"Common Essential","n_dependent_lines":1205,"n_total_lines":1208,"dependency_fraction":0.9975165562913907},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDK9","stoichiometry":10.0},{"gene":"LARP7","stoichiometry":10.0},{"gene":"BYSL","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SRP68","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MEPCE","total_profiled":1310},"omim":[{"mim_id":"619601","title":"BCDIN3 DOMAIN-CONTAINING RNA METHYLTRANSFERASE; BCDIN3D","url":"https://www.omim.org/entry/619601"},{"mim_id":"611478","title":"METHYLPHOSPHATE CAPPING ENZYME; MEPCE","url":"https://www.omim.org/entry/611478"},{"mim_id":"606515","title":"RNA, 7SK, SMALL NUCLEAR; RN7SK","url":"https://www.omim.org/entry/606515"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MEPCE"},"hgnc":{"alias_symbol":["FLJ20257"],"prev_symbol":["BCDIN3"]},"alphafold":{"accession":"Q7L2J0","domains":[{"cath_id":"3.40.50.150","chopping":"410-496_528-538_545-684","consensus_level":"high","plddt":93.4921,"start":410,"end":684}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L2J0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L2J0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L2J0-F1-predicted_aligned_error_v6.png","plddt_mean":62.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEPCE","jax_strain_url":"https://www.jax.org/strain/search?query=MEPCE"},"sequence":{"accession":"Q7L2J0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L2J0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L2J0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L2J0"}},"corpus_meta":[{"pmid":"19906723","id":"PMC_19906723","title":"A capping-independent function of MePCE in stabilizing 7SK snRNA and facilitating the assembly of 7SK snRNP.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19906723","citation_count":114,"is_preprint":false},{"pmid":"23471002","id":"PMC_23471002","title":"RNA elements directing in vivo assembly of the 7SK/MePCE/Larp7 transcriptional regulatory snRNP.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23471002","citation_count":55,"is_preprint":false},{"pmid":"30559425","id":"PMC_30559425","title":"Structural basis of 7SK RNA 5'-γ-phosphate methylation and retention by MePCE.","date":"2018","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/30559425","citation_count":36,"is_preprint":false},{"pmid":"29425494","id":"PMC_29425494","title":"Crosstalk between the RNA Methylation and Histone-Binding Activities of MePCE Regulates P-TEFb Activation on Chromatin.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29425494","citation_count":29,"is_preprint":false},{"pmid":"32048991","id":"PMC_32048991","title":"JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32048991","citation_count":28,"is_preprint":false},{"pmid":"31467394","id":"PMC_31467394","title":"de novo MEPCE nonsense variant associated with a neurodevelopmental disorder causes disintegration of 7SK snRNP and enhanced RNA polymerase II activation.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31467394","citation_count":17,"is_preprint":false},{"pmid":"33416148","id":"PMC_33416148","title":"Long non‑coding RNA ST8SIA6‑AS1 promotes the migration and invasion of hypoxia‑treated hepatocellular carcinoma cells through the miR‑338/MEPCE axis.","date":"2020","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/33416148","citation_count":15,"is_preprint":false},{"pmid":"35217638","id":"PMC_35217638","title":"A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35217638","citation_count":11,"is_preprint":false},{"pmid":"39009594","id":"PMC_39009594","title":"LARP3, LARP7, and MePCE are involved in the early stage of human telomerase RNA biogenesis.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39009594","citation_count":5,"is_preprint":false},{"pmid":"38100593","id":"PMC_38100593","title":"Drosophila Amus and Bin3 methylases functionally replace mammalian MePCE for capping and the stabilization of U6 and 7SK snRNAs.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38100593","citation_count":3,"is_preprint":false},{"pmid":"37982586","id":"PMC_37982586","title":"Catalytic activity of the Bin3/MePCE methyltransferase domain is dispensable for 7SK snRNP function in Drosophila melanogaster.","date":"2024","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37982586","citation_count":2,"is_preprint":false},{"pmid":"40411785","id":"PMC_40411785","title":"MePCE promotes homologous recombination through coordinating R-loop resolution at DNA double-stranded breaks.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40411785","citation_count":1,"is_preprint":false},{"pmid":"37333392","id":"PMC_37333392","title":"Catalytic activity of the Bin3/MEPCE methyltransferase domain is dispensable for 7SK snRNP function in Drosophila melanogaster.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37333392","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.29.651232","title":"Tissue specific function of the  <i>Drosophila</i>  7SK snRNP in controlling motoneuron synaptic growth","date":"2025-05-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.29.651232","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8701,"output_tokens":3340,"usd":0.038102,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10785,"output_tokens":3985,"usd":0.076775,"stage2_stop_reason":"end_turn"},"total_usd":0.114877,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"MePCE caps 7SK snRNA in a LARP7-free state, likely co-transcriptionally. Upon incorporation into the 7SK snRNP, MePCE interacts with LARP7, which occludes MePCE's catalytic center and abolishes its capping activity. Despite loss of capping activity within the snRNP, MePCE retains a capping-independent function that promotes the LARP7–7SK interaction, stabilizing 7SK and facilitating assembly of a stable MePCE–LARP7–7SK subcomplex.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, in vitro capping assays, RNAi knockdown with rescue experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vitro enzymatic assay, RNAi knockdown), replicated concept across subsequent papers\",\n      \"pmids\": [\"19906723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MePCE binds to the short 5'-terminal G1-U4/U106-G111 helix-tail motif of 7SK snRNA; both the overall RNA structure and specific nucleotides provide information for MePCE's specific binding. LARP7 binds the 3'-terminal hairpin and U-rich tail. These interactions direct assembly of the core 7SK/MePCE/LARP7 snRNP in vivo.\",\n      \"method\": \"In vivo RNA-protein interaction assays (immunoprecipitation of RNA–protein complexes with mutant 7SK constructs)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo binding assays with systematic RNA mutants, single lab\",\n      \"pmids\": [\"23471002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"X-ray crystal structures (2.0 Å and 2.1 Å) of the human MePCE methyltransferase domain bound to SAH and uncapped or capped 7SK substrates reveal that 7SK recognition is achieved via protein contacts to a 5'-hairpin–single-stranded RNA region, explaining MePCE specificity for 7SK and U6. The structures capture SAH and product RNA in near-transition-state geometry. Binding experiments show MePCE has higher affinity for capped versus uncapped 7SK, and kinetic data support slow product release, providing the mechanism for 7SK retention by MePCE after cap methylation.\",\n      \"method\": \"X-ray crystallography (2.0 Å / 2.1 Å), binding affinity measurements, kinetic assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structures with kinetic and binding validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30559425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MePCE binds to the histone H4 tail on chromatin and serves as a P-TEFb activator at specific genes controlling cellular identity. This histone-binding activity abolishes MePCE's RNA methyltransferase activity toward 7SK, explaining why chromatin-bound MePCE–P-TEFb complexes are not associated with the full 7SK snRNP and are competent to activate RNAP II. This crosstalk between histone-binding and RNA methylation activities regulates P-TEFb activation on chromatin in a 7SK- and Brd4-independent manner.\",\n      \"method\": \"ChIP, co-immunoprecipitation, in vitro histone-binding assays, RNA methyltransferase activity assays, RNAi knockdown with gene expression readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, enzymatic assay), single lab\",\n      \"pmids\": [\"29425494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD6 cleaves MePCE proteolytically in vivo and in vitro. Crystal structure of JMJD6 bound to methyl-arginine and enzymatic assays establish MePCE as a cognate substrate for JMJD6's proteolytic activity. Cleavage of MePCE disrupts the 7SK snRNP complex, releasing P-TEFb, and Jmjd6 knockout/overexpression modulates RNAP II CTD phosphorylation downstream.\",\n      \"method\": \"X-ray crystallography (JMJD6–methyl-arginine), in vitro and in vivo proteolytic assays, binding assays, Jmjd6 knockout and overexpression with CTD phosphorylation readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro enzymatic assay plus in vivo genetic models with functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"32048991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A de novo MEPCE nonsense variant (p.Arg518*) causes nonsense-mediated mRNA decay, reducing MEPCE protein levels, which leads to secondary downregulation of LARP7 and 7SK snRNA, upregulation of HEXIM1, reduced HEXIM1–Cyclin-T1 binding, and hyperphosphorylation of the RNAP II CTD — indicating enhanced P-TEFb activation. Ectopic MEPCE expression rescued increased expression of P-TEFb-sensitive genes, establishing MEPCE's repressive role in P-TEFb-dependent transcription.\",\n      \"method\": \"Patient fibroblast analysis, mRNA/protein quantification, co-immunoprecipitation (HEXIM1–Cyclin-T1), RNAP II CTD phosphorylation assay, ectopic MEPCE rescue experiment, flavopiridol treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived loss-of-function model with rescue, multiple molecular readouts, single lab\",\n      \"pmids\": [\"31467394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In human cells, MePCE is required for stability of both U6 and 7SK snRNAs. A conserved 'Bin3-Box' domain present only in enzymes associated with 7SK regulation is important for Bin3/MePCE function with 7SK but not U6. An Amus–MePCE hybrid bearing the MePCE methyltransferase domain rescues U6 stability in Drosophila lacking Amus, demonstrating the conserved U6-capping function of the methyltransferase domain.\",\n      \"method\": \"Human cell MePCE depletion (snRNA stability assay), Drosophila genetic rescue with hybrid proteins, targeted mutagenesis of Bin3-Box\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue with domain-swap hybrid plus mutagenesis, single lab\",\n      \"pmids\": [\"38100593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Drosophila, a catalytic-dead Bin3 mutant (Bin3Y795A) can still bind and stabilize 7SK snRNA and rescues all bin3 mutant phenotypes (reduced fecundity, neuromuscular defects), demonstrating that the methyltransferase catalytic activity of Bin3/MePCE is dispensable for 7SK snRNP stability and function in vivo. A metazoan-specific motif (MSM) outside the methyltransferase domain is required for a 7SK-independent, tissue-specific function of Bin3.\",\n      \"method\": \"Drosophila genetics (bin3 null mutants, catalytic point mutant Bin3Y795A, MSM deletion mutant Bin3ΔMSM), genetic epistasis with P-TEFb reduction, 7SK snRNA stability assay\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — catalytic point mutant with full phenotypic rescue plus epistasis genetics, multiple alleles and phenotypes tested\",\n      \"pmids\": [\"37982586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In fission yeast, the MePCE ortholog Bmc1 (Bin3/MePCE 1) functions together with Pof8 (LARP7 ortholog) and Thc1 in recognizing correctly folded telomerase RNA, promoting recruitment of the Lsm2-8 complex and assembly of functional telomerase holoenzyme; Bmc1 is required for wildtype telomerase activity and telomere length maintenance.\",\n      \"method\": \"Affinity purification of Pof8, telomerase activity assay, telomere length analysis, genetic knockouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification plus functional assays in fission yeast ortholog, single lab\",\n      \"pmids\": [\"35217638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In human cells, LARP7 and MePCE are involved in early-stage telomerase RNA (hTR) biogenesis: their depletion inhibits conversion of the 3'-extended short (exS) precursor form into mature hTR and causes cytoplasmic accumulation of hTR, resulting in telomere shortening.\",\n      \"method\": \"Biochemical fractionation, RNA analysis of hTR processing intermediates, LARP7/MePCE depletion, telomere length measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — depletion with specific RNA processing and telomere readouts, multiple methods, single lab\",\n      \"pmids\": [\"39009594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Chromatin-associated MePCE interacts with R-loop processing and DNA repair factors and is recruited to DNA double-strand breaks (DSBs). MePCE depletion impairs DSB repair by homologous recombination, decreases RAD51 loading, and enhances R-loop levels at AsiSI-induced DSBs. MePCE depletion also increases LARP7 interaction with R-loops; LARP7 is degraded by BRCA1/BARD1 upon DSB, revealing dynamic regulation of the 7SK RNP at DSBs.\",\n      \"method\": \"Co-immunoprecipitation (MePCE with R-loop/repair factors), ChIP at AsiSI-induced DSBs, HR repair assay, RAD51 foci, R-loop immunofluorescence (S9.6), MePCE depletion\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, functional HR assay, RAD51 loading), single lab\",\n      \"pmids\": [\"40411785\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MePCE (BCDIN3/FLJ20257) is a multifunctional methyltransferase that co-transcriptionally caps the 5'-γ-phosphate of 7SK (and U6) snRNA, then is retained on capped 7SK through slow product release; within the assembled 7SK snRNP its catalytic activity is suppressed by LARP7 occluding its active site, yet MePCE retains a catalysis-independent scaffolding function that stabilizes LARP7–7SK interactions, maintains the inhibitory P-TEFb-sequestering complex, and—on chromatin—binds the histone H4 tail (abolishing its RNA methyltransferase activity) to activate P-TEFb at specific genes; MePCE is also cleaved by the protease JMJD6 to release P-TEFb, participates in hTR precursor processing and telomerase biogenesis, and at DNA double-strand breaks promotes homologous recombination by coordinating R-loop resolution in a manner involving dynamic remodeling of the 7SK RNP.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MEPCE encodes a SAM-dependent methyltransferase that co-transcriptionally caps the 5'-\\u03b3-phosphate of 7SK and U6 snRNAs, an activity central to the assembly and regulation of the P-TEFb-sequestering 7SK snRNP [#0, #6]. MePCE recognizes 7SK through protein contacts to a 5'-hairpin\\u2013single-stranded RNA motif, and crystal structures of its methyltransferase domain bound to SAH and capped/uncapped 7SK capture the reaction in near-transition-state geometry; higher affinity for capped product plus slow product release explain why MePCE remains stably retained on 7SK after capping [#1, #2]. Within the assembled snRNP, LARP7 binding occludes the MePCE catalytic center and abolishes capping activity, yet MePCE retains a catalysis-independent scaffolding role that stabilizes the LARP7\\u20137SK interaction and the core MePCE\\u2013LARP7\\u20137SK subcomplex [#0]; consistent with this, a catalytic-dead ortholog still binds and stabilizes 7SK and fully rescues loss-of-function phenotypes in vivo, establishing that catalytic activity is dispensable for 7SK snRNP function [#7]. Through this complex MePCE acts as a repressor of P-TEFb-dependent transcription, and reducing MePCE leads to downregulation of LARP7 and 7SK, weakened HEXIM1\\u2013Cyclin-T1 binding, and hyperphosphorylation of the RNAP II CTD reflecting de-repressed P-TEFb [#5]. On chromatin, MePCE binds the histone H4 tail\\u2014which abolishes its RNA methyltransferase activity\\u2014and acts as a 7SK- and Brd4-independent P-TEFb activator at genes controlling cellular identity, while proteolytic cleavage of MePCE by JMJD6 disrupts the 7SK snRNP to release active P-TEFb [#3, #4]. Beyond transcriptional control, MePCE together with LARP7 participates in early hTR precursor processing and telomerase biogenesis [#8, #9], and chromatin-associated MePCE promotes homologous-recombination repair of DNA double-strand breaks by supporting RAD51 loading and limiting R-loop accumulation through dynamic remodeling of the 7SK RNP [#10]. A de novo MEPCE nonsense variant causing protein loss has been directly linked to a neurodevelopmental phenotype via patient fibroblast analysis and ectopic-MEPCE rescue [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that MePCE both caps 7SK and, separately, scaffolds the snRNP, resolving how a capping enzyme becomes a stable structural component after its enzymatic job is done.\",\n      \"evidence\": \"Biochemical fractionation, Co-IP, in vitro capping assays, and RNAi rescue in human cells\",\n      \"pmids\": [\"19906723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LARP7 occlusion of the active site not resolved\", \"Did not define which RNA elements direct specific 7SK binding\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped the RNA determinants of snRNP assembly, showing MePCE and LARP7 bind opposite ends of 7SK to nucleate the core complex.\",\n      \"evidence\": \"In vivo RNA-protein interaction assays with systematic 7SK mutants\",\n      \"pmids\": [\"23471002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Atomic-resolution recognition mechanism not defined\", \"Single lab, in vivo binding only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the atomic mechanism for 7SK/U6 specificity and for post-capping retention, explaining why MePCE stays bound to its product.\",\n      \"evidence\": \"X-ray crystallography of the MePCE MTase domain with SAH and capped/uncapped 7SK, plus binding and kinetic assays\",\n      \"pmids\": [\"30559425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full snRNP with LARP7 occlusion not solved\", \"Catalytic chemistry inferred from near-transition-state geometry\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a second, chromatin-based mode in which histone H4 binding switches off MePCE methyltransferase activity and converts it into a P-TEFb activator independent of the full 7SK snRNP.\",\n      \"evidence\": \"ChIP, Co-IP, in vitro histone-binding and RNA methyltransferase assays, RNAi with expression readouts\",\n      \"pmids\": [\"29425494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of recruitment to specific genes not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the functional consequence of MEPCE loss in vivo, linking it to de-repressed P-TEFb and to a human disease phenotype.\",\n      \"evidence\": \"Patient fibroblast analysis, mRNA/protein quantification, Co-IP, CTD phosphorylation assay, and ectopic MEPCE rescue\",\n      \"pmids\": [\"31467394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single de novo variant; broader genotype-phenotype spectrum unestablished\", \"Secondary downregulation of LARP7/7SK mechanism not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a regulated mechanism for releasing P-TEFb by establishing MePCE as a proteolytic substrate of JMJD6.\",\n      \"evidence\": \"JMJD6\\u2013methyl-arginine crystal structure, in vitro/in vivo proteolytic assays, Jmjd6 knockout/overexpression with CTD phosphorylation readout\",\n      \"pmids\": [\"32048991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals triggering cleavage not defined\", \"Cleavage site fate and product stability unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended MePCE function beyond 7SK by showing the ortholog assembles functional telomerase via recognition of correctly folded telomerase RNA.\",\n      \"evidence\": \"Affinity purification of Pof8, telomerase activity and telomere length assays, genetic knockouts in fission yeast\",\n      \"pmids\": [\"35217638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog system; direct human telomerase role addressed separately\", \"Structural basis of RNA folding recognition unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Clarified the conserved versus specialized roles of MePCE by separating its U6-capping function from a 'Bin3-Box' domain dedicated to 7SK regulation.\",\n      \"evidence\": \"Human MePCE depletion snRNA stability assays plus Drosophila domain-swap hybrid rescue and Bin3-Box mutagenesis\",\n      \"pmids\": [\"38100593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of Bin3-Box specificity for 7SK not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated genetically that MePCE catalytic activity is dispensable for 7SK snRNP stability and function, and identified a separable 7SK-independent tissue role.\",\n      \"evidence\": \"Drosophila catalytic-dead Bin3Y795A and MSM-deletion mutants, phenotypic rescue, and epistasis with reduced P-TEFb\",\n      \"pmids\": [\"37982586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function of the metazoan-specific motif unknown\", \"Whether human MePCE catalysis is similarly dispensable not directly shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed MePCE in human telomerase biogenesis by showing it is required to convert precursor hTR into the mature form and prevent its cytoplasmic mislocalization.\",\n      \"evidence\": \"Biochemical fractionation, hTR processing-intermediate analysis, LARP7/MePCE depletion, telomere length measurement\",\n      \"pmids\": [\"39009594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role of MePCE catalysis in hTR processing not isolated\", \"Step at which MePCE acts on the precursor not pinpointed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a chromatin/genome-maintenance role in which MePCE supports homologous-recombination repair through dynamic 7SK RNP remodeling at DNA breaks.\",\n      \"evidence\": \"Co-IP with R-loop/repair factors, ChIP at AsiSI-induced DSBs, HR assay, RAD51 foci, and S9.6 R-loop immunofluorescence\",\n      \"pmids\": [\"40411785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MePCE methyltransferase activity is required at DSBs unknown\", \"Direct recruitment mechanism to breaks not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MePCE's distinct activities\\u2014capping, 7SK scaffolding, chromatin H4 binding, telomerase biogenesis, and DSB repair\\u2014are coordinated and switched within a cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of MePCE in alternate complexes\", \"Signals partitioning MePCE between 7SK snRNP, chromatin, and DNA-repair functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 6, 9]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"7SK snRNP\",\n      \"MePCE\\u2013LARP7\\u20137SK core subcomplex\"\n    ],\n    \"partners\": [\n      \"LARP7\",\n      \"JMJD6\",\n      \"HEXIM1\",\n      \"CCNT1\",\n      \"RAD51\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}