{"gene":"LSM10","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"LSM10 (Lsm10) is a novel 14 kDa Sm-like protein that replaces Sm D1 in the U7 snRNP Sm core ring; purified U7 snRNPs from HeLa cells lack Sm D1 and D2 but contain Lsm10, and its incorporation into U7 snRNPs is largely dictated by the special Sm-binding site of U7 snRNA.","method":"Biochemical fractionation and affinity purification of U7 snRNPs from HeLa cells, microsequencing of isolated polypeptides","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical purification and microsequencing identifying protein composition, replicated by multiple subsequent studies","pmids":["11574479"],"is_preprint":false},{"year":2001,"finding":"Lsm10 is enriched in Cajal bodies of the cell nucleus, co-localizing with U7 snRNA.","method":"Immunofluorescence microscopy / subcellular localization in HeLa cells","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, immunofluorescence localization, replicated in subsequent papers","pmids":["11574479"],"is_preprint":false},{"year":2003,"finding":"The U7-specific Sm core containing Lsm10 (and Lsm11) is assembled by a specialized SMN complex that contains Lsm10 and Lsm11 but lacks Sm D1/D2; assembly depends on the noncanonical Sm-binding site of U7 snRNA.","method":"In vitro assembly assays, co-immunoprecipitation, biochemical reconstitution with specialized SMN complex","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods (in vitro assembly, Co-IP), replicated across labs","pmids":["12975319"],"is_preprint":false},{"year":2003,"finding":"Drosophila Lsm10 (dLsm10) associates with dLsm11 and Sm B but not with Sm D1 and D2, and Drosophila Lsm10 and Lsm11 can assemble into U7 snRNPs in mammalian cells, demonstrating evolutionary conservation of the unique U7 snRNP composition.","method":"Immunoprecipitation studies in Drosophila S2 cells; cross-species assembly assays in mammalian cells","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and cross-species assembly, single lab","pmids":["14624008"],"is_preprint":false},{"year":2005,"finding":"Lsm10 and Lsm11 associate with pICln (a subunit of the PRMT5 methylosome complex) in vitro and in vivo without receiving symmetrical dimethylarginine (sDMA) modifications, and their binding to SMN is independent of methylation activity; two separate binding sites in SMN exist for Sm/Lsm proteins.","method":"Co-immunoprecipitation in vivo and in vitro binding assays; methylation assays; SMN binding studies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and in vitro binding, single lab, two orthogonal methods","pmids":["16087681"],"is_preprint":false},{"year":2006,"finding":"Overexpression of Lsm10 and Lsm11 increases cellular levels of U7 snRNP but has no effect on histone pre-mRNA processing; knockdown of U7 snRNP components including Lsm10 by RNAi causes reduction in cell growth and cell cycle arrest in early G1.","method":"Reporter gene assay (GFP fused to histone 3' end), RNAi knockdown, flow cytometry for cell cycle analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus RNAi with cell cycle readout, single lab, multiple methods","pmids":["16914750"],"is_preprint":false},{"year":2009,"finding":"Lsm10, SmB, and SmD3 (components of the U7-specific Sm core) interact in a U7-dependent manner with the region between the cleavage site and U7-binding site in histone pre-mRNA, and function as a molecular ruler to determine the site of 3'-end cleavage.","method":"Biotin affinity pulldown of histone pre-mRNA processing complexes, UV cross-linking studies","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification and UV cross-linking, single lab, two complementary methods","pmids":["19470752"],"is_preprint":false},{"year":2009,"finding":"In Drosophila, loss of Lsm10 disrupts histone pre-mRNA processing, causing production of polyadenylated histone mRNA from cryptic downstream sites; Lsm10 protein fails to accumulate in Lsm11 mutants, suggesting Lsm10-Lsm11 dimers are precursors for U7 snRNP assembly; Lsm10 and Lsm11 are necessary for localization of U7 snRNA to the histone locus body.","method":"Drosophila genetic loss-of-function (Lsm10 and Lsm11 null mutants), RT-PCR for polyadenylated histone mRNA, immunostaining, anti-trimethylguanosine immunoprecipitation","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mutants with multiple orthogonal molecular readouts (processing assay, localization, protein stability), single lab but rigorous","pmids":["19620235"],"is_preprint":false},{"year":2009,"finding":"In normal human somatic and embryonic stem cells, Lsm10-containing U7 snRNP co-localizes with p220(NPAT) and the histone gene locus in Histone Locus Bodies (HLBs); in certain cancer cell lines (HeLa S3, MCF7), this co-localization is disrupted with most Lsm10 residing in Cajal bodies instead.","method":"In situ immunofluorescence microscopy and FISH in human cell lines","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunofluorescence localization with FISH, replicated across multiple cell types, single lab","pmids":["19277982"],"is_preprint":false},{"year":2011,"finding":"In Drosophila, direct interaction between FLASH (amino acids 105–154) and dLsm11 (amino acids 1–78) is essential for histone pre-mRNA processing in vivo; a two-amino-acid mutation in dLsm11 that prevents dFLASH binding—without affecting U7 snRNP localization to the HLB—cannot rescue lethality or processing defects caused by Lsm11 null mutation.","method":"Drosophila genetic rescue experiments, in vitro binding/pulldown assays, site-directed mutagenesis, dominant-negative analysis","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic rescue with site-directed mutagenesis and in vitro binding, rigorous controls, Drosophila model","pmids":["21525146"],"is_preprint":false},{"year":2012,"finding":"Depletion of Lsm10 (a component of the U7 snRNP-specific Sm ring) by siRNA in HeLa cells results in elevated levels of replication-dependent histone mRNAs under cell cycle-arrested conditions, acting at the transcriptional level; U7 snRNP (identified via Lsm10 component) interacts with hnRNP UL1, which mediates U7 snRNP-dependent transcriptional repression of histone genes.","method":"siRNA knockdown, pulse-chase experiments, mass spectrometry of captured U7 snRNP, hnRNP UL1 knockdown/overexpression, chromatin immunoprecipitation (ChIP)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with pulse-chase, MS, and ChIP, multiple orthogonal methods, single lab","pmids":["22451911"],"is_preprint":false},{"year":2017,"finding":"U7 snRNP (containing Lsm10/Lsm11) is recruited to histone pre-mRNA in a FLASH-dependent manner; SLBP stabilizes U7 snRNP binding via two regions (helix B of its RNA-binding domain and C-terminal region), and this stabilization requires FLASH but not polyadenylation factors.","method":"In vitro histone pre-mRNA processing and binding assays, mutagenesis of SLBP domains, pulldown assays with Drosophila and human SLBP","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro processing assays with domain mutagenesis, single lab, multiple constructs tested","pmids":["28289156"],"is_preprint":false},{"year":2022,"finding":"Co-expression of U7-specific Lsm10 and Lsm11 proteins selectively enhances U7 snRNP assembly, corrects histone mRNA processing defects, and rescues key structural and functional neuromuscular pathology (NMJ denervation, decreased synaptic transmission, skeletal muscle atrophy) in SMA mice; U7 snRNP dysfunction drives selective loss of synaptic organizing protein Agrin at NMJs.","method":"Mouse SMA model (in vivo co-expression of Lsm10 and Lsm11), U7 snRNP assembly assays, histone mRNA processing assays, electrophysiology, immunostaining of NMJ","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic rescue in mammalian model with multiple orthogonal readouts (molecular, electrophysiological, structural), single lab but rigorous","pmids":["36130491"],"is_preprint":false},{"year":2023,"finding":"A heterodimer of Lsm10 and Lsm11 tightly interacts with the PRMT5/MEP50/pICln methylosome complex; the interaction is mediated by PRMT5 which binds Lsm11 but does not methylate Lsm10; cryo-EM structural studies demonstrate the mode of interaction.","method":"Biochemical co-purification, cryo-EM structural analysis, in vitro methylation assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with in vitro biochemistry and methylation assays, peer-reviewed","pmids":["37562960"],"is_preprint":false},{"year":2025,"finding":"Two proteins, PTBP1 and IGF2BP3, bind U7 snRNA in a manner dependent on its unique Sm site and upstream CUCUUU motif; hnRNP A1 also binds U7 snRNA and interacts with SMN, suggesting it may substitute for Gemin5 in directing assembly of the U7-specific Sm ring containing Lsm10 and Lsm11.","method":"RNA pulldown/affinity purification from mammalian extracts, co-immunoprecipitation of hnRNP A1 with SMN, binding competition assays","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNA pulldown and Co-IP identifying new interactors, single lab, single paper, mechanism proposed but not fully reconstituted","pmids":["40592581"],"is_preprint":false}],"current_model":"LSM10 (Lsm10) is a U7 snRNP-specific Sm-like protein that replaces Sm D1 in a unique heptameric Sm ring assembled around the noncanonical Sm-binding site of U7 snRNA; it forms a heterodimer with Lsm11 that is recognized by the PRMT5/MEP50/pICln methylosome and by the SMN complex for snRNP biogenesis, localizes with U7 snRNP to Cajal bodies and histone locus bodies, and is essential for correct 3'-end endonucleolytic processing of replication-dependent histone pre-mRNAs and for U7 snRNP-dependent transcriptional repression of histone genes outside S phase, with components of the U7 Sm ring including Lsm10 also acting as a molecular ruler to define the cleavage site."},"narrative":{"mechanistic_narrative":"LSM10 (Lsm10) is a U7 snRNP-specific Sm-like protein that defines the noncanonical Sm core required for 3'-end processing of replication-dependent histone pre-mRNAs [PMID:11574479, PMID:19620235]. It substitutes for Sm D1 in the heptameric Sm ring assembled around the special Sm-binding site of U7 snRNA, which dictates its selective incorporation [PMID:11574479], and this unique composition is conserved from Drosophila to mammals [PMID:14624008]. Lsm10 functions as an obligate partner of Lsm11: the two form a heterodimer that serves as the precursor for U7 snRNP assembly by a specialized SMN complex lacking Sm D1/D2 [PMID:12975319, PMID:19620235], and is handed off through the PRMT5/MEP50/pICln methylosome, where PRMT5 binds Lsm11 but leaves Lsm10 unmethylated [PMID:16087681, PMID:37562960]. Within the assembled U7 snRNP, Lsm10 together with SmB and SmD3 contacts histone pre-mRNA between the U7-binding site and the cleavage site, acting as a molecular ruler that defines the endonucleolytic cut [PMID:19470752], with recruitment to substrate occurring in a FLASH- and SLBP-dependent manner [PMID:28289156]. Lsm10-containing U7 snRNP localizes to Cajal bodies and to histone locus bodies at the histone gene cluster [PMID:11574479, PMID:19277982], and beyond co-transcriptional processing it mediates transcriptional repression of histone genes outside S phase via hnRNP UL1 [PMID:22451911]. Restoring Lsm10/Lsm11 levels enhances U7 snRNP assembly and rescues histone-processing and neuromuscular pathology in SMA mice, linking U7 snRNP function to spinal muscular atrophy disease biology [PMID:36130491].","teleology":[{"year":2001,"claim":"Established that U7 snRNP has a distinct protein composition by identifying Lsm10 as a novel Sm-like protein that replaces Sm D1, answering what makes U7 snRNP biochemically unique.","evidence":"Biochemical purification of U7 snRNPs from HeLa cells with microsequencing, plus immunofluorescence localization","pmids":["11574479"],"confidence":"High","gaps":["Did not resolve how Lsm10 selectively recognizes the U7 Sm site at atomic resolution","Functional consequence of D1 replacement for processing not yet tested"]},{"year":2003,"claim":"Showed that the U7-specific Sm core is built by a specialized SMN complex acting on the noncanonical U7 Sm site, and that the unique composition is evolutionarily conserved.","evidence":"In vitro assembly assays and Co-IP with a specialized SMN complex; reciprocal Co-IP and cross-species assembly in Drosophila and mammalian cells","pmids":["12975319","14624008"],"confidence":"High","gaps":["Order of Sm/Lsm loading onto the ring not defined","How the SMN complex discriminates the U7 Sm site mechanistically unresolved"]},{"year":2005,"claim":"Defined how Lsm10/Lsm11 enter the assembly chaperone pathway, showing they bind pICln and SMN without themselves being symmetrically dimethylated.","evidence":"In vivo and in vitro Co-IP, methylation assays, and SMN binding studies","pmids":["16087681"],"confidence":"Medium","gaps":["Structural basis of the methylation-independent SMN interaction not determined","Single-lab finding"]},{"year":2006,"claim":"Demonstrated that U7 snRNP levels are limiting for assembly but that Lsm10 is essential for cell cycle progression, linking U7 snRNP function to proliferation.","evidence":"Histone 3'-end GFP reporter assay, RNAi knockdown, and flow cytometry cell cycle analysis in HeLa cells","pmids":["16914750"],"confidence":"Medium","gaps":["Did not establish whether G1 arrest is a direct consequence of histone processing failure","Overexpression had no processing effect, leaving the rate-limiting step unclear"]},{"year":2009,"claim":"Revealed the catalytic logic and in vivo requirement of Lsm10, showing the Sm core acts as a molecular ruler for cleavage-site selection and that Lsm10 loss causes aberrant polyadenylated histone mRNA and mislocalization.","evidence":"Biotin pulldown and UV cross-linking of processing complexes; Drosophila Lsm10/Lsm11 null mutants with RT-PCR, immunostaining, and TMG IP; immunofluorescence/FISH in human cells","pmids":["19470752","19620235","19277982"],"confidence":"High","gaps":["Identity of the endonuclease positioned by the ruler not addressed here","Cause of HLB-to-Cajal-body redistribution in cancer cells unexplained"]},{"year":2011,"claim":"Mapped the functional handoff from U7 snRNP to the processing machinery by showing FLASH–Lsm11 contact is essential for processing independently of HLB localization.","evidence":"Drosophila genetic rescue with site-directed mutagenesis and in vitro binding/dominant-negative analysis","pmids":["21525146"],"confidence":"High","gaps":["Direct role of Lsm10 (vs Lsm11) in the FLASH contact not separated","How FLASH bridges to the catalytic step not resolved"]},{"year":2012,"claim":"Uncovered a second, transcriptional role for Lsm10-containing U7 snRNP in repressing histone genes outside S phase via hnRNP UL1.","evidence":"siRNA knockdown, pulse-chase, mass spectrometry of captured U7 snRNP, hnRNP UL1 perturbation, and ChIP in HeLa cells","pmids":["22451911"],"confidence":"Medium","gaps":["Mechanism coupling U7 snRNP to transcriptional machinery at the chromatin level incomplete","Single-lab finding"]},{"year":2017,"claim":"Defined how the substrate is engaged, showing SLBP stabilizes U7 snRNP binding to histone pre-mRNA in a FLASH-dependent manner.","evidence":"In vitro processing and binding assays with SLBP domain mutagenesis and human/Drosophila pulldowns","pmids":["28289156"],"confidence":"Medium","gaps":["Quantitative contribution of Lsm10 to SLBP-stabilized binding not isolated","In vitro system may not capture full assembly context"]},{"year":2022,"claim":"Connected Lsm10/Lsm11 dosage to disease, showing co-expression rescues U7 snRNP assembly, histone processing, and neuromuscular pathology in SMA mice.","evidence":"In vivo co-expression in a mouse SMA model with assembly/processing assays, electrophysiology, and NMJ immunostaining","pmids":["36130491"],"confidence":"High","gaps":["Causal chain from histone processing to Agrin loss at NMJs not fully mechanistic","Whether Lsm10 alone (vs the dimer) is sufficient not tested"]},{"year":2023,"claim":"Provided the structural basis for chaperone recognition, showing the Lsm10/Lsm11 heterodimer engages the PRMT5/MEP50/pICln methylosome through PRMT5 binding to Lsm11 without methylating Lsm10.","evidence":"Biochemical co-purification, cryo-EM structural analysis, and in vitro methylation assays","pmids":["37562960"],"confidence":"High","gaps":["Subsequent transfer from methylosome to SMN not structurally resolved","Role of Lsm10 surfaces in the interface not detailed"]},{"year":2025,"claim":"Identified new U7 snRNA-binding factors (PTBP1, IGF2BP3, hnRNP A1) that may direct assembly of the Lsm10/Lsm11-containing Sm ring, addressing how the noncanonical Sm site is selected.","evidence":"RNA pulldown from mammalian extracts, Co-IP of hnRNP A1 with SMN, and binding competition assays","pmids":["40592581"],"confidence":"Medium","gaps":["hnRNP A1 substitution for Gemin5 proposed but not reconstituted","Direct effect of these factors on Lsm10 incorporation not demonstrated","Single-lab finding"]},{"year":null,"claim":"The identity of the endonuclease whose cleavage site is defined by the Lsm10-containing molecular ruler, and the structural transition from methylosome handoff to the mature catalytic U7 snRNP, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the full processing-competent U7 snRNP on substrate","Direct catalytic partner positioned by the ruler not defined","Mechanism of cell-type-specific HLB targeting unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,6,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10]}],"complexes":["U7 snRNP","SMN complex","PRMT5/MEP50/pICln methylosome"],"partners":["LSM11","SMN1","PRMT5","PICLN","SMB","SMD3","HNRNP UL1","HNRNP A1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969L4","full_name":"U7 snRNA-associated Sm-like protein LSm10","aliases":[],"length_aa":123,"mass_kda":14.1,"function":"Appears to function in the U7 snRNP complex that is involved in histone 3'-end processing. Increases U7 snRNA levels but not histone 3'-end pre-mRNA processing activity, when overexpressed. Required for cell cycle progression from G1 to S phases. Binds specifically to U7 snRNA. Binds to the downstream cleavage product (DCP) of histone pre-mRNA in a U7 snRNP dependent manner","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q969L4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/LSM10","classification":"Common Essential","n_dependent_lines":483,"n_total_lines":1208,"dependency_fraction":0.39983443708609273},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LSM10","total_profiled":1310},"omim":[{"mim_id":"617910","title":"LSM11, U7 SMALL NUCLEAR RNA-ASSOCIATED PROTEIN; LSM11","url":"https://www.omim.org/entry/617910"},{"mim_id":"617909","title":"LSM10, U7 SMALL NUCLEAR RNA-ASSOCIATED PROTEIN; LSM10","url":"https://www.omim.org/entry/617909"},{"mim_id":"617908","title":"ZINC FINGER PROTEIN 473; ZNF473","url":"https://www.omim.org/entry/617908"},{"mim_id":"617876","title":"RNA, U7 SMALL NUCLEAR 1; RNU7-1","url":"https://www.omim.org/entry/617876"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LSM10"},"hgnc":{"alias_symbol":["MGC15749"],"prev_symbol":[]},"alphafold":{"accession":"Q969L4","domains":[{"cath_id":"2.30.30.100","chopping":"6-105","consensus_level":"high","plddt":95.1245,"start":6,"end":105}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969L4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969L4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969L4-F1-predicted_aligned_error_v6.png","plddt_mean":88.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LSM10","jax_strain_url":"https://www.jax.org/strain/search?query=LSM10"},"sequence":{"accession":"Q969L4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969L4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969L4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969L4"}},"corpus_meta":[{"pmid":"12975319","id":"PMC_12975319","title":"Unique Sm core structure of U7 snRNPs: assembly by a specialized SMN complex and the role of a new component, Lsm11, in histone RNA processing.","date":"2003","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/12975319","citation_count":182,"is_preprint":false},{"pmid":"11574479","id":"PMC_11574479","title":"Purified U7 snRNPs lack the Sm proteins D1 and D2 but contain Lsm10, a new 14 kDa Sm D1-like protein.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11574479","citation_count":138,"is_preprint":false},{"pmid":"15526162","id":"PMC_15526162","title":"The special Sm core structure of the U7 snRNP: far-reaching significance of a small nuclear ribonucleoprotein.","date":"2004","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/15526162","citation_count":120,"is_preprint":false},{"pmid":"21525146","id":"PMC_21525146","title":"Interaction between FLASH and Lsm11 is essential for histone pre-mRNA processing in vivo in Drosophila.","date":"2011","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21525146","citation_count":41,"is_preprint":false},{"pmid":"16087681","id":"PMC_16087681","title":"Toward an assembly line for U7 snRNPs: interactions of U7-specific Lsm proteins with PRMT5 and SMN complexes.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16087681","citation_count":37,"is_preprint":false},{"pmid":"19277982","id":"PMC_19277982","title":"The subnuclear organization of histone gene regulatory proteins and 3' end processing factors of normal somatic and embryonic stem cells is compromised in selected human cancer cell types.","date":"2009","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19277982","citation_count":31,"is_preprint":false},{"pmid":"19620235","id":"PMC_19620235","title":"The Drosophila U7 snRNP proteins Lsm10 and Lsm11 are required for histone pre-mRNA processing and play an essential role in development.","date":"2009","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19620235","citation_count":30,"is_preprint":false},{"pmid":"22451911","id":"PMC_22451911","title":"U7 small nuclear ribonucleoprotein represses histone gene transcription in cell cycle-arrested cells.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22451911","citation_count":29,"is_preprint":false},{"pmid":"28289156","id":"PMC_28289156","title":"U7 snRNP is recruited to histone pre-mRNA in a FLASH-dependent manner by two separate regions of the stem-loop binding protein.","date":"2017","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28289156","citation_count":29,"is_preprint":false},{"pmid":"36130491","id":"PMC_36130491","title":"SMN controls neuromuscular junction integrity through U7 snRNP.","date":"2022","source":"Cell 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/20687925","citation_count":16,"is_preprint":false},{"pmid":"37562960","id":"PMC_37562960","title":"In vitro methylation of the U7 snRNP subunits Lsm11 and SmE by the PRMT5/MEP50/pICln methylosome.","date":"2023","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/37562960","citation_count":5,"is_preprint":false},{"pmid":"37215023","id":"PMC_37215023","title":"In vitro methylation of the U7 snRNP subunits Lsm11 and SmE by the PRMT5/MEP50/pICln methylosome.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37215023","citation_count":0,"is_preprint":false},{"pmid":"40592581","id":"PMC_40592581","title":"Proteins that recognize unique features of U7 snRNA and may substitute for Gemin5 in the assembly of U7-specific Sm ring.","date":"2025","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/40592581","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11869,"output_tokens":3792,"usd":0.046243,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11300,"output_tokens":3831,"usd":0.076137,"stage2_stop_reason":"end_turn"},"total_usd":0.12238,"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\": 2001,\n      \"finding\": \"LSM10 (Lsm10) is a novel 14 kDa Sm-like protein that replaces Sm D1 in the U7 snRNP Sm core ring; purified U7 snRNPs from HeLa cells lack Sm D1 and D2 but contain Lsm10, and its incorporation into U7 snRNPs is largely dictated by the special Sm-binding site of U7 snRNA.\",\n      \"method\": \"Biochemical fractionation and affinity purification of U7 snRNPs from HeLa cells, microsequencing of isolated polypeptides\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical purification and microsequencing identifying protein composition, replicated by multiple subsequent studies\",\n      \"pmids\": [\"11574479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Lsm10 is enriched in Cajal bodies of the cell nucleus, co-localizing with U7 snRNA.\",\n      \"method\": \"Immunofluorescence microscopy / subcellular localization in HeLa cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, immunofluorescence localization, replicated in subsequent papers\",\n      \"pmids\": [\"11574479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The U7-specific Sm core containing Lsm10 (and Lsm11) is assembled by a specialized SMN complex that contains Lsm10 and Lsm11 but lacks Sm D1/D2; assembly depends on the noncanonical Sm-binding site of U7 snRNA.\",\n      \"method\": \"In vitro assembly assays, co-immunoprecipitation, biochemical reconstitution with specialized SMN complex\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods (in vitro assembly, Co-IP), replicated across labs\",\n      \"pmids\": [\"12975319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Drosophila Lsm10 (dLsm10) associates with dLsm11 and Sm B but not with Sm D1 and D2, and Drosophila Lsm10 and Lsm11 can assemble into U7 snRNPs in mammalian cells, demonstrating evolutionary conservation of the unique U7 snRNP composition.\",\n      \"method\": \"Immunoprecipitation studies in Drosophila S2 cells; cross-species assembly assays in mammalian cells\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and cross-species assembly, single lab\",\n      \"pmids\": [\"14624008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Lsm10 and Lsm11 associate with pICln (a subunit of the PRMT5 methylosome complex) in vitro and in vivo without receiving symmetrical dimethylarginine (sDMA) modifications, and their binding to SMN is independent of methylation activity; two separate binding sites in SMN exist for Sm/Lsm proteins.\",\n      \"method\": \"Co-immunoprecipitation in vivo and in vitro binding assays; methylation assays; SMN binding studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and in vitro binding, single lab, two orthogonal methods\",\n      \"pmids\": [\"16087681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpression of Lsm10 and Lsm11 increases cellular levels of U7 snRNP but has no effect on histone pre-mRNA processing; knockdown of U7 snRNP components including Lsm10 by RNAi causes reduction in cell growth and cell cycle arrest in early G1.\",\n      \"method\": \"Reporter gene assay (GFP fused to histone 3' end), RNAi knockdown, flow cytometry for cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus RNAi with cell cycle readout, single lab, multiple methods\",\n      \"pmids\": [\"16914750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Lsm10, SmB, and SmD3 (components of the U7-specific Sm core) interact in a U7-dependent manner with the region between the cleavage site and U7-binding site in histone pre-mRNA, and function as a molecular ruler to determine the site of 3'-end cleavage.\",\n      \"method\": \"Biotin affinity pulldown of histone pre-mRNA processing complexes, UV cross-linking studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification and UV cross-linking, single lab, two complementary methods\",\n      \"pmids\": [\"19470752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In Drosophila, loss of Lsm10 disrupts histone pre-mRNA processing, causing production of polyadenylated histone mRNA from cryptic downstream sites; Lsm10 protein fails to accumulate in Lsm11 mutants, suggesting Lsm10-Lsm11 dimers are precursors for U7 snRNP assembly; Lsm10 and Lsm11 are necessary for localization of U7 snRNA to the histone locus body.\",\n      \"method\": \"Drosophila genetic loss-of-function (Lsm10 and Lsm11 null mutants), RT-PCR for polyadenylated histone mRNA, immunostaining, anti-trimethylguanosine immunoprecipitation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mutants with multiple orthogonal molecular readouts (processing assay, localization, protein stability), single lab but rigorous\",\n      \"pmids\": [\"19620235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In normal human somatic and embryonic stem cells, Lsm10-containing U7 snRNP co-localizes with p220(NPAT) and the histone gene locus in Histone Locus Bodies (HLBs); in certain cancer cell lines (HeLa S3, MCF7), this co-localization is disrupted with most Lsm10 residing in Cajal bodies instead.\",\n      \"method\": \"In situ immunofluorescence microscopy and FISH in human cell lines\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunofluorescence localization with FISH, replicated across multiple cell types, single lab\",\n      \"pmids\": [\"19277982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In Drosophila, direct interaction between FLASH (amino acids 105–154) and dLsm11 (amino acids 1–78) is essential for histone pre-mRNA processing in vivo; a two-amino-acid mutation in dLsm11 that prevents dFLASH binding—without affecting U7 snRNP localization to the HLB—cannot rescue lethality or processing defects caused by Lsm11 null mutation.\",\n      \"method\": \"Drosophila genetic rescue experiments, in vitro binding/pulldown assays, site-directed mutagenesis, dominant-negative analysis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic rescue with site-directed mutagenesis and in vitro binding, rigorous controls, Drosophila model\",\n      \"pmids\": [\"21525146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Depletion of Lsm10 (a component of the U7 snRNP-specific Sm ring) by siRNA in HeLa cells results in elevated levels of replication-dependent histone mRNAs under cell cycle-arrested conditions, acting at the transcriptional level; U7 snRNP (identified via Lsm10 component) interacts with hnRNP UL1, which mediates U7 snRNP-dependent transcriptional repression of histone genes.\",\n      \"method\": \"siRNA knockdown, pulse-chase experiments, mass spectrometry of captured U7 snRNP, hnRNP UL1 knockdown/overexpression, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with pulse-chase, MS, and ChIP, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22451911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"U7 snRNP (containing Lsm10/Lsm11) is recruited to histone pre-mRNA in a FLASH-dependent manner; SLBP stabilizes U7 snRNP binding via two regions (helix B of its RNA-binding domain and C-terminal region), and this stabilization requires FLASH but not polyadenylation factors.\",\n      \"method\": \"In vitro histone pre-mRNA processing and binding assays, mutagenesis of SLBP domains, pulldown assays with Drosophila and human SLBP\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro processing assays with domain mutagenesis, single lab, multiple constructs tested\",\n      \"pmids\": [\"28289156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Co-expression of U7-specific Lsm10 and Lsm11 proteins selectively enhances U7 snRNP assembly, corrects histone mRNA processing defects, and rescues key structural and functional neuromuscular pathology (NMJ denervation, decreased synaptic transmission, skeletal muscle atrophy) in SMA mice; U7 snRNP dysfunction drives selective loss of synaptic organizing protein Agrin at NMJs.\",\n      \"method\": \"Mouse SMA model (in vivo co-expression of Lsm10 and Lsm11), U7 snRNP assembly assays, histone mRNA processing assays, electrophysiology, immunostaining of NMJ\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic rescue in mammalian model with multiple orthogonal readouts (molecular, electrophysiological, structural), single lab but rigorous\",\n      \"pmids\": [\"36130491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A heterodimer of Lsm10 and Lsm11 tightly interacts with the PRMT5/MEP50/pICln methylosome complex; the interaction is mediated by PRMT5 which binds Lsm11 but does not methylate Lsm10; cryo-EM structural studies demonstrate the mode of interaction.\",\n      \"method\": \"Biochemical co-purification, cryo-EM structural analysis, in vitro methylation assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with in vitro biochemistry and methylation assays, peer-reviewed\",\n      \"pmids\": [\"37562960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Two proteins, PTBP1 and IGF2BP3, bind U7 snRNA in a manner dependent on its unique Sm site and upstream CUCUUU motif; hnRNP A1 also binds U7 snRNA and interacts with SMN, suggesting it may substitute for Gemin5 in directing assembly of the U7-specific Sm ring containing Lsm10 and Lsm11.\",\n      \"method\": \"RNA pulldown/affinity purification from mammalian extracts, co-immunoprecipitation of hnRNP A1 with SMN, binding competition assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNA pulldown and Co-IP identifying new interactors, single lab, single paper, mechanism proposed but not fully reconstituted\",\n      \"pmids\": [\"40592581\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LSM10 (Lsm10) is a U7 snRNP-specific Sm-like protein that replaces Sm D1 in a unique heptameric Sm ring assembled around the noncanonical Sm-binding site of U7 snRNA; it forms a heterodimer with Lsm11 that is recognized by the PRMT5/MEP50/pICln methylosome and by the SMN complex for snRNP biogenesis, localizes with U7 snRNP to Cajal bodies and histone locus bodies, and is essential for correct 3'-end endonucleolytic processing of replication-dependent histone pre-mRNAs and for U7 snRNP-dependent transcriptional repression of histone genes outside S phase, with components of the U7 Sm ring including Lsm10 also acting as a molecular ruler to define the cleavage site.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LSM10 (Lsm10) is a U7 snRNP-specific Sm-like protein that defines the noncanonical Sm core required for 3'-end processing of replication-dependent histone pre-mRNAs [#0, #7]. It substitutes for Sm D1 in the heptameric Sm ring assembled around the special Sm-binding site of U7 snRNA, which dictates its selective incorporation [#0], and this unique composition is conserved from Drosophila to mammals [#3]. Lsm10 functions as an obligate partner of Lsm11: the two form a heterodimer that serves as the precursor for U7 snRNP assembly by a specialized SMN complex lacking Sm D1/D2 [#2, #7], and is handed off through the PRMT5/MEP50/pICln methylosome, where PRMT5 binds Lsm11 but leaves Lsm10 unmethylated [#4, #13]. Within the assembled U7 snRNP, Lsm10 together with SmB and SmD3 contacts histone pre-mRNA between the U7-binding site and the cleavage site, acting as a molecular ruler that defines the endonucleolytic cut [#6], with recruitment to substrate occurring in a FLASH- and SLBP-dependent manner [#11]. Lsm10-containing U7 snRNP localizes to Cajal bodies and to histone locus bodies at the histone gene cluster [#1, #8], and beyond co-transcriptional processing it mediates transcriptional repression of histone genes outside S phase via hnRNP UL1 [#10]. Restoring Lsm10/Lsm11 levels enhances U7 snRNP assembly and rescues histone-processing and neuromuscular pathology in SMA mice, linking U7 snRNP function to spinal muscular atrophy disease biology [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that U7 snRNP has a distinct protein composition by identifying Lsm10 as a novel Sm-like protein that replaces Sm D1, answering what makes U7 snRNP biochemically unique.\",\n      \"evidence\": \"Biochemical purification of U7 snRNPs from HeLa cells with microsequencing, plus immunofluorescence localization\",\n      \"pmids\": [\"11574479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how Lsm10 selectively recognizes the U7 Sm site at atomic resolution\", \"Functional consequence of D1 replacement for processing not yet tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed that the U7-specific Sm core is built by a specialized SMN complex acting on the noncanonical U7 Sm site, and that the unique composition is evolutionarily conserved.\",\n      \"evidence\": \"In vitro assembly assays and Co-IP with a specialized SMN complex; reciprocal Co-IP and cross-species assembly in Drosophila and mammalian cells\",\n      \"pmids\": [\"12975319\", \"14624008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of Sm/Lsm loading onto the ring not defined\", \"How the SMN complex discriminates the U7 Sm site mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined how Lsm10/Lsm11 enter the assembly chaperone pathway, showing they bind pICln and SMN without themselves being symmetrically dimethylated.\",\n      \"evidence\": \"In vivo and in vitro Co-IP, methylation assays, and SMN binding studies\",\n      \"pmids\": [\"16087681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the methylation-independent SMN interaction not determined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that U7 snRNP levels are limiting for assembly but that Lsm10 is essential for cell cycle progression, linking U7 snRNP function to proliferation.\",\n      \"evidence\": \"Histone 3'-end GFP reporter assay, RNAi knockdown, and flow cytometry cell cycle analysis in HeLa cells\",\n      \"pmids\": [\"16914750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether G1 arrest is a direct consequence of histone processing failure\", \"Overexpression had no processing effect, leaving the rate-limiting step unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed the catalytic logic and in vivo requirement of Lsm10, showing the Sm core acts as a molecular ruler for cleavage-site selection and that Lsm10 loss causes aberrant polyadenylated histone mRNA and mislocalization.\",\n      \"evidence\": \"Biotin pulldown and UV cross-linking of processing complexes; Drosophila Lsm10/Lsm11 null mutants with RT-PCR, immunostaining, and TMG IP; immunofluorescence/FISH in human cells\",\n      \"pmids\": [\"19470752\", \"19620235\", \"19277982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the endonuclease positioned by the ruler not addressed here\", \"Cause of HLB-to-Cajal-body redistribution in cancer cells unexplained\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped the functional handoff from U7 snRNP to the processing machinery by showing FLASH–Lsm11 contact is essential for processing independently of HLB localization.\",\n      \"evidence\": \"Drosophila genetic rescue with site-directed mutagenesis and in vitro binding/dominant-negative analysis\",\n      \"pmids\": [\"21525146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct role of Lsm10 (vs Lsm11) in the FLASH contact not separated\", \"How FLASH bridges to the catalytic step not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Uncovered a second, transcriptional role for Lsm10-containing U7 snRNP in repressing histone genes outside S phase via hnRNP UL1.\",\n      \"evidence\": \"siRNA knockdown, pulse-chase, mass spectrometry of captured U7 snRNP, hnRNP UL1 perturbation, and ChIP in HeLa cells\",\n      \"pmids\": [\"22451911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling U7 snRNP to transcriptional machinery at the chromatin level incomplete\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined how the substrate is engaged, showing SLBP stabilizes U7 snRNP binding to histone pre-mRNA in a FLASH-dependent manner.\",\n      \"evidence\": \"In vitro processing and binding assays with SLBP domain mutagenesis and human/Drosophila pulldowns\",\n      \"pmids\": [\"28289156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of Lsm10 to SLBP-stabilized binding not isolated\", \"In vitro system may not capture full assembly context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected Lsm10/Lsm11 dosage to disease, showing co-expression rescues U7 snRNP assembly, histone processing, and neuromuscular pathology in SMA mice.\",\n      \"evidence\": \"In vivo co-expression in a mouse SMA model with assembly/processing assays, electrophysiology, and NMJ immunostaining\",\n      \"pmids\": [\"36130491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain from histone processing to Agrin loss at NMJs not fully mechanistic\", \"Whether Lsm10 alone (vs the dimer) is sufficient not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the structural basis for chaperone recognition, showing the Lsm10/Lsm11 heterodimer engages the PRMT5/MEP50/pICln methylosome through PRMT5 binding to Lsm11 without methylating Lsm10.\",\n      \"evidence\": \"Biochemical co-purification, cryo-EM structural analysis, and in vitro methylation assays\",\n      \"pmids\": [\"37562960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subsequent transfer from methylosome to SMN not structurally resolved\", \"Role of Lsm10 surfaces in the interface not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified new U7 snRNA-binding factors (PTBP1, IGF2BP3, hnRNP A1) that may direct assembly of the Lsm10/Lsm11-containing Sm ring, addressing how the noncanonical Sm site is selected.\",\n      \"evidence\": \"RNA pulldown from mammalian extracts, Co-IP of hnRNP A1 with SMN, and binding competition assays\",\n      \"pmids\": [\"40592581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"hnRNP A1 substitution for Gemin5 proposed but not reconstituted\", \"Direct effect of these factors on Lsm10 incorporation not demonstrated\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the endonuclease whose cleavage site is defined by the Lsm10-containing molecular ruler, and the structural transition from methylosome handoff to the mature catalytic U7 snRNP, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the full processing-competent U7 snRNP on substrate\", \"Direct catalytic partner positioned by the ruler not defined\", \"Mechanism of cell-type-specific HLB targeting unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"U7 snRNP\",\n      \"SMN complex\",\n      \"PRMT5/MEP50/pICln methylosome\"\n    ],\n    \"partners\": [\n      \"LSM11\",\n      \"SMN1\",\n      \"PRMT5\",\n      \"pICln\",\n      \"SmB\",\n      \"SmD3\",\n      \"hnRNP UL1\",\n      \"hnRNP A1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}