{"gene":"LSM2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"LSM2 and LSM4, but not other LSM genes, act as allele-specific low-copy suppressors of mutations in Lsm8p in yeast, and overexpression of LSM2 increases levels of both Lsm8p and U6 snRNPs. This is consistent with Lsm2p and Lsm4p directly contacting Lsm8p within the Lsm2-8 ring, and with Lsm2-8 acting redundantly with the La protein (Lhp1p) to stabilize nascent U6 snRNA.","method":"Genetic epistasis (allele-specific suppressor screen), overexpression analysis in Saccharomyces cerevisiae","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple allele combinations, single lab, no direct biochemical reconstitution of contact","pmids":["11333229"],"is_preprint":false},{"year":2004,"finding":"The nuclear Lsm2-8p complex is required for decapping and 5' degradation of nuclear pre-mRNAs. Lsm8p (but not cytoplasmic Lsm1p) can be UV cross-linked to nuclear poly(A)+ RNA, demonstrating direct interaction of the Lsm2-8p complex with nuclear RNA substrates and targeting them for decapping.","method":"UV cross-linking, genetic deletion analysis (lsm mutants), mRNA stability assays in yeast","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct UV cross-linking plus genetic knockouts with specific RNA decay phenotypes, replicated across multiple lsm subunit deletions","pmids":["15485930"],"is_preprint":false},{"year":2004,"finding":"A third Lsm complex comprising Lsm2-Lsm7 (lacking both Lsm1 and Lsm8) associates with the box H/ACA snoRNA snR5 in yeast; in vitro reconstitution showed the 3' end of snR5 is critical for Lsm protein recognition. This complex is partly distinct from the canonical snR5-Gar1p/Nhp2p complex, and Lsm proteins are present in nucleoli.","method":"In vitro reconstitution of Lsm-snR5 binding, sequential immunoprecipitation, glycerol gradient sedimentation, subcellular fractionation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution plus sequential IP and fractionation, single lab but multiple orthogonal methods","pmids":["15075370"],"is_preprint":false},{"year":2007,"finding":"The complete Lsm2-8 complex is required for nuclear accumulation of U6 snRNA in yeast; nuclear accumulation of Lsm proteins depends on complex formation, with Lsm8p playing a crucial role and Lsm2p and Lsm4p being the strongest determinants of Lsm8p nuclear localization. Lsm1p and Lsm8p compete for shared subunits (including Lsm2), controlling the balance between nuclear and cytoplasmic Lsm complexes.","method":"Fluorescence microscopy, genetic deletion and overexpression/depletion experiments in yeast, subcellular localization assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional consequence, replicated with complementary overexpression/depletion and competition assays across two papers from same group","pmids":["17251193","18029398"],"is_preprint":false},{"year":2007,"finding":"Overexpression and depletion experiments in yeast show that Lsm1p and Lsm8p compete for incorporation of shared subunits (including Lsm2) into cytoplasmic Lsm1-7 versus nuclear Lsm2-8 complexes, respectively. Under stress conditions, Lsm proteins shift from nucleus to cytoplasm, indicating this competition is biologically regulated.","method":"Overexpression and depletion in yeast, fluorescence microscopy/subcellular localization under stress","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments and genetic competition assays, single lab","pmids":["18029398"],"is_preprint":false},{"year":2011,"finding":"LSM5, LSM6, and LSM7 form a hexameric LSm657 intermediate (crystal structure at 2.5 Å), and pull-down and NMR experiments demonstrate that this complex can incorporate LSm2-3 as an assembly step towards the native LSm1-7 and LSm2-8 heptamers. LSM2 is part of a heterodimeric LSm2-3 building block that integrates into this assembly intermediate.","method":"X-ray crystallography (2.5 Å), NMR spectroscopy, pull-down assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus NMR and pull-down in vitro, single lab with multiple orthogonal methods","pmids":["22001694"],"is_preprint":false},{"year":2013,"finding":"Lsm2 and Lsm3 bridge the interaction between the C-terminus of Pat1 (Pat1C) and the Lsm1-7 complex to activate mRNA decapping. Crystal structure of the Lsm2-3-Pat1C complex reveals that Pat1C forms an asymmetric complex with three Pat1C molecules surrounding a heptameric Lsm2-3 ring. Structure-based mutagenesis confirmed these Lsm2-3-Pat1C interactions are required for decapping activation in vivo. The Lsm2-3-Pat1C complex stimulates decapping in vitro similarly to Lsm1-7-Pat1C.","method":"Crystal structure, in vitro decapping assay, structure-based mutagenesis, co-immunoprecipitation","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro functional assay plus mutagenesis validated in vivo, multiple orthogonal methods in one study","pmids":["24247251"],"is_preprint":false},{"year":2018,"finding":"Structure-guided alanine scanning of the yeast Lsm2-8 ring shows that Lsm2-R63A causes a severe growth defect by disrupting binding to the 3'-terminal UUU trinucleotide of U6 snRNA. Deletion of LSM2 is lethal but is rescued by overexpression of U6 snRNA or the U6 snRNP subunit Prp24, indicating that abetting U6 snRNA is the only essential function of Lsm2 (within the Lsm2-8 ring).","method":"Alanine-scanning mutagenesis, genetic rescue by U6 snRNA overexpression, synthetic lethality screens in yeast","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutagenesis with defined growth phenotypes plus genetic epistasis rescue experiments, replicated across multiple Lsm subunit deletions","pmids":["29615482"],"is_preprint":false},{"year":2020,"finding":"High-resolution cryo-EM/crystal structures of the Lsm2-8 complex bound to RNA reveal that the unique 2',3'-cyclic phosphate end of U6 snRNA is a prime determinant of Lsm2-8 specificity. Lsm2 is part of the heptameric ring that discriminates against non-U6 RNAs partly based on the cyclic phosphate end group.","method":"High-resolution structural determination (four structures of Lsm complexes), RNA-binding specificity assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple high-resolution structures with functional RNA-binding specificity data, orthogonal validation across Lsm1-7 and Lsm2-8 complexes","pmids":["32518066"],"is_preprint":false},{"year":2020,"finding":"In C. elegans, the LSM2-8 complex contributes to silencing of H3K27me3-marked heterochromatic genes by degrading selected transcripts through the XRN-2 exoribonuclease. Disruption of LSM2-8 leads to mRNA stabilization at these loci; this pathway does not target or require H3K9 methylation, defining a distinct post-transcriptional silencing mechanism at Polycomb-marked loci.","method":"Genetic knockdown/knockout in C. elegans, RNA stability assays, epistasis with xrn-2 and H3K27me3 pathway components","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function genetics with defined molecular phenotype (mRNA stabilization), epistasis with XRN-2, multiple reporter and endogenous loci tested","pmids":["32251399"],"is_preprint":false},{"year":2017,"finding":"In human cells, Pat1b forms a nuclear complex with the Lsm2-8 heptamer that binds U6 snRNA and associates with SART3 and U4/U6.U5 tri-snRNP components in Cajal bodies. Co-immunoprecipitation and RNAi demonstrated that Pat1b/Lsm2-8/U6 snRNA/SART3 interactions are physically connected. Pat1b depletion altered alternative splicing events, establishing a role for the nuclear Lsm2-8/Pat1b complex in pre-mRNA processing.","method":"Co-immunoprecipitation, immunofluorescence, RNAi knockdown, RNA sequencing for splicing analysis in human cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with functional RNAi validation and RNA-seq, single lab","pmids":["28768202"],"is_preprint":false},{"year":2025,"finding":"Single-molecule colocalization spectroscopy (CoSMoS) showed that Lsm2-8 association with unprocessed U6 snRNA is highly dependent on the chaperone Prp24, whereas 3'-end-processed U6 snRNA (with 3' phosphate) can rapidly recruit Lsm2-8 independently of Prp24. Prp24 promotes both recruitment and retention of Lsm2-8, suggesting kinetic selection for modified or Prp24-bound U6 as a discrimination mechanism.","method":"Colocalization single-molecule spectroscopy (CoSMoS), kinetic analysis with processed vs. unprocessed U6 snRNA variants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative single-molecule kinetics with defined molecular variants (processed/unprocessed RNA, ±Prp24), single lab but rigorous in vitro reconstitution","pmids":["40216252"],"is_preprint":false}],"current_model":"LSM2 is a core subunit of both the nuclear Lsm2-8 and cytoplasmic Lsm1-7 heptameric ring complexes; within the Lsm2-8 ring it directly contacts Lsm8p and binds the 2',3'-cyclic phosphate end of U6 snRNA to mediate nuclear retention and U6 snRNP assembly (facilitated by Prp24 and 3'-end processing), while in the Lsm1-7 context LSM2 and LSM3 together bridge Pat1 binding to activate mRNA decapping; LSM2-8 additionally targets nuclear pre-mRNAs and H3K27me3-marked transcripts for decapping/XRN-2-mediated decay, and the balance between nuclear and cytoplasmic LSM2-containing complexes is controlled by competition between Lsm1 and Lsm8 for shared subunits."},"narrative":{"mechanistic_narrative":"LSM2 is a core Sm-like subunit shared between two heptameric LSm ring complexes that govern distinct RNA fates: the nuclear Lsm2-8 ring and the cytoplasmic Lsm1-7 ring [PMID:17251193, PMID:18029398]. Within the assembly pathway, LSM2 functions as part of a heterodimeric Lsm2-3 building block that integrates into an LSm5-6-7 hexameric intermediate en route to the mature heptamers [PMID:22001694]. In the nuclear Lsm2-8 context, LSM2 directly contacts Lsm8p [PMID:11333229] and the ring binds the 3'-terminal UUU and the unique 2',3'-cyclic phosphate end of U6 snRNA, a feature that confers specificity and discriminates against non-U6 RNAs [PMID:29615482, PMID:32518066]; this binding underlies U6 snRNA nuclear accumulation and stabilization, and is the only essential function of Lsm2, since LSM2 deletion lethality is rescued by U6 snRNA or Prp24 overexpression [PMID:17251193, PMID:18029398, PMID:29615482]. Kinetically, the chaperone Prp24 promotes recruitment and retention of Lsm2-8 onto unprocessed U6 snRNA, while 3'-end-processed U6 recruits the ring rapidly and independently [PMID:40216252]. The Lsm2-8 complex also targets nuclear pre-mRNAs for decapping and 5' degradation [PMID:15485930], associates with Pat1b/SART3/U4-U6.U5 tri-snRNP components in Cajal bodies to influence alternative splicing [PMID:28768202], and silences H3K27me3-marked transcripts via XRN-2-mediated decay [PMID:32251399]. In the cytoplasmic Lsm1-7 context, Lsm2 and Lsm3 bridge the C-terminus of Pat1 to the ring to activate mRNA decapping [PMID:24247251]. The partitioning of LSM2 between nuclear and cytoplasmic complexes is set by competition between Lsm1 and Lsm8 for the shared subunit and shifts toward the cytoplasm under stress [PMID:17251193, PMID:18029398].","teleology":[{"year":2001,"claim":"Established that LSM2 physically associates with and stabilizes Lsm8p, placing it within the U6 snRNP-associated Lsm2-8 ring rather than acting independently.","evidence":"Allele-specific suppressor screen and overexpression analysis in S. cerevisiae","pmids":["11333229"],"confidence":"Medium","gaps":["Direct biochemical reconstitution of the Lsm2-Lsm8 contact not demonstrated","Did not define the RNA-binding contribution of Lsm2 specifically"]},{"year":2004,"claim":"Showed the nuclear Lsm2-8 complex acts beyond U6 metabolism by decapping and degrading nuclear pre-mRNAs, defining a nuclear RNA-decay role distinct from the cytoplasmic Lsm1-7 pathway.","evidence":"UV cross-linking and lsm-deletion mRNA stability assays in yeast; plus reconstitution of a Lsm2-7 complex binding box H/ACA snoRNA snR5","pmids":["15485930","15075370"],"confidence":"High","gaps":["Did not resolve which subunits make direct RNA contacts","Physiological RNA substrate repertoire of nuclear Lsm2-8 not fully mapped"]},{"year":2007,"claim":"Demonstrated that complete Lsm2-8 ring assembly is required for nuclear accumulation of U6 snRNA and that Lsm1/Lsm8 compete for shared subunits including Lsm2, revealing how LSM2 is partitioned between nuclear and cytoplasmic complexes.","evidence":"Fluorescence microscopy with genetic deletion, overexpression and depletion under stress in yeast","pmids":["17251193","18029398"],"confidence":"High","gaps":["Molecular trigger linking stress to the nuclear-cytoplasmic shift not identified","Stoichiometry of competition not quantified"]},{"year":2011,"claim":"Defined the assembly order of the LSm rings, showing LSM2 enters as a Lsm2-3 heterodimer that docks onto an LSm5-6-7 hexameric intermediate.","evidence":"X-ray crystallography (2.5 Å), NMR, and pull-down assays in vitro","pmids":["22001694"],"confidence":"High","gaps":["In-cell ordering and chaperone requirements of assembly not established","How the same intermediate is routed to Lsm1-7 vs Lsm2-8 not resolved"]},{"year":2013,"claim":"Showed that the Lsm2-3 module functions as the bridge connecting Pat1 to the ring to activate mRNA decapping, assigning LSM2 a direct mechanistic role in cytoplasmic decay.","evidence":"Crystal structure of Lsm2-3-Pat1C, in vitro decapping assay, structure-based mutagenesis validated in vivo, and co-IP","pmids":["24247251"],"confidence":"High","gaps":["How Pat1 binding is coordinated with substrate mRNA engagement not detailed","Whether the same Lsm2 surface is used in the nuclear Lsm2-8 context not addressed"]},{"year":2018,"claim":"Established that U6 snRNA binding is the sole essential function of Lsm2, pinpointing residue R63 as the contact for the 3'-terminal UUU.","evidence":"Alanine-scanning mutagenesis with growth phenotypes and genetic rescue by U6 snRNA/Prp24 overexpression in yeast","pmids":["29615482"],"confidence":"High","gaps":["Did not address the cyclic-phosphate recognition mechanism structurally","Essentiality of Lsm2 in non-U6 (decapping) roles not separable in this assay"]},{"year":2020,"claim":"Resolved the structural basis of U6 specificity, showing the 2',3'-cyclic phosphate end is read by the Lsm2-8 ring, and extended the silencing role to Polycomb-marked transcripts.","evidence":"High-resolution cryo-EM/crystal structures with RNA-binding specificity assays; loss-of-function genetics and xrn-2 epistasis in C. elegans","pmids":["32518066","32251399"],"confidence":"High","gaps":["Conservation of the H3K27me3/XRN-2 silencing route in mammals not tested here","How chromatin marks recruit Lsm2-8 to specific loci not defined"]},{"year":2017,"claim":"Showed the human nuclear Lsm2-8/Pat1b complex localizes to Cajal bodies with SART3 and tri-snRNP components and influences alternative splicing, extending the U6/splicing role to human cells.","evidence":"Co-immunoprecipitation, immunofluorescence, RNAi and RNA-seq in human cells","pmids":["28768202"],"confidence":"Medium","gaps":["Direct causal link between Lsm2-8 binding and individual splicing changes not established","Single-lab co-IP without orthogonal structural validation"]},{"year":2025,"claim":"Defined the kinetic discrimination mechanism, showing Prp24 drives Lsm2-8 recruitment/retention on unprocessed U6 while 3'-processed U6 recruits the ring autonomously.","evidence":"Single-molecule colocalization spectroscopy (CoSMoS) with processed/unprocessed U6 variants ± Prp24","pmids":["40216252"],"confidence":"High","gaps":["In-cell relevance of the kinetic selection not directly tested","Single-lab in vitro reconstitution"]},{"year":null,"claim":"How the LSM2-containing nuclear decapping/silencing pathways (pre-mRNA decay, H3K27me3-linked XRN-2 decay, splicing) are mechanistically integrated and regulated in mammalian cells remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mammalian structural data for substrate-specific recruitment to chromatin","Regulatory inputs controlling nuclear vs cytoplasmic LSM2 partitioning in human cells unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7,8,1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,1]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,6]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,6,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10,9]}],"complexes":["Lsm2-8 complex","Lsm1-7 complex","Lsm2-7/snR5 complex","Cajal body U4/U6.U5 tri-snRNP-associated Pat1b complex"],"partners":["LSM8","LSM3","PATL1","SART3","PRPF24","LSM4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y333","full_name":"U6 snRNA-associated Sm-like protein LSm2","aliases":["Protein G7b","Small nuclear ribonuclear protein D homolog","snRNP core Sm-like protein Sm-x5"],"length_aa":95,"mass_kda":10.8,"function":"Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex) (PubMed:28781166). The heptameric LSM2-8 complex binds specifically to the 3'-terminal U-tract of U6 snRNA (PubMed:10523320)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y333/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/LSM2","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SNRPF","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LSM2","total_profiled":1310},"omim":[{"mim_id":"621191","title":"LEUKODYSTROPHY AND CEREBELLAR ATROPHY; LDCA","url":"https://www.omim.org/entry/621191"},{"mim_id":"611684","title":"SPLICEOSOME-ASSOCIATED FACTOR 3, U4/U6 RECYCLING PROTEIN; SART3","url":"https://www.omim.org/entry/611684"},{"mim_id":"607288","title":"LSM8 PROTEIN; LSM8","url":"https://www.omim.org/entry/607288"},{"mim_id":"607287","title":"LSM7 PROTEIN; LSM7","url":"https://www.omim.org/entry/607287"},{"mim_id":"607286","title":"LSM6 PROTEIN; LSM6","url":"https://www.omim.org/entry/607286"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LSM2"},"hgnc":{"alias_symbol":["G7b","YBL026W"],"prev_symbol":["C6orf28"]},"alphafold":{"accession":"Q9Y333","domains":[{"cath_id":"2.30.30.100","chopping":"1-95","consensus_level":"medium","plddt":94.7314,"start":1,"end":95}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y333","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y333-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y333-F1-predicted_aligned_error_v6.png","plddt_mean":94.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LSM2","jax_strain_url":"https://www.jax.org/strain/search?query=LSM2"},"sequence":{"accession":"Q9Y333","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y333.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y333/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y333"}},"corpus_meta":[{"pmid":"11333229","id":"PMC_11333229","title":"Multiple functional interactions between components of the Lsm2-Lsm8 complex, U6 snRNA, and the yeast La protein.","date":"2001","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11333229","citation_count":65,"is_preprint":false},{"pmid":"15485930","id":"PMC_15485930","title":"Nuclear pre-mRNA decapping and 5' degradation in yeast require the Lsm2-8p complex.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15485930","citation_count":57,"is_preprint":false},{"pmid":"15075370","id":"PMC_15075370","title":"An Lsm2-Lsm7 complex in Saccharomyces cerevisiae associates with the small nucleolar RNA snR5.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15075370","citation_count":37,"is_preprint":false},{"pmid":"24247251","id":"PMC_24247251","title":"Lsm2 and Lsm3 bridge the interaction of the Lsm1-7 complex with Pat1 for decapping activation.","date":"2013","source":"Cell 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Lsm2-8p complex and competition between nuclear and cytoplasmic Lsm complexes.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/18029398","citation_count":26,"is_preprint":false},{"pmid":"32251399","id":"PMC_32251399","title":"LSM2-8 and XRN-2 contribute to the silencing of H3K27me3-marked genes through targeted RNA decay.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32251399","citation_count":19,"is_preprint":false},{"pmid":"22001694","id":"PMC_22001694","title":"Structure of the LSm657 complex: an assembly intermediate of the LSm1-7 and LSm2-8 rings.","date":"2011","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22001694","citation_count":15,"is_preprint":false},{"pmid":"36016928","id":"PMC_36016928","title":"The cytoplasmic LSm1-7 and nuclear LSm2-8 complexes exert opposite effects on Hepatitis B virus biosynthesis and interferon 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Assembly","date":"2025-02-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.25.639938","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11691,"output_tokens":3426,"usd":0.043231,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10873,"output_tokens":3707,"usd":0.07352,"stage2_stop_reason":"end_turn"},"total_usd":0.116751,"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\": \"LSM2 and LSM4, but not other LSM genes, act as allele-specific low-copy suppressors of mutations in Lsm8p in yeast, and overexpression of LSM2 increases levels of both Lsm8p and U6 snRNPs. This is consistent with Lsm2p and Lsm4p directly contacting Lsm8p within the Lsm2-8 ring, and with Lsm2-8 acting redundantly with the La protein (Lhp1p) to stabilize nascent U6 snRNA.\",\n      \"method\": \"Genetic epistasis (allele-specific suppressor screen), overexpression analysis in Saccharomyces cerevisiae\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple allele combinations, single lab, no direct biochemical reconstitution of contact\",\n      \"pmids\": [\"11333229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The nuclear Lsm2-8p complex is required for decapping and 5' degradation of nuclear pre-mRNAs. Lsm8p (but not cytoplasmic Lsm1p) can be UV cross-linked to nuclear poly(A)+ RNA, demonstrating direct interaction of the Lsm2-8p complex with nuclear RNA substrates and targeting them for decapping.\",\n      \"method\": \"UV cross-linking, genetic deletion analysis (lsm mutants), mRNA stability assays in yeast\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct UV cross-linking plus genetic knockouts with specific RNA decay phenotypes, replicated across multiple lsm subunit deletions\",\n      \"pmids\": [\"15485930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A third Lsm complex comprising Lsm2-Lsm7 (lacking both Lsm1 and Lsm8) associates with the box H/ACA snoRNA snR5 in yeast; in vitro reconstitution showed the 3' end of snR5 is critical for Lsm protein recognition. This complex is partly distinct from the canonical snR5-Gar1p/Nhp2p complex, and Lsm proteins are present in nucleoli.\",\n      \"method\": \"In vitro reconstitution of Lsm-snR5 binding, sequential immunoprecipitation, glycerol gradient sedimentation, subcellular fractionation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution plus sequential IP and fractionation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15075370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The complete Lsm2-8 complex is required for nuclear accumulation of U6 snRNA in yeast; nuclear accumulation of Lsm proteins depends on complex formation, with Lsm8p playing a crucial role and Lsm2p and Lsm4p being the strongest determinants of Lsm8p nuclear localization. Lsm1p and Lsm8p compete for shared subunits (including Lsm2), controlling the balance between nuclear and cytoplasmic Lsm complexes.\",\n      \"method\": \"Fluorescence microscopy, genetic deletion and overexpression/depletion experiments in yeast, subcellular localization assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional consequence, replicated with complementary overexpression/depletion and competition assays across two papers from same group\",\n      \"pmids\": [\"17251193\", \"18029398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Overexpression and depletion experiments in yeast show that Lsm1p and Lsm8p compete for incorporation of shared subunits (including Lsm2) into cytoplasmic Lsm1-7 versus nuclear Lsm2-8 complexes, respectively. Under stress conditions, Lsm proteins shift from nucleus to cytoplasm, indicating this competition is biologically regulated.\",\n      \"method\": \"Overexpression and depletion in yeast, fluorescence microscopy/subcellular localization under stress\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments and genetic competition assays, single lab\",\n      \"pmids\": [\"18029398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LSM5, LSM6, and LSM7 form a hexameric LSm657 intermediate (crystal structure at 2.5 Å), and pull-down and NMR experiments demonstrate that this complex can incorporate LSm2-3 as an assembly step towards the native LSm1-7 and LSm2-8 heptamers. LSM2 is part of a heterodimeric LSm2-3 building block that integrates into this assembly intermediate.\",\n      \"method\": \"X-ray crystallography (2.5 Å), NMR spectroscopy, pull-down assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus NMR and pull-down in vitro, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22001694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lsm2 and Lsm3 bridge the interaction between the C-terminus of Pat1 (Pat1C) and the Lsm1-7 complex to activate mRNA decapping. Crystal structure of the Lsm2-3-Pat1C complex reveals that Pat1C forms an asymmetric complex with three Pat1C molecules surrounding a heptameric Lsm2-3 ring. Structure-based mutagenesis confirmed these Lsm2-3-Pat1C interactions are required for decapping activation in vivo. The Lsm2-3-Pat1C complex stimulates decapping in vitro similarly to Lsm1-7-Pat1C.\",\n      \"method\": \"Crystal structure, in vitro decapping assay, structure-based mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro functional assay plus mutagenesis validated in vivo, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24247251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Structure-guided alanine scanning of the yeast Lsm2-8 ring shows that Lsm2-R63A causes a severe growth defect by disrupting binding to the 3'-terminal UUU trinucleotide of U6 snRNA. Deletion of LSM2 is lethal but is rescued by overexpression of U6 snRNA or the U6 snRNP subunit Prp24, indicating that abetting U6 snRNA is the only essential function of Lsm2 (within the Lsm2-8 ring).\",\n      \"method\": \"Alanine-scanning mutagenesis, genetic rescue by U6 snRNA overexpression, synthetic lethality screens in yeast\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutagenesis with defined growth phenotypes plus genetic epistasis rescue experiments, replicated across multiple Lsm subunit deletions\",\n      \"pmids\": [\"29615482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"High-resolution cryo-EM/crystal structures of the Lsm2-8 complex bound to RNA reveal that the unique 2',3'-cyclic phosphate end of U6 snRNA is a prime determinant of Lsm2-8 specificity. Lsm2 is part of the heptameric ring that discriminates against non-U6 RNAs partly based on the cyclic phosphate end group.\",\n      \"method\": \"High-resolution structural determination (four structures of Lsm complexes), RNA-binding specificity assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple high-resolution structures with functional RNA-binding specificity data, orthogonal validation across Lsm1-7 and Lsm2-8 complexes\",\n      \"pmids\": [\"32518066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In C. elegans, the LSM2-8 complex contributes to silencing of H3K27me3-marked heterochromatic genes by degrading selected transcripts through the XRN-2 exoribonuclease. Disruption of LSM2-8 leads to mRNA stabilization at these loci; this pathway does not target or require H3K9 methylation, defining a distinct post-transcriptional silencing mechanism at Polycomb-marked loci.\",\n      \"method\": \"Genetic knockdown/knockout in C. elegans, RNA stability assays, epistasis with xrn-2 and H3K27me3 pathway components\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function genetics with defined molecular phenotype (mRNA stabilization), epistasis with XRN-2, multiple reporter and endogenous loci tested\",\n      \"pmids\": [\"32251399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In human cells, Pat1b forms a nuclear complex with the Lsm2-8 heptamer that binds U6 snRNA and associates with SART3 and U4/U6.U5 tri-snRNP components in Cajal bodies. Co-immunoprecipitation and RNAi demonstrated that Pat1b/Lsm2-8/U6 snRNA/SART3 interactions are physically connected. Pat1b depletion altered alternative splicing events, establishing a role for the nuclear Lsm2-8/Pat1b complex in pre-mRNA processing.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, RNAi knockdown, RNA sequencing for splicing analysis in human cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with functional RNAi validation and RNA-seq, single lab\",\n      \"pmids\": [\"28768202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Single-molecule colocalization spectroscopy (CoSMoS) showed that Lsm2-8 association with unprocessed U6 snRNA is highly dependent on the chaperone Prp24, whereas 3'-end-processed U6 snRNA (with 3' phosphate) can rapidly recruit Lsm2-8 independently of Prp24. Prp24 promotes both recruitment and retention of Lsm2-8, suggesting kinetic selection for modified or Prp24-bound U6 as a discrimination mechanism.\",\n      \"method\": \"Colocalization single-molecule spectroscopy (CoSMoS), kinetic analysis with processed vs. unprocessed U6 snRNA variants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative single-molecule kinetics with defined molecular variants (processed/unprocessed RNA, ±Prp24), single lab but rigorous in vitro reconstitution\",\n      \"pmids\": [\"40216252\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LSM2 is a core subunit of both the nuclear Lsm2-8 and cytoplasmic Lsm1-7 heptameric ring complexes; within the Lsm2-8 ring it directly contacts Lsm8p and binds the 2',3'-cyclic phosphate end of U6 snRNA to mediate nuclear retention and U6 snRNP assembly (facilitated by Prp24 and 3'-end processing), while in the Lsm1-7 context LSM2 and LSM3 together bridge Pat1 binding to activate mRNA decapping; LSM2-8 additionally targets nuclear pre-mRNAs and H3K27me3-marked transcripts for decapping/XRN-2-mediated decay, and the balance between nuclear and cytoplasmic LSM2-containing complexes is controlled by competition between Lsm1 and Lsm8 for shared subunits.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LSM2 is a core Sm-like subunit shared between two heptameric LSm ring complexes that govern distinct RNA fates: the nuclear Lsm2-8 ring and the cytoplasmic Lsm1-7 ring [#3, #4]. Within the assembly pathway, LSM2 functions as part of a heterodimeric Lsm2-3 building block that integrates into an LSm5-6-7 hexameric intermediate en route to the mature heptamers [#5]. In the nuclear Lsm2-8 context, LSM2 directly contacts Lsm8p [#0] and the ring binds the 3'-terminal UUU and the unique 2',3'-cyclic phosphate end of U6 snRNA, a feature that confers specificity and discriminates against non-U6 RNAs [#7, #8]; this binding underlies U6 snRNA nuclear accumulation and stabilization, and is the only essential function of Lsm2, since LSM2 deletion lethality is rescued by U6 snRNA or Prp24 overexpression [#3, #7]. Kinetically, the chaperone Prp24 promotes recruitment and retention of Lsm2-8 onto unprocessed U6 snRNA, while 3'-end-processed U6 recruits the ring rapidly and independently [#11]. The Lsm2-8 complex also targets nuclear pre-mRNAs for decapping and 5' degradation [#1], associates with Pat1b/SART3/U4-U6.U5 tri-snRNP components in Cajal bodies to influence alternative splicing [#10], and silences H3K27me3-marked transcripts via XRN-2-mediated decay [#9]. In the cytoplasmic Lsm1-7 context, Lsm2 and Lsm3 bridge the C-terminus of Pat1 to the ring to activate mRNA decapping [#6]. The partitioning of LSM2 between nuclear and cytoplasmic complexes is set by competition between Lsm1 and Lsm8 for the shared subunit and shifts toward the cytoplasm under stress [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that LSM2 physically associates with and stabilizes Lsm8p, placing it within the U6 snRNP-associated Lsm2-8 ring rather than acting independently.\",\n      \"evidence\": \"Allele-specific suppressor screen and overexpression analysis in S. cerevisiae\",\n      \"pmids\": [\"11333229\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct biochemical reconstitution of the Lsm2-Lsm8 contact not demonstrated\", \"Did not define the RNA-binding contribution of Lsm2 specifically\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed the nuclear Lsm2-8 complex acts beyond U6 metabolism by decapping and degrading nuclear pre-mRNAs, defining a nuclear RNA-decay role distinct from the cytoplasmic Lsm1-7 pathway.\",\n      \"evidence\": \"UV cross-linking and lsm-deletion mRNA stability assays in yeast; plus reconstitution of a Lsm2-7 complex binding box H/ACA snoRNA snR5\",\n      \"pmids\": [\"15485930\", \"15075370\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not resolve which subunits make direct RNA contacts\", \"Physiological RNA substrate repertoire of nuclear Lsm2-8 not fully mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that complete Lsm2-8 ring assembly is required for nuclear accumulation of U6 snRNA and that Lsm1/Lsm8 compete for shared subunits including Lsm2, revealing how LSM2 is partitioned between nuclear and cytoplasmic complexes.\",\n      \"evidence\": \"Fluorescence microscopy with genetic deletion, overexpression and depletion under stress in yeast\",\n      \"pmids\": [\"17251193\", \"18029398\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular trigger linking stress to the nuclear-cytoplasmic shift not identified\", \"Stoichiometry of competition not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the assembly order of the LSm rings, showing LSM2 enters as a Lsm2-3 heterodimer that docks onto an LSm5-6-7 hexameric intermediate.\",\n      \"evidence\": \"X-ray crystallography (2.5 Å), NMR, and pull-down assays in vitro\",\n      \"pmids\": [\"22001694\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In-cell ordering and chaperone requirements of assembly not established\", \"How the same intermediate is routed to Lsm1-7 vs Lsm2-8 not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that the Lsm2-3 module functions as the bridge connecting Pat1 to the ring to activate mRNA decapping, assigning LSM2 a direct mechanistic role in cytoplasmic decay.\",\n      \"evidence\": \"Crystal structure of Lsm2-3-Pat1C, in vitro decapping assay, structure-based mutagenesis validated in vivo, and co-IP\",\n      \"pmids\": [\"24247251\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How Pat1 binding is coordinated with substrate mRNA engagement not detailed\", \"Whether the same Lsm2 surface is used in the nuclear Lsm2-8 context not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that U6 snRNA binding is the sole essential function of Lsm2, pinpointing residue R63 as the contact for the 3'-terminal UUU.\",\n      \"evidence\": \"Alanine-scanning mutagenesis with growth phenotypes and genetic rescue by U6 snRNA/Prp24 overexpression in yeast\",\n      \"pmids\": [\"29615482\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not address the cyclic-phosphate recognition mechanism structurally\", \"Essentiality of Lsm2 in non-U6 (decapping) roles not separable in this assay\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the structural basis of U6 specificity, showing the 2',3'-cyclic phosphate end is read by the Lsm2-8 ring, and extended the silencing role to Polycomb-marked transcripts.\",\n      \"evidence\": \"High-resolution cryo-EM/crystal structures with RNA-binding specificity assays; loss-of-function genetics and xrn-2 epistasis in C. elegans\",\n      \"pmids\": [\"32518066\", \"32251399\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Conservation of the H3K27me3/XRN-2 silencing route in mammals not tested here\", \"How chromatin marks recruit Lsm2-8 to specific loci not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the human nuclear Lsm2-8/Pat1b complex localizes to Cajal bodies with SART3 and tri-snRNP components and influences alternative splicing, extending the U6/splicing role to human cells.\",\n      \"evidence\": \"Co-immunoprecipitation, immunofluorescence, RNAi and RNA-seq in human cells\",\n      \"pmids\": [\"28768202\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct causal link between Lsm2-8 binding and individual splicing changes not established\", \"Single-lab co-IP without orthogonal structural validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the kinetic discrimination mechanism, showing Prp24 drives Lsm2-8 recruitment/retention on unprocessed U6 while 3'-processed U6 recruits the ring autonomously.\",\n      \"evidence\": \"Single-molecule colocalization spectroscopy (CoSMoS) with processed/unprocessed U6 variants ± Prp24\",\n      \"pmids\": [\"40216252\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In-cell relevance of the kinetic selection not directly tested\", \"Single-lab in vitro reconstitution\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the LSM2-containing nuclear decapping/silencing pathways (pre-mRNA decay, H3K27me3-linked XRN-2 decay, splicing) are mechanistically integrated and regulated in mammalian cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No mammalian structural data for substrate-specific recruitment to chromatin\", \"Regulatory inputs controlling nuclear vs cytoplasmic LSM2 partitioning in human cells unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7, 8, 1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 1]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 6, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10, 9]}\n    ],\n    \"complexes\": [\"Lsm2-8 complex\", \"Lsm1-7 complex\", \"Lsm2-7/snR5 complex\", \"Cajal body U4/U6.U5 tri-snRNP-associated Pat1b complex\"],\n    \"partners\": [\"LSM8\", \"LSM3\", \"PATL1\", \"SART3\", \"PRPF24\", \"LSM4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}