The 3' exonuclease TOE1 selectively processes snRNAs through recognition of Sm complex assembly and 5’ cap trimethylation [gene specific seq]
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ABSTRACT:
PROVIDER: PRJNA1005225 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25634100.fastq.gz | Fastqsanger.gz | |||
| SRR25634100_1.fastq.gz | Fastqsanger.gz | |||
| SRR25634100_2.fastq.gz | Fastqsanger.gz | |||
| SRR25634101.fastq.gz | Fastqsanger.gz | |||
| SRR25634101_1.fastq.gz | Fastqsanger.gz |
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Project description:Competing exonucleases that promote 3’ end maturation or degradation direct quality control of small non-coding RNAs, but how these enzymes distinguish normal from aberrant RNAs is poorly understood. The Pontocerebellar Hypoplasia 7 (PCH7)-associated 3’ exonuclease TOE1 promotes maturation of canonical small nuclear RNAs (snRNAs). Here, we demonstrate that TOE1 achieves specificity towards canonical snRNAs by recognizing Sm complex assembly and cap trimethylation, two features that distinguish snRNAs undergoing correct biogenesis from other small non-coding RNAs. Indeed, disruption of Sm complex assembly via snRNA mutations or protein depletions obstructs snRNA processing by TOE1, and in vitro snRNA processing by TOE1 is stimulated by a trimethylated cap. An unstable snRNA variant that normally fails to undergo maturation becomes fully processed by TOE1 when its degenerate Sm binding motif is converted into a canonical one. Our findings uncover the molecular basis for how TOE1 distinguishes snRNAs from other small non-coding RNAs and explain how TOE1 promotes maturation specifically of canonical snRNAs undergoing proper processing.
2023-09-06 | GSE240773 | GEO
Project description:Competing exonucleases that promote 3’ end maturation or degradation direct quality control of small non-coding RNAs, but how these enzymes distinguish normal from aberrant RNAs is poorly understood. The Pontocerebellar Hypoplasia 7 (PCH7)-associated 3’ exonuclease TOE1 promotes maturation of canonical small nuclear RNAs (snRNAs). Here, we demonstrate that TOE1 achieves specificity towards canonical snRNAs by recognizing Sm complex assembly and cap trimethylation, two features that distinguish snRNAs undergoing correct biogenesis from other small non-coding RNAs. Indeed, disruption of Sm complex assembly via snRNA mutations or protein depletions obstructs snRNA processing by TOE1, and in vitro snRNA processing by TOE1 is stimulated by a trimethylated cap. An unstable snRNA variant that normally fails to undergo maturation becomes fully processed by TOE1 when its degenerate Sm binding motif is converted into a canonical one. Our findings uncover the molecular basis for how TOE1 distinguishes snRNAs from other small non-coding RNAs and explain how TOE1 promotes maturation specifically of canonical snRNAs undergoing proper processing.
2023-09-06 | GSE240772 | GEO
Project description:The 3' exonuclease TOE1 selectively processes snRNAs through recognition of Sm complex assembly and 5’ cap trimethylation [global seq]
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Project description:Small nuclear RNAs (snRNAs) are required for the structure and function of the spliceosome. The RNA exonuclease TOE1 trims and matures the 3’ ends of snRNAs, but how this post-transcriptional process contributes to spliceosome activity remains poorly understood. Here we report a potent and selective covalent ligand that targets TOE1 specifically when bound to the Sm complex. We find that this compound acts as a “molecular clamp”, dramatically stabilizing TOE1 interactions with the Sm complex and triggering excessive trimming of snRNA 3’ termini in cells. We show that this over-trimming activity is tunable by factors that include the expression levels of TOE1 and auxiliary splicing regulators like SNRPB2, which create synthetic lethality interactions with TOE1 ligands that alter splicing and impair cancer cell growth. Our findings demonstrate the feasibility of chemically modulating spliceosome function through targeting the processing of its snRNA components, which may have broad therapeutic implications for splicing-related diseases.
2025-11-11 | PXD070450 | Pride
Project description:Small nuclear RNAs (snRNAs) are required for the structure and function of the spliceosome. The RNA exonuclease TOE1 trims and matures the 3’ ends of snRNAs, but how this post-transcriptional process contributes to spliceosome activity remains poorly understood. Here we report a potent and selective covalent ligand that targets TOE1 specifically when bound to the Sm complex. We find that this compound acts as a “molecular clamp”, dramatically stabilizing TOE1 interactions with the Sm complex and triggering excessive trimming of snRNA 3’ termini in cells. We show that this over-trimming activity is tunable by factors that include the expression levels of TOE1 and auxiliary splicing regulators like SNRPB2, which create synthetic lethality interactions with TOE1 ligands that alter splicing and impair cancer cell growth. Our findings demonstrate the feasibility of chemically modulating spliceosome function through targeting the processing of its snRNA components, which may have broad therapeutic implications for splicing-related diseases.
2025-11-11 | PXD070432 | Pride
Project description:Small nuclear RNAs (snRNAs) are required for the structure and function of the spliceosome. The RNA exonuclease TOE1 trims and matures the 3’ ends of snRNAs, but how this post-transcriptional process contributes to spliceosome activity remains poorly understood. Here we report a potent and selective covalent ligand that targets TOE1 specifically when bound to the Sm complex. We find that this compound acts as a “molecular clamp”, dramatically stabilizing TOE1 interactions with the Sm complex and triggering excessive trimming of snRNA 3’ termini in cells. We show that this over-trimming activity is tunable by factors that include the expression levels of TOE1 and auxiliary splicing regulators like SNRPB2, which create synthetic lethality interactions with TOE1 ligands that alter splicing and impair cancer cell growth. Our findings demonstrate the feasibility of chemically modulating spliceosome function through targeting the processing of its snRNA components, which may have broad therapeutic implications for splicing-related diseases.
2025-11-11 | PXD070435 | Pride
Project description:Competing exonucleases that promote 3' end maturation or degradation direct quality control of small non-coding RNAs, but how these enzymes distinguish normal from aberrant RNAs is poorly understood. The Pontocerebellar Hypoplasia 7 (PCH7)-associated 3' exonuclease TOE1 promotes maturation of canonical small nuclear RNAs (snRNAs). Here, we demonstrate that TOE1 achieves specificity towards canonical snRNAs by recognizing Sm complex assembly and cap trimethylation, two features that distinguish snRNAs undergoing correct biogenesis from other small non-coding RNAs. Indeed, disruption of Sm complex assembly via snRNA mutations or protein depletions obstructs snRNA processing by TOE1, and in vitro snRNA processing by TOE1 is stimulated by a trimethylated cap. An unstable snRNA variant that normally fails to undergo maturation becomes fully processed by TOE1 when its degenerate Sm binding motif is converted into a canonical one. Our findings uncover the molecular basis for how TOE1 distinguishes snRNAs from other small non-coding RNAs and explain how TOE1 promotes maturation specifically of canonical snRNAs undergoing proper processing.
| S-EPMC10462049 | biostudies-literature
Project description:Competing exonucleases that promote 3' end maturation or degradation direct quality control of small non-coding RNAs, but how these enzymes distinguish normal from aberrant RNAs is poorly understood. The Pontocerebellar Hypoplasia 7 (PCH7)-associated 3' exonuclease TOE1 promotes maturation of canonical small nuclear RNAs (snRNAs). Here, we demonstrate that TOE1 achieves specificity toward canonical snRNAs through their Sm complex assembly and cap trimethylation, two features that distinguish snRNAs undergoing correct biogenesis from other small non-coding RNAs. Indeed, disruption of Sm complex assembly via snRNA mutations or protein depletions obstructs snRNA processing by TOE1, and in vitro snRNA processing by TOE1 is stimulated by a trimethylated cap. An unstable snRNA variant that normally fails to undergo maturation becomes fully processed by TOE1 when its degenerate Sm binding motif is converted into a canonical one. Our findings uncover the molecular basis for how TOE1 distinguishes snRNAs from other small non-coding RNAs and explain how TOE1 promotes maturation specifically of canonical snRNAs undergoing proper processing.
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Project description:Processing of RNA polymerase II-transcribed spliceosomal small nuclear RNAs (snRNAs) initiates with cleavage by the Integrator complex, but the factors that subsequently remove 3’ end extensions from metazoan snRNAs have remained unknown. We studied human families with a unique recessive syndromic constellation of pontocerebellar atrophy with ambiguous genitalia, uncovering biallelic inactivating mutations in TOE1, which encodes a conserved unconventional deadenylase. TOE1 demonstrated tight association with snRNA-protein (snRNP) complexes with specificity for incompletely processed pre-snRNAs containing 3’ end extensions that often included post-transcriptionally added tails. Human cells deficient for TOE1 catalytic activity showed accumulation of 3’-end extended U1, U2, U4 and U5 pre-snRNAs, and TOE1 immuno-isolated from human cells was capable of processing 3’-end extended snRNPs in vitro. The missense mutations identified in patients impaired TOE1 stability and snRNA processing in patient cells, which was associated with defects in splicing. Our findings reveal the cause of a unique brain malformation and uncover a long-sought 3’ exonuclease required for snRNA processing.
2016-12-31 | GSE71536 | GEO
Project description:Sm-ring assembly is important for the biogenesis, stability, and function of uridine-rich small nuclear RNAs (U snRNAs) involved in pre-mRNA splicing and histone pre-mRNA 3’ end processing. Assembly of Sm-rings occurs in the cytoplasm and is dependent on a specific sequence and structure motif (Sm-site), ATP, and the Survival motor neuron (SMN) protein complex. The following study informatically investigates the occurence of Sm-sites within the mouse and human transcriptomes and biochemically assesses whether these sites can accept Sm-rings. Sm-sites were found on snRNAs, but are highly prevalent in the 3’ untranslated regions (3’UTR) of long mRNAs. RNA immunoprecipitation experiments confirm that Sm-site containing mRNAs associate with Sm-proteins in the cytoplasm. Established Sm-ring assembly assays were modified to identify polyA-RNAs that specifically associate with Sm-proteins in an ATP-dependent manner, modeling newly assembled Sm-rings. Sm-rings were then specifically assembled onto candidate Sm-site containing mRNAs in an ATP and Sm-site dependent manner. mRNAs containing Sm-sites are down-regulated in models of SMA, suggesting reduced Sm-ring assembly on these mRNAs may contribute to the mechanism of SMA pathogenesis. Together, this study establishes that Sm-site containing mRNAs can accept Sm-rings and identifies a novel mechanism for Sm-proteins in regulation of cytoplasmic mRNAs.
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