Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA291458 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2134480.fastq.gz | Fastqsanger.gz | |||
| SRR2134490.fastq.gz | Fastqsanger.gz | |||
| SRR2134500.fastq.gz | Fastqsanger.gz | |||
| SRR2134510.fastq.gz | Fastqsanger.gz | |||
| SRR2134520.fastq.gz | Fastqsanger.gz |
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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: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: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: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:Molecular Characterization of Pontocerebellar Hypoplasia
| PRJNA1062911 | ENA
Project description:Molecular Characterization of Pontocerebellar Hypoplasia
| PRJNA1062912 | ENA
Project description:Poly(A)-specific ribonuclease (PARN) and target of EGR1 protein 1 (TOE1) are nuclear granule-associated deadenylases, whose mutations are linked to multiple human diseases. Here, we applied mTAIL-seq and RNA sequencing (RNA-seq) to systematically identify the substrates of PARN and TOE1 and elucidate their molecular functions. We found that PARN and TOE1 do not modulate the length of mRNA poly(A) tails. Rather, they promote the maturation of nuclear small non-coding RNAs (ncRNAs). PARN and TOE1 act redundantly on some ncRNAs, most prominently small Cajal body-specific RNAs (scaRNAs). scaRNAs are strongly downregulated when PARN and TOE1 are compromised together, leading to defects in small nuclear RNA (snRNA) pseudouridylation. They also function redundantly in the biogenesis of telomerase RNA component (TERC), which shares sequence motifs found in H/ACA box scaRNAs. Our findings extend the knowledge of nuclear ncRNA biogenesis, and they provide insights into the pathology of PARN/TOE1-associated genetic disorders whose therapeutic treatments are currently unavailable.
2018-03-30 | GSE111511 | GEO