{"gene":"LSM4","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2001,"finding":"LSm4 contains symmetrically dimethylated arginine (sDMA) residues in vivo, identified by mass spectrometry and protein sequencing. These sDMA modifications are required for LSm4 binding to the Tudor domain of SMN; inhibition of dimethylation by S-adenosylhomocysteine abolished this interaction. The cytoplasmic PRMT responsible for symmetrical dimethylation of LSm4 was identified in HeLa S100 cytosolic extract.","method":"Mass spectrometry, protein sequencing, in vitro methylation assay with HeLa cytosolic/nuclear extracts, synthetic peptide competition, SAH inhibition","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (mass spec, sequencing, in vitro assay, inhibitor studies) in a single highly-cited study","pmids":["11720283"],"is_preprint":false},{"year":2016,"finding":"The C-terminal RGG domain of human LSm4 promotes processing body (P-body) formation in human cells. Symmetric dimethylation of arginines within the RGG domain by PRMT5 stimulates PB accumulation. An RGG-domain deletion mutant of LSm4 failed to rescue PB formation even though it retained Lsm1-7 assembly, decapping factor association, mRNA decay activity, and translational repression. Depletion of PRMT5 resulted in loss of PBs. The histone acetyltransferase HAT1-RBBP7 complex was identified as a novel interactor of the Lsm4 RGG domain.","method":"RGG domain deletion mutagenesis, siRNA depletion of endogenous Lsm4 and PRMT5, rescue experiments, co-immunoprecipitation, fluorescence microscopy of PBs, mRNA decay and translation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, clean KD/KO with defined cellular phenotype, multiple orthogonal methods in single study","pmids":["27247266"],"is_preprint":false},{"year":2013,"finding":"The C-terminal extension of Lsm4 interacts directly with the histone mRNP, contacting both the stem-loop binding protein (SLBP) and 3'hExo. Mutations in the C-terminal tail of Lsm4 that prevent SLBP and 3'hExo binding reduce the rate of histone mRNA degradation when DNA synthesis is inhibited.","method":"Co-immunoprecipitation/pulldown, mutagenesis of C-terminal tail, histone mRNA degradation assays upon DNA synthesis inhibition","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 — direct binding assays combined with mutagenesis and functional mRNA decay readout","pmids":["24255165"],"is_preprint":false},{"year":2000,"finding":"Mouse Lsm4 is essential for early embryonic development; homozygous knockout mice survive to blastocyst stage and implant but die shortly thereafter, demonstrating that Lsm4 function in splicing is essential and cannot be compensated by other Lsm proteins.","method":"Promoter trap gene targeting in murine ES cells, homozygous knockout mouse analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined lethal phenotype in mouse model","pmids":["10629062"],"is_preprint":false},{"year":2005,"finding":"ICln interacts with LSm4 via its pleckstrin homology (PH) domain-like structure, suggesting a physical link between cell volume regulation and RNA splicing/mRNA degradation pathways.","method":"Pulldown/co-immunoprecipitation, structural determination of ICln PH domain by NMR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single pulldown interaction, structural context provided but LSm4 functional consequence not fully established","pmids":["15905169"],"is_preprint":false},{"year":2008,"finding":"LSm4 associates with ICln and the plasma membrane under isotonic conditions. Upon hypotonic cell swelling, LSm4 dissociates from the plasma membrane and from ICln. Overexpression of LSm4 inhibits ICln translocation to the cell membrane and markedly inhibits the activation kinetics and current density of the swelling-dependent anion channel IClswell, establishing LSm4 as a co-factor in cell volume regulation.","method":"FRET, subcellular fractionation biochemistry, electrophysiology, overexpression experiments in NIH3T3 and HEK293 cells","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by FRET tied to functional electrophysiological consequence, single lab","pmids":["19088440"],"is_preprint":false},{"year":2012,"finding":"Crystal structures of S. pombe Lsm4 (and Lsm3, Lsm5/6/7) were solved, revealing a conserved Sm fold. Lsm4 forms a trimer in the crystal lattice and undergoes dynamic monomer-trimer equilibrium in solution by analytical ultracentrifugation. RNA binding assays showed no direct RNA binding for isolated Lsm4.","method":"X-ray crystallography, analytical ultracentrifugation, RNA binding assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation (RNA binding assays, AUC) for fission yeast ortholog","pmids":["22615807"],"is_preprint":false},{"year":2001,"finding":"In K. lactis and S. cerevisiae, only the first 72 amino acids of KlLsm4p containing the Sm-like domain are sufficient to restore cell viability in cells lacking wild-type Lsm4, but loss of the carboxy-terminal region causes remarkable loss of viability in stationary phase, establishing a distinct functional role for the C-terminal domain.","method":"Complementation assay with C-terminal truncation mutants in K. lactis and S. cerevisiae","journal":"Yeast (Chichester, England)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic complementation with defined domain truncations, yeast ortholog study","pmids":["11561292"],"is_preprint":false},{"year":2016,"finding":"Combined deletion of EDC3 and the Q/N-rich C-terminal region of Lsm4 in S. cerevisiae reduces mRNA stability, increases dependence on Ccr4-mediated deadenylation and mRNA decapping, alters mRNA decay factor levels, and causes nuclear accumulation of the decapping enzyme Dcp2, placing Lsm4's C-terminal domain and Edc3 together in a pathway that regulates mRNA stability and P-body-dependent mRNA fate.","method":"Genetic double mutant analysis, mRNA stability assays, subcellular localization of Dcp2, epistasis with deadenylation and decapping pathways in S. cerevisiae","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis in yeast ortholog with multiple defined molecular phenotypes, single lab","pmids":["27543059"],"is_preprint":false},{"year":2023,"finding":"Purified full-length human LSm4 protein undergoes concentration-dependent liquid-liquid phase separation (LLPS) in vitro. The C-terminal low-complexity domain is implicated in LLPS. High salt concentrations and 1,6-hexanediol block LLPS, and droplet fusion is observed, consistent with liquid-like properties.","method":"In vitro LLPS assay with purified recombinant mCherry-LSm4, fluorescence microscopy (DeltaVision), hexanediol and salt perturbation, disordered region prediction","journal":"Molekuliarnaia biologiia","confidence":"Medium","confidence_rationale":"Tier 1 in vitro reconstitution, but single lab and no mutagenesis validation of specific domain","pmids":["36976747"],"is_preprint":false},{"year":2025,"finding":"Under hypoxic conditions, reduced tRF-31 binding to LSm4 decreases LSm4 ubiquitination and enhances its protein stability, leading to nuclear translocation of LSm4 where it promotes splicing of EDN1 pre-mRNA. Overexpression of tRF-31 inhibits hypoxia-induced proliferation of pulmonary artery endothelial cells by this mechanism.","method":"tRF-31 overexpression/knockdown, LSm4 ubiquitination assay, subcellular fractionation, RNA splicing assay, RNA binding assay (tRF-31 / LSm4 interaction), proliferation assays","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding, ubiquitination, localization, and splicing assays in single study; single lab","pmids":["41354297"],"is_preprint":false},{"year":2016,"finding":"SF3B4 interacts with LSm4 (confirmed by co-immunoprecipitation), and overexpression of LSm4 reverses inhibition of NSCLC cell proliferation, invasion, migration, and stemness caused by SF3B4 knockdown, placing LSm4 downstream of SF3B4 in a cancer-relevant pathway.","method":"Co-immunoprecipitation, knockdown rescue by LSm4 overexpression, cell functional assays","journal":"Thoracic cancer","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP, rescue experiment in cancer cell line, no defined molecular mechanism for LSm4 activity","pmids":["38462740"],"is_preprint":false}],"current_model":"LSm4 is a core subunit of the cytoplasmic Lsm1–7 complex that adopts a conserved Sm fold and engages in multiple RNA metabolic processes: its Sm domain mediates assembly into the Lsm1–7 ring and association with U6 snRNA for pre-mRNA splicing, while its C-terminal RGG domain (symmetrically dimethylated by the cytoplasmic PRMT5) drives liquid-liquid phase separation and P-body assembly, and also contacts SLBP and 3'hExo on the histone mRNP to promote oligouridylated histone mRNA degradation; additionally, sDMA-modified LSm4 binds the SMN Tudor domain to support snRNP biogenesis, and LSm4 functions at the plasma membrane as a co-factor in cell volume regulation through interaction with ICln."},"narrative":{"teleology":[{"year":2000,"claim":"The question of whether LSm4 is individually essential or redundant with other Lsm proteins was resolved by showing that homozygous Lsm4-knockout mice die shortly after implantation, establishing a non-redundant requirement for LSm4 in early development.","evidence":"Promoter-trap gene targeting and knockout mouse analysis","pmids":["10629062"],"confidence":"High","gaps":["Specific RNA targets or splicing events disrupted in Lsm4-null embryos were not identified","Whether lethality reflects loss of splicing, mRNA decay, or both was not resolved"]},{"year":2001,"claim":"The discovery that LSm4 carries symmetric dimethylarginine (sDMA) modifications and that these are required for Tudor-domain binding to SMN established a post-translational regulatory axis linking LSm4 to snRNP biogenesis.","evidence":"Mass spectrometry, protein sequencing, in vitro methylation with HeLa extracts, SAH inhibition","pmids":["11720283"],"confidence":"High","gaps":["Whether sDMA modification is constitutive or regulated was not determined","Functional consequence of disrupting LSm4–SMN interaction on snRNP assembly was not directly tested"]},{"year":2001,"claim":"Yeast complementation with C-terminal truncations showed that the Sm-fold domain alone supports viability but the C-terminal domain is essential for stationary-phase survival, delineating two functionally separable domains.","evidence":"Complementation assays with domain truncation mutants in K. lactis and S. cerevisiae","pmids":["11561292"],"confidence":"Medium","gaps":["Molecular targets of the C-terminal domain in stationary phase were not identified","Whether the C-terminal domain function is conserved in mammals was not addressed"]},{"year":2005,"claim":"Identification of ICln as a physical partner of LSm4 suggested a link between RNA metabolism and cell volume regulation, though the functional significance for LSm4 was initially unclear.","evidence":"Co-immunoprecipitation and NMR structural analysis of ICln PH domain","pmids":["15905169"],"confidence":"Medium","gaps":["Whether the ICln–LSm4 interaction is direct or bridged was not resolved with purified proteins","Functional consequence for RNA processing was not tested"]},{"year":2008,"claim":"FRET and electrophysiology experiments showed LSm4 resides at the plasma membrane under isotonic conditions and dissociates upon swelling, directly modulating IClswell channel kinetics, thereby establishing a non-canonical function for LSm4 in cell volume regulation.","evidence":"FRET, subcellular fractionation, electrophysiology in NIH3T3 and HEK293 cells","pmids":["19088440"],"confidence":"Medium","gaps":["Mechanism by which LSm4 inhibits IClswell is unknown","Whether this plasma membrane pool is distinct from the mRNA decay pool was not addressed"]},{"year":2012,"claim":"Crystal structures of fission yeast Lsm4 confirmed the conserved Sm fold and revealed a monomer–trimer equilibrium, while RNA binding assays showed isolated Lsm4 does not bind RNA, indicating it functions only in the assembled ring context.","evidence":"X-ray crystallography, analytical ultracentrifugation, RNA binding assays with S. pombe Lsm4","pmids":["22615807"],"confidence":"High","gaps":["No structure of the full heptameric ring including Lsm4 was obtained","C-terminal low-complexity domain was absent from constructs"]},{"year":2013,"claim":"The C-terminal tail of LSm4 was shown to directly contact SLBP and 3′hExo on histone mRNPs, and mutations disrupting these interactions reduced histone mRNA degradation, defining a substrate-specific role for LSm4 beyond general mRNA decay.","evidence":"Co-immunoprecipitation/pulldown, mutagenesis, histone mRNA decay assays upon DNA synthesis inhibition","pmids":["24255165"],"confidence":"High","gaps":["Whether oligouridylation is required upstream of LSm4 engagement was not addressed","Structural basis of the C-tail–SLBP/3′hExo interaction is unknown"]},{"year":2016,"claim":"Definitive evidence that the LSm4 RGG domain is dispensable for Lsm1–7 assembly, decapping, and mRNA decay but is specifically required for P-body formation established that P-body condensation is mechanistically separable from mRNA decay; PRMT5-mediated sDMA of the RGG domain drives this condensation.","evidence":"RGG deletion rescue, PRMT5 knockdown, fluorescence microscopy, mRNA decay and translation assays in human cells","pmids":["27247266"],"confidence":"High","gaps":["Whether sDMA-dependent P-body formation feeds back to regulate specific mRNAs is unknown","The role of the HAT1–RBBP7 interaction identified in this study remains uncharacterized"]},{"year":2016,"claim":"Genetic epistasis in yeast showed that combined loss of Edc3 and the Lsm4 C-terminal Q/N-rich domain reduces mRNA stability and causes nuclear mislocalization of Dcp2, revealing redundant scaffolding roles of Lsm4 and Edc3 in organizing cytoplasmic mRNA decay.","evidence":"Double mutant analysis, mRNA stability assays, Dcp2 localization in S. cerevisiae","pmids":["27543059"],"confidence":"Medium","gaps":["Whether the yeast Q/N-rich domain and the mammalian RGG domain are functionally analogous remains formally untested","Mechanism of Dcp2 nuclear accumulation is unknown"]},{"year":2023,"claim":"In vitro reconstitution demonstrated that purified full-length LSm4 undergoes concentration-dependent liquid–liquid phase separation, directly attributing the condensation-driving activity to LSm4 itself rather than to co-factors.","evidence":"Purified recombinant mCherry-LSm4 LLPS assay, hexanediol and salt perturbation, fluorescence microscopy","pmids":["36976747"],"confidence":"Medium","gaps":["The specific residues or modifications within the low-complexity domain driving LLPS were not mapped by mutagenesis","Behavior of LSm4 within the full Lsm1–7 complex in LLPS was not tested"]},{"year":2025,"claim":"Under hypoxia, reduced tRF-31 binding to LSm4 decreases its ubiquitination and stabilizes the protein, causing nuclear translocation where LSm4 promotes EDN1 pre-mRNA splicing — revealing a tRNA-fragment-based regulatory mechanism governing LSm4 stability and nuclear splicing function.","evidence":"tRF-31 overexpression/knockdown, ubiquitination assays, subcellular fractionation, splicing and proliferation assays in pulmonary artery endothelial cells","pmids":["41354297"],"confidence":"Medium","gaps":["The E3 ubiquitin ligase targeting LSm4 was not identified","Whether tRF-31-mediated regulation applies to other cell types or stress conditions is unknown","The specificity of EDN1 as an LSm4 splicing target needs broader transcriptomic validation"]},{"year":null,"claim":"Key open questions include the structural basis of the Lsm4 C-terminal domain interactions with SLBP/3′hExo, the identity of the E3 ligase controlling LSm4 turnover, whether P-body condensation driven by LSm4 feeds back to regulate specific mRNA fates, and the physiological relevance of the plasma membrane LSm4–ICln interaction.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of the C-terminal RGG/low-complexity domain in complex with any partner","No genome-wide identification of LSm4-dependent splicing or decay targets","Relationship between PRMT5-dependent sDMA and tRF-31/ubiquitination regulatory axes is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,6,9]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]}],"complexes":["Lsm1-7 complex","Lsm2-8 complex (U6 snRNP)"],"partners":["SMN1","PRMT5","SLBP","ERI1","CLNS1A","EDC3","SF3B4","RBBP7"],"other_free_text":[]},"mechanistic_narrative":"LSM4 is a core subunit of the heptameric Lsm1–7 ring that functions in cytoplasmic mRNA decay, P-body assembly, and nuclear pre-mRNA splicing. Its N-terminal Sm fold mediates incorporation into the Lsm ring and is essential for viability, as demonstrated by early embryonic lethality in homozygous knockout mice and yeast complementation studies [PMID:10629062, PMID:11561292, PMID:22615807]. The C-terminal low-complexity/RGG domain drives liquid–liquid phase separation and P-body formation through PRMT5-dependent symmetric dimethylation of arginines, and independently contacts SLBP and 3′hExo on the histone mRNP to promote replication-dependent histone mRNA degradation [PMID:27247266, PMID:24255165, PMID:36976747]. Symmetric dimethylarginine modifications on LSm4 also mediate binding to the SMN Tudor domain, linking LSm4 to snRNP biogenesis, while an interaction with ICln at the plasma membrane implicates LSm4 in swelling-activated anion channel regulation [PMID:11720283, PMID:19088440]."},"prefetch_data":{"uniprot":{"accession":"Q9Y4Z0","full_name":"U6 snRNA-associated Sm-like protein LSm4","aliases":["Glycine-rich protein","GRP"],"length_aa":139,"mass_kda":15.3,"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/Q9Y4Z0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/LSM4","classification":"Common Essential","n_dependent_lines":1202,"n_total_lines":1208,"dependency_fraction":0.9950331125827815},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"PRPF4B","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SF3A2","stoichiometry":0.2},{"gene":"SF3B1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LSM4","total_profiled":1310},"omim":[{"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"},{"mim_id":"607285","title":"LSM5 PROTEIN; LSM5","url":"https://www.omim.org/entry/607285"},{"mim_id":"607284","title":"LSM4 PROTEIN; LSM4","url":"https://www.omim.org/entry/607284"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LSM4"},"hgnc":{"alias_symbol":["YER112W"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y4Z0","domains":[{"cath_id":"2.30.30.100","chopping":"2-87","consensus_level":"high","plddt":94.7445,"start":2,"end":87}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4Z0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4Z0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4Z0-F1-predicted_aligned_error_v6.png","plddt_mean":75.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LSM4","jax_strain_url":"https://www.jax.org/strain/search?query=LSM4"},"sequence":{"accession":"Q9Y4Z0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y4Z0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y4Z0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4Z0"}},"corpus_meta":[{"pmid":"11720283","id":"PMC_11720283","title":"Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B' and the Sm-like protein LSm4, and their interaction with the SMN protein.","date":"2001","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11720283","citation_count":313,"is_preprint":false},{"pmid":"21258002","id":"PMC_21258002","title":"Arabidopsis floral initiator SKB1 confers high salt tolerance by regulating transcription and pre-mRNA splicing through altering histone H4R3 and small nuclear ribonucleoprotein LSM4 methylation.","date":"2011","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/21258002","citation_count":137,"is_preprint":false},{"pmid":"33285422","id":"PMC_33285422","title":"Circ_0025033 promotes the progression of ovarian cancer by activating the expression of LSM4 via targeting miR-184.","date":"2020","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/33285422","citation_count":60,"is_preprint":false},{"pmid":"27247266","id":"PMC_27247266","title":"The C-Terminal RGG Domain of Human Lsm4 Promotes Processing Body Formation Stimulated by Arginine Dimethylation.","date":"2016","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27247266","citation_count":48,"is_preprint":false},{"pmid":"15905169","id":"PMC_15905169","title":"ICln159 folds into a pleckstrin homology domain-like structure. Interaction with kinases and the splicing factor LSm4.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15905169","citation_count":32,"is_preprint":false},{"pmid":"24255165","id":"PMC_24255165","title":"The C-terminal extension of Lsm4 interacts directly with the 3' end of the histone mRNP and is required for efficient histone mRNA degradation.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24255165","citation_count":29,"is_preprint":false},{"pmid":"34515495","id":"PMC_34515495","title":"AtMC1 Associates With LSM4 to Regulate Plant Immunity Through Modulating Pre-mRNA Splicing.","date":"2021","source":"Molecular plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/34515495","citation_count":20,"is_preprint":false},{"pmid":"11561292","id":"PMC_11561292","title":"Isolation and study of KlLSM4, a Kluyveromyces lactis gene homologous to the essential gene LSM4 of Saccharomyces cerevisiae.","date":"2001","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11561292","citation_count":20,"is_preprint":false},{"pmid":"16169287","id":"PMC_16169287","title":"HIR1, the co-repressor of histone gene transcription of Saccharomyces cerevisiae, acts as a multicopy suppressor of the apoptotic phenotypes of the LSM4 mRNA degradation mutant.","date":"2005","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/16169287","citation_count":18,"is_preprint":false},{"pmid":"19088440","id":"PMC_19088440","title":"LSm4 associates with the plasma membrane and acts as a co-factor in cell volume regulation.","date":"2008","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19088440","citation_count":15,"is_preprint":false},{"pmid":"22615807","id":"PMC_22615807","title":"Crystal structures of Lsm3, Lsm4 and Lsm5/6/7 from Schizosaccharomyces pombe.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22615807","citation_count":15,"is_preprint":false},{"pmid":"35096017","id":"PMC_35096017","title":"Clinical Significance and Potential Role of LSM4 Overexpression in Hepatocellular Carcinoma: An Integrated Analysis Based on Multiple Databases.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35096017","citation_count":12,"is_preprint":false},{"pmid":"27543059","id":"PMC_27543059","title":"The decapping activator Edc3 and the Q/N-rich domain of Lsm4 function together to enhance mRNA stability and alter mRNA decay pathway dependence in Saccharomyces cerevisiae.","date":"2016","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/27543059","citation_count":11,"is_preprint":false},{"pmid":"35748489","id":"PMC_35748489","title":"Long noncoding RNA LINC01419 promotes hepatocellular carcinoma malignancy by mediating miR-485-5p/LSM4 axis.","date":"2022","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35748489","citation_count":8,"is_preprint":false},{"pmid":"26316593","id":"PMC_26316593","title":"NEM1 acts as a suppressor of apoptotic phenotypes in LSM4 yeast mutants.","date":"2015","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/26316593","citation_count":8,"is_preprint":false},{"pmid":"38462740","id":"PMC_38462740","title":"METTL3-mediated the m6A modification of SF3B4 facilitates the development of non-small cell lung cancer by enhancing LSM4 expression.","date":"2024","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38462740","citation_count":7,"is_preprint":false},{"pmid":"10629062","id":"PMC_10629062","title":"Peri-implantation lethality in mice lacking the Sm motif-containing protein Lsm4.","date":"2000","source":"Molecular and cellular 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biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/36976747","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10987,"output_tokens":3053,"usd":0.039378},"stage2":{"model":"claude-opus-4-6","input_tokens":6395,"output_tokens":2956,"usd":0.158812},"total_usd":0.19819,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"LSm4 contains symmetrically dimethylated arginine (sDMA) residues in vivo, identified by mass spectrometry and protein sequencing. These sDMA modifications are required for LSm4 binding to the Tudor domain of SMN; inhibition of dimethylation by S-adenosylhomocysteine abolished this interaction. The cytoplasmic PRMT responsible for symmetrical dimethylation of LSm4 was identified in HeLa S100 cytosolic extract.\",\n      \"method\": \"Mass spectrometry, protein sequencing, in vitro methylation assay with HeLa cytosolic/nuclear extracts, synthetic peptide competition, SAH inhibition\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (mass spec, sequencing, in vitro assay, inhibitor studies) in a single highly-cited study\",\n      \"pmids\": [\"11720283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The C-terminal RGG domain of human LSm4 promotes processing body (P-body) formation in human cells. Symmetric dimethylation of arginines within the RGG domain by PRMT5 stimulates PB accumulation. An RGG-domain deletion mutant of LSm4 failed to rescue PB formation even though it retained Lsm1-7 assembly, decapping factor association, mRNA decay activity, and translational repression. Depletion of PRMT5 resulted in loss of PBs. The histone acetyltransferase HAT1-RBBP7 complex was identified as a novel interactor of the Lsm4 RGG domain.\",\n      \"method\": \"RGG domain deletion mutagenesis, siRNA depletion of endogenous Lsm4 and PRMT5, rescue experiments, co-immunoprecipitation, fluorescence microscopy of PBs, mRNA decay and translation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, clean KD/KO with defined cellular phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"27247266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The C-terminal extension of Lsm4 interacts directly with the histone mRNP, contacting both the stem-loop binding protein (SLBP) and 3'hExo. Mutations in the C-terminal tail of Lsm4 that prevent SLBP and 3'hExo binding reduce the rate of histone mRNA degradation when DNA synthesis is inhibited.\",\n      \"method\": \"Co-immunoprecipitation/pulldown, mutagenesis of C-terminal tail, histone mRNA degradation assays upon DNA synthesis inhibition\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assays combined with mutagenesis and functional mRNA decay readout\",\n      \"pmids\": [\"24255165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mouse Lsm4 is essential for early embryonic development; homozygous knockout mice survive to blastocyst stage and implant but die shortly thereafter, demonstrating that Lsm4 function in splicing is essential and cannot be compensated by other Lsm proteins.\",\n      \"method\": \"Promoter trap gene targeting in murine ES cells, homozygous knockout mouse analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined lethal phenotype in mouse model\",\n      \"pmids\": [\"10629062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ICln interacts with LSm4 via its pleckstrin homology (PH) domain-like structure, suggesting a physical link between cell volume regulation and RNA splicing/mRNA degradation pathways.\",\n      \"method\": \"Pulldown/co-immunoprecipitation, structural determination of ICln PH domain by NMR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown interaction, structural context provided but LSm4 functional consequence not fully established\",\n      \"pmids\": [\"15905169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LSm4 associates with ICln and the plasma membrane under isotonic conditions. Upon hypotonic cell swelling, LSm4 dissociates from the plasma membrane and from ICln. Overexpression of LSm4 inhibits ICln translocation to the cell membrane and markedly inhibits the activation kinetics and current density of the swelling-dependent anion channel IClswell, establishing LSm4 as a co-factor in cell volume regulation.\",\n      \"method\": \"FRET, subcellular fractionation biochemistry, electrophysiology, overexpression experiments in NIH3T3 and HEK293 cells\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by FRET tied to functional electrophysiological consequence, single lab\",\n      \"pmids\": [\"19088440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structures of S. pombe Lsm4 (and Lsm3, Lsm5/6/7) were solved, revealing a conserved Sm fold. Lsm4 forms a trimer in the crystal lattice and undergoes dynamic monomer-trimer equilibrium in solution by analytical ultracentrifugation. RNA binding assays showed no direct RNA binding for isolated Lsm4.\",\n      \"method\": \"X-ray crystallography, analytical ultracentrifugation, RNA binding assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation (RNA binding assays, AUC) for fission yeast ortholog\",\n      \"pmids\": [\"22615807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In K. lactis and S. cerevisiae, only the first 72 amino acids of KlLsm4p containing the Sm-like domain are sufficient to restore cell viability in cells lacking wild-type Lsm4, but loss of the carboxy-terminal region causes remarkable loss of viability in stationary phase, establishing a distinct functional role for the C-terminal domain.\",\n      \"method\": \"Complementation assay with C-terminal truncation mutants in K. lactis and S. cerevisiae\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic complementation with defined domain truncations, yeast ortholog study\",\n      \"pmids\": [\"11561292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Combined deletion of EDC3 and the Q/N-rich C-terminal region of Lsm4 in S. cerevisiae reduces mRNA stability, increases dependence on Ccr4-mediated deadenylation and mRNA decapping, alters mRNA decay factor levels, and causes nuclear accumulation of the decapping enzyme Dcp2, placing Lsm4's C-terminal domain and Edc3 together in a pathway that regulates mRNA stability and P-body-dependent mRNA fate.\",\n      \"method\": \"Genetic double mutant analysis, mRNA stability assays, subcellular localization of Dcp2, epistasis with deadenylation and decapping pathways in S. cerevisiae\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis in yeast ortholog with multiple defined molecular phenotypes, single lab\",\n      \"pmids\": [\"27543059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Purified full-length human LSm4 protein undergoes concentration-dependent liquid-liquid phase separation (LLPS) in vitro. The C-terminal low-complexity domain is implicated in LLPS. High salt concentrations and 1,6-hexanediol block LLPS, and droplet fusion is observed, consistent with liquid-like properties.\",\n      \"method\": \"In vitro LLPS assay with purified recombinant mCherry-LSm4, fluorescence microscopy (DeltaVision), hexanediol and salt perturbation, disordered region prediction\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 in vitro reconstitution, but single lab and no mutagenesis validation of specific domain\",\n      \"pmids\": [\"36976747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under hypoxic conditions, reduced tRF-31 binding to LSm4 decreases LSm4 ubiquitination and enhances its protein stability, leading to nuclear translocation of LSm4 where it promotes splicing of EDN1 pre-mRNA. Overexpression of tRF-31 inhibits hypoxia-induced proliferation of pulmonary artery endothelial cells by this mechanism.\",\n      \"method\": \"tRF-31 overexpression/knockdown, LSm4 ubiquitination assay, subcellular fractionation, RNA splicing assay, RNA binding assay (tRF-31 / LSm4 interaction), proliferation assays\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding, ubiquitination, localization, and splicing assays in single study; single lab\",\n      \"pmids\": [\"41354297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SF3B4 interacts with LSm4 (confirmed by co-immunoprecipitation), and overexpression of LSm4 reverses inhibition of NSCLC cell proliferation, invasion, migration, and stemness caused by SF3B4 knockdown, placing LSm4 downstream of SF3B4 in a cancer-relevant pathway.\",\n      \"method\": \"Co-immunoprecipitation, knockdown rescue by LSm4 overexpression, cell functional assays\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP, rescue experiment in cancer cell line, no defined molecular mechanism for LSm4 activity\",\n      \"pmids\": [\"38462740\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LSm4 is a core subunit of the cytoplasmic Lsm1–7 complex that adopts a conserved Sm fold and engages in multiple RNA metabolic processes: its Sm domain mediates assembly into the Lsm1–7 ring and association with U6 snRNA for pre-mRNA splicing, while its C-terminal RGG domain (symmetrically dimethylated by the cytoplasmic PRMT5) drives liquid-liquid phase separation and P-body assembly, and also contacts SLBP and 3'hExo on the histone mRNP to promote oligouridylated histone mRNA degradation; additionally, sDMA-modified LSm4 binds the SMN Tudor domain to support snRNP biogenesis, and LSm4 functions at the plasma membrane as a co-factor in cell volume regulation through interaction with ICln.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LSM4 is a core subunit of the heptameric Lsm1–7 ring that functions in cytoplasmic mRNA decay, P-body assembly, and nuclear pre-mRNA splicing. Its N-terminal Sm fold mediates incorporation into the Lsm ring and is essential for viability, as demonstrated by early embryonic lethality in homozygous knockout mice and yeast complementation studies [PMID:10629062, PMID:11561292, PMID:22615807]. The C-terminal low-complexity/RGG domain drives liquid–liquid phase separation and P-body formation through PRMT5-dependent symmetric dimethylation of arginines, and independently contacts SLBP and 3′hExo on the histone mRNP to promote replication-dependent histone mRNA degradation [PMID:27247266, PMID:24255165, PMID:36976747]. Symmetric dimethylarginine modifications on LSm4 also mediate binding to the SMN Tudor domain, linking LSm4 to snRNP biogenesis, while an interaction with ICln at the plasma membrane implicates LSm4 in swelling-activated anion channel regulation [PMID:11720283, PMID:19088440].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The question of whether LSm4 is individually essential or redundant with other Lsm proteins was resolved by showing that homozygous Lsm4-knockout mice die shortly after implantation, establishing a non-redundant requirement for LSm4 in early development.\",\n      \"evidence\": \"Promoter-trap gene targeting and knockout mouse analysis\",\n      \"pmids\": [\"10629062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific RNA targets or splicing events disrupted in Lsm4-null embryos were not identified\", \"Whether lethality reflects loss of splicing, mRNA decay, or both was not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The discovery that LSm4 carries symmetric dimethylarginine (sDMA) modifications and that these are required for Tudor-domain binding to SMN established a post-translational regulatory axis linking LSm4 to snRNP biogenesis.\",\n      \"evidence\": \"Mass spectrometry, protein sequencing, in vitro methylation with HeLa extracts, SAH inhibition\",\n      \"pmids\": [\"11720283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether sDMA modification is constitutive or regulated was not determined\", \"Functional consequence of disrupting LSm4–SMN interaction on snRNP assembly was not directly tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Yeast complementation with C-terminal truncations showed that the Sm-fold domain alone supports viability but the C-terminal domain is essential for stationary-phase survival, delineating two functionally separable domains.\",\n      \"evidence\": \"Complementation assays with domain truncation mutants in K. lactis and S. cerevisiae\",\n      \"pmids\": [\"11561292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets of the C-terminal domain in stationary phase were not identified\", \"Whether the C-terminal domain function is conserved in mammals was not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of ICln as a physical partner of LSm4 suggested a link between RNA metabolism and cell volume regulation, though the functional significance for LSm4 was initially unclear.\",\n      \"evidence\": \"Co-immunoprecipitation and NMR structural analysis of ICln PH domain\",\n      \"pmids\": [\"15905169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the ICln–LSm4 interaction is direct or bridged was not resolved with purified proteins\", \"Functional consequence for RNA processing was not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"FRET and electrophysiology experiments showed LSm4 resides at the plasma membrane under isotonic conditions and dissociates upon swelling, directly modulating IClswell channel kinetics, thereby establishing a non-canonical function for LSm4 in cell volume regulation.\",\n      \"evidence\": \"FRET, subcellular fractionation, electrophysiology in NIH3T3 and HEK293 cells\",\n      \"pmids\": [\"19088440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LSm4 inhibits IClswell is unknown\", \"Whether this plasma membrane pool is distinct from the mRNA decay pool was not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Crystal structures of fission yeast Lsm4 confirmed the conserved Sm fold and revealed a monomer–trimer equilibrium, while RNA binding assays showed isolated Lsm4 does not bind RNA, indicating it functions only in the assembled ring context.\",\n      \"evidence\": \"X-ray crystallography, analytical ultracentrifugation, RNA binding assays with S. pombe Lsm4\",\n      \"pmids\": [\"22615807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the full heptameric ring including Lsm4 was obtained\", \"C-terminal low-complexity domain was absent from constructs\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The C-terminal tail of LSm4 was shown to directly contact SLBP and 3′hExo on histone mRNPs, and mutations disrupting these interactions reduced histone mRNA degradation, defining a substrate-specific role for LSm4 beyond general mRNA decay.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown, mutagenesis, histone mRNA decay assays upon DNA synthesis inhibition\",\n      \"pmids\": [\"24255165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether oligouridylation is required upstream of LSm4 engagement was not addressed\", \"Structural basis of the C-tail–SLBP/3′hExo interaction is unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Definitive evidence that the LSm4 RGG domain is dispensable for Lsm1–7 assembly, decapping, and mRNA decay but is specifically required for P-body formation established that P-body condensation is mechanistically separable from mRNA decay; PRMT5-mediated sDMA of the RGG domain drives this condensation.\",\n      \"evidence\": \"RGG deletion rescue, PRMT5 knockdown, fluorescence microscopy, mRNA decay and translation assays in human cells\",\n      \"pmids\": [\"27247266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether sDMA-dependent P-body formation feeds back to regulate specific mRNAs is unknown\", \"The role of the HAT1–RBBP7 interaction identified in this study remains uncharacterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic epistasis in yeast showed that combined loss of Edc3 and the Lsm4 C-terminal Q/N-rich domain reduces mRNA stability and causes nuclear mislocalization of Dcp2, revealing redundant scaffolding roles of Lsm4 and Edc3 in organizing cytoplasmic mRNA decay.\",\n      \"evidence\": \"Double mutant analysis, mRNA stability assays, Dcp2 localization in S. cerevisiae\",\n      \"pmids\": [\"27543059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the yeast Q/N-rich domain and the mammalian RGG domain are functionally analogous remains formally untested\", \"Mechanism of Dcp2 nuclear accumulation is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vitro reconstitution demonstrated that purified full-length LSm4 undergoes concentration-dependent liquid–liquid phase separation, directly attributing the condensation-driving activity to LSm4 itself rather than to co-factors.\",\n      \"evidence\": \"Purified recombinant mCherry-LSm4 LLPS assay, hexanediol and salt perturbation, fluorescence microscopy\",\n      \"pmids\": [\"36976747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific residues or modifications within the low-complexity domain driving LLPS were not mapped by mutagenesis\", \"Behavior of LSm4 within the full Lsm1–7 complex in LLPS was not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Under hypoxia, reduced tRF-31 binding to LSm4 decreases its ubiquitination and stabilizes the protein, causing nuclear translocation where LSm4 promotes EDN1 pre-mRNA splicing — revealing a tRNA-fragment-based regulatory mechanism governing LSm4 stability and nuclear splicing function.\",\n      \"evidence\": \"tRF-31 overexpression/knockdown, ubiquitination assays, subcellular fractionation, splicing and proliferation assays in pulmonary artery endothelial cells\",\n      \"pmids\": [\"41354297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The E3 ubiquitin ligase targeting LSm4 was not identified\", \"Whether tRF-31-mediated regulation applies to other cell types or stress conditions is unknown\", \"The specificity of EDN1 as an LSm4 splicing target needs broader transcriptomic validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of the Lsm4 C-terminal domain interactions with SLBP/3′hExo, the identity of the E3 ligase controlling LSm4 turnover, whether P-body condensation driven by LSm4 feeds back to regulate specific mRNA fates, and the physiological relevance of the plasma membrane LSm4–ICln interaction.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of the C-terminal RGG/low-complexity domain in complex with any partner\", \"No genome-wide identification of LSm4-dependent splicing or decay targets\", \"Relationship between PRMT5-dependent sDMA and tRF-31/ubiquitination regulatory axes is unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 6, 9]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"Lsm1-7 complex\",\n      \"Lsm2-8 complex (U6 snRNP)\"\n    ],\n    \"partners\": [\n      \"SMN1\",\n      \"PRMT5\",\n      \"SLBP\",\n      \"ERI1\",\n      \"CLNS1A\",\n      \"EDC3\",\n      \"SF3B4\",\n      \"RBBP7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}