Affinage

LSM5

U6 snRNA-associated Sm-like protein LSm5 · UniProt Q9Y4Y9

Length
91 aa
Mass
9.9 kDa
Annotated
2026-06-10
21 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LSM5 is a core subunit of the heteroheptameric Lsm rings that govern small nuclear RNA stability and mRNA decay, functioning within the nuclear Lsm2-8 complex that binds U6 snRNA and the cytoplasmic Lsm1-7 complex (PMID:32518066, PMID:18433897). Structural studies of both rings bound to RNA show that Lsm5 uniquely recognizes purine bases at the 3' end of RNA substrates, accounting for its divergent sequence relative to the other Lsm subunits; the Lsm2-8 ring preferentially engages the 2',3' cyclic phosphate end of U6 snRNA while Lsm1-7 discriminates against cyclic phosphates and binds oligouridylate tracts with terminal purines (PMID:32518066). Lsm5 assembles into the mature rings through a defined hexameric intermediate: it adopts the canonical Sm fold and forms an Lsm5-Lsm6-Lsm7 sub-complex that binds oligo(U) and recruits Lsm2/3 toward native ring assembly (PMID:22001694, PMID:22615807). The sole essential cellular function of Lsm5 within Lsm2-8 is to support U6 snRNA biogenesis or stability: deletion of LSM5 is lethal but is fully rescued by U6 snRNA overexpression, and Lsm5 acts redundantly with the La protein homolog Lhp1p to stabilize the 3' end of nascent U6 snRNA (PMID:11333229, PMID:29615482). In human colon cancer cells, LSM5 knockdown suppresses proliferation and promotes apoptosis associated with induction of the p53-CDKN1A-TNFRSF10B axis (PMID:38994171).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2001 Medium

    Established that Lsm5's biological role is to stabilize nascent U6 snRNA, defining the functional output of the Lsm2-8 ring through its genetic redundancy with the La protein homolog.

    Evidence Genetic epistasis, deletion analysis and suppressor screens in S. cerevisiae

    PMID:11333229

    Open questions at the time
    • Did not resolve the structural basis of U6 recognition
    • Redundancy with Lhp1p inferred genetically, not by direct biochemistry
  2. 2008 Medium

    Showed how Lsm5 is physically recruited during ring assembly and confirmed its membership in the nuclear U6-binding Lsm2-8 complex in a divergent eukaryote, generalizing the assembly logic across species.

    Evidence Pull-down from yeast lysate with a crystallized Lsm3 octamer, and TAP-tag purification plus RNAi and localization in Trypanosoma brucei

    PMID:18329667 PMID:18433897

    Open questions at the time
    • Pull-down does not define stoichiometry or order of incorporation in vivo
    • Trypanosome localization is ortholog-based
  3. 2012 High

    Defined an Lsm5-Lsm6-Lsm7 hexameric assembly intermediate as a shared precursor for both cytoplasmic and nuclear rings, establishing the structural pathway to mature complexes.

    Evidence X-ray crystallography, NMR, analytical ultracentrifugation, pull-down and RNA binding assays (yeast and S. pombe)

    PMID:22001694 PMID:22615807

    Open questions at the time
    • Does not establish kinetics or in-cell ordering of assembly
    • RNA binding by the intermediate not linked to a specific cellular substrate
  4. 2018 High

    Demonstrated that the single essential function of Lsm5 within Lsm2-8 is to support U6 snRNA, by rescuing the lethal deletion with U6 overexpression and revealing internal genetic redundancy across ring residues.

    Evidence Alanine-scanning mutagenesis, genetic complementation and high-copy U6 suppression in S. cerevisiae

    PMID:29615482

    Open questions at the time
    • Does not address non-essential roles of Lsm5 in mRNA decay
    • Synthetic lethality mechanism not biochemically resolved
  5. 2020 High

    Provided the structural mechanism for Lsm5's unique substrate specificity, showing it recognizes 3'-terminal purines and explaining how Lsm2-8 versus Lsm1-7 discriminate between cyclic-phosphate U6 ends and oligouridylate tracts.

    Evidence Four high-resolution crystal/cryo-EM structures of Lsm1-7 and Lsm2-8 bound to RNA, with RNA binding assays

    PMID:32518066

    Open questions at the time
    • Does not define dynamics of 3'-end loading in vivo
    • Functional consequence of purine recognition for specific transcripts not tested
  6. 2024 Low

    Linked LSM5 to a cellular phenotype in human cancer cells, placing it upstream of a p53-dependent apoptotic axis, though without direct molecular mechanism.

    Evidence Lentiviral shRNA knockdown with proliferation/apoptosis assays, GeneChip profiling and Western blotting in colon cancer cells

    PMID:38994171

    Open questions at the time
    • Mechanistic placement is indirect with no direct binding or enzymatic evidence
    • Connection to RNA-processing role of LSM5 unestablished
    • Single lab, single cancer context

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Lsm5's RNA-binding and assembly functions in the Lsm1-7 ring contribute mechanistically to mRNA decay, and whether its cancer-cell phenotype derives from its RNA-processing role, remain unresolved.
  • No direct evidence linking Lsm5 to specific mRNA decay substrates
  • Mechanism connecting LSM5 to the p53 axis unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0005198 structural molecule activity 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3
Partners
LSM2LSM3LSM6LSM7
Complex memberships
Lsm1-7 complexLsm2-8 complexLsm5-6-7 sub-complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Crystal/cryo-EM structures of Lsm1-7 and Lsm2-8 complexes bound to RNA reveal that Lsm5 uniquely recognizes purine bases at the 3' end of RNA substrates, explaining its divergent sequence relative to other Lsm subunits. The Lsm2-8 complex preferentially binds the 2',3' cyclic phosphate end of U6 snRNA, while Lsm1-7 strongly discriminates against cyclic phosphates and binds oligouridylate tracts with terminal purines. Lsm1-7 loads onto RNA from the 3' end, and removal of the Lsm1 carboxy-terminal region allows Lsm1-7 to scan along RNA, suggesting a gated mechanism for accessing internal binding sites. High-resolution structural determination (four crystal/cryo-EM structures) combined with RNA binding assays RNA (New York, N.Y.) High 32518066
2001 Genetic epistasis in S. cerevisiae showed that deletion of LSM5 causes the La protein homolog Lhp1p to become required for growth, indicating that Lsm5 (as part of the Lsm2-8 complex) acts redundantly with Lhp1p to stabilize nascent U6 snRNA at its 3' end. LSM2 and LSM4, but not LSM5, act as allele-specific low-copy suppressors of lsm8 mutations. Genetic epistasis (deletion analysis, suppressor screens, growth assays in S. cerevisiae) Genetics Medium 11333229
2018 Structure-guided alanine-scanning mutagenesis of the Lsm2-8 ring in S. cerevisiae, including residues in Lsm5's RNA-binding sites and intersubunit interfaces, showed that most single mutations are benign for vegetative growth, but pairwise combinations of benign lsm mutations (including lsm5 alleles) reveal synthetic lethality and growth defects, indicating internal genetic redundancy in the ring. Critically, the lethal single-gene deletion lsm5Δ was rescued by overexpression of U6 snRNA from a high-copy plasmid, demonstrating that the only essential function of Lsm5 (within Lsm2-8) is to support U6 snRNA biogenesis or function. Alanine scanning mutagenesis, genetic complementation, high-copy suppressor analysis in S. cerevisiae RNA (New York, N.Y.) High 29615482
2011 The 2.5 Å crystal structure of the LSm5/6/7 sub-complex reveals that Lsm5, Lsm6, and Lsm7 display the canonical Sm fold and arrange into a hexameric ring, constituting an assembly intermediate on the pathway to both the cytoplasmic Lsm1-7 and nuclear Lsm2-8 rings. NMR and pull-down experiments confirmed that the Lsm657 hexameric complex can incorporate Lsm23 to assemble further towards native Lsm rings. X-ray crystallography (2.5 Å), high-resolution NMR spectroscopy, pull-down assays Journal of molecular biology High 22001694
2012 Crystal structures of the Lsm5/6/7 sub-complex from S. pombe reveal that Lsm5, Lsm6, and Lsm7 form a hexameric ring within the crystal lattice, and analytical ultracentrifugation confirmed the hexameric state in solution. RNA binding assays showed that the Lsm5/6/7 sub-complex binds oligo(U), and structural analysis defined the intersubunit interaction order as Lsm5-Lsm6-Lsm7. X-ray crystallography, analytical ultracentrifugation, RNA binding assays PloS one High 22615807
2008 Pull-down experiments from yeast lysate demonstrated that homomeric Lsm3 octamers can directly recruit Lsm5 (along with Lsm6 and Lsm2) from yeast lysate, providing evidence for specific protein-protein interactions mediated by the variable loops and termini of Lsm subunits during ring assembly. Pull-down from yeast lysate using crystallized Lsm3 octamer Journal of molecular biology Medium 18329667
2008 In Trypanosoma brucei, TAP-tagged Lsm5 purification and RNAi silencing identified Lsm5 as a component of the heptameric Lsm2-8 complex that binds U6 snRNA. Localization studies showed that Lsm5 (as part of this complex) resides in the nucleus near the nucleolus, and Lsm proteins were not detected in cytoplasmic bodies tagged with YFP-Dhh1. TAP-tag purification, RNAi silencing, fluorescence localization studies Molecular and biochemical parasitology Medium 18433897
2024 Lentiviral knockdown of LSM5 in colon cancer cells suppressed proliferation and promoted apoptosis, and was associated with upregulation of p53, CDKN1A, and TNFRSF10B as assessed by GeneChip assay and Western blotting, placing LSM5 upstream of the p53-CDKN1A-TNFRSF10B apoptotic axis. Lentiviral shRNA knockdown, proliferation and apoptosis assays, GeneChip transcriptomic profiling, Western blotting World journal of gastrointestinal oncology Low 38994171

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Genome-wide association mapping for identification of quantitative trait loci for rectal temperature during heat stress in Holstein cattle. PloS one 86 23935954
2001 Multiple functional interactions between components of the Lsm2-Lsm8 complex, U6 snRNA, and the yeast La protein. Genetics 65 11333229
2014 Role for LSM genes in the regulation of circadian rhythms. Proceedings of the National Academy of Sciences of the United States of America 56 25288739
2020 Molecular basis for the distinct cellular functions of the Lsm1-7 and Lsm2-8 complexes. RNA (New York, N.Y.) 34 32518066
2008 Crystal structure of Lsm3 octamer from Saccharomyces cerevisiae: implications for Lsm ring organisation and recruitment. Journal of molecular biology 25 18329667
2008 Identification of the heptameric Lsm complex that binds U6 snRNA in Trypanosoma brucei. Molecular and biochemical parasitology 25 18433897
2022 Identification of LSM Family Members as Novel Unfavorable Biomarkers in Hepatocellular Carcinoma. Frontiers in oncology 24 35646684
2017 Strong association of SLC1A1 and DPF3 gene variants with idiopathic male infertility in Han Chinese. Asian journal of andrology 23 27232852
2003 Identification of differentially expressed genes like cofilin2 in growing collateral arteries. Biochemical and biophysical research communications 18 12507514
2012 Crystal structures of Lsm3, Lsm4 and Lsm5/6/7 from Schizosaccharomyces pombe. PloS one 15 22615807
2011 Structure of the LSm657 complex: an assembly intermediate of the LSm1-7 and LSm2-8 rings. Journal of molecular biology 15 22001694
2023 Identification of LSM family members as potential chemoresistance predictive and therapeutic biomarkers for gastric cancer. Frontiers in oncology 13 37007092
2018 Defining essential elements and genetic interactions of the yeast Lsm2-8 ring and demonstration that essentiality of Lsm2-8 is bypassed via overexpression of U6 snRNA or the U6 snRNP subunit Prp24. RNA (New York, N.Y.) 8 29615482
2023 A MACHINE LEARNING MODEL DERIVED FROM ANALYSIS OF TIME-COURSE GENE-EXPRESSION DATASETS REVEALS TEMPORALLY STABLE GENE MARKERS PREDICTIVE OF SEPSIS MORTALITY. Shock (Augusta, Ga.) 7 37752077
2022 CBX3 is associated with metastasis and glutathione/glycosphingolipid metabolism in colon adenocarcinoma. Journal of gastrointestinal oncology 7 35284119
2024 Sm-like 5 knockdown inhibits proliferation and promotes apoptosis of colon cancer cells by upregulating p53, CDKN1A and TNFRSF10B. World journal of gastrointestinal oncology 5 38994171
2024 Transcriptomics data integration and analysis to uncover hallmark genes in hypertrophic cardiomyopathy. American journal of translational research 4 38463581
2025 Integrated Single-cell RNA-seq and Bulk RNA-seq Identify Diagnostic Biomarkers for Postmenopausal Osteoporosis. Current medicinal chemistry 3 39364870
2024 Peripheral Blood CD8+ T-Lymphocyte Immune Response in Benign and Subpopulations of Breast Cancer Patients. International journal of molecular sciences 2 38928129
2025 Identification of RNA processing factor LSM5 as a new adverse biomarker in nasopharyngeal carcinoma. Scientific reports 1 40121338
2022 Effect of Different Irrigants on the Adhesive Interface and Influence on the Push Out Strength of Fiber Posts. Operative dentistry 1 36121721

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