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A Molecular Clamp Targeting the TOE1:Sm Complex Imparts Tunable Regulation of Splicing

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Haoxin Li

LAB HEAD: Benjamin Cravatt

PROVIDER: PXD070450 | Pride | 2025-11-11

REPOSITORIES: Pride

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			Action	DRS
	SEC-MS_C80S-TOE1_set1.tsv	Tabular
	SEC-MS_C80S-TOE1_set1_01.raw	Raw
	SEC-MS_C80S-TOE1_set1_02.raw	Raw
	SEC-MS_C80S-TOE1_set1_03.raw	Raw
	SEC-MS_C80S-TOE1_set1_04.raw	Raw

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Project description:In this study we investigated snRNA-mediated modulation of pre-mRNA splicing across the human transcriptome. We first quantified the relative abundance of snRNAs across a comprehensive range of healthy adult and fetal tissues, revealing a surprising variation in the relative snRNA levels both inter- and intra-tissue. To study the role of snRNAs in cancer-relevant splicing, we used breast cancer as a model, since it exhibits a high rate of aberrant splicing48, but a low frequency of mutations in the splicing machinery52. We observed fluctuations in snRNA adundance across the majority of patients, across all breast cancer subtypes. To investigate the impact of snRNA levels using a controlled system, we knocked down snRNAs in vitro, to analyze splicing both transcriptome-wide and at the level of individual exons and introns. Depletion of each specific snRNA resulted in differential splicing across more than a thousand exon junctions within mRNA transcripts. Knock-down of U1 and U2 levels was primarily associated with changes in exon inclusion rates, whereas U4 and U6 depletion predominantly caused incomplete intron removal and a resulting retention of introns in the mature mRNA. Rather than being driven by a single factor, the observed splicing changes were associated with multiple other splicing-relevant features and mechanisms, including mRNA transcription, intron size, and nucleotide composition. The snRNA-mediated changes to the splicing program were enriched within genes encoding components of core cellular pathways and processes, including multiple aspects of RNA and protein metabolism, and thereby have the potential to impact cell growth and identity. The exons and introns that were sensitive to snRNA levels displayed a high variability in splicing in vivo across primary breast cancer samples, indicating that snRNA dysregulation may contribute to aberrant splicing in cancer. We suggest that the cellular composition of snRNAs constitutes a previously unrecognized layer of splicing regulation within the cell, and that variations or disruptions in the relative abundance of the snRNAs can affect the transcriptome of both healthy and malignant cells.

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A Molecular Clamp Targeting the TOE1:Sm Complex Imparts Tunable Regulation of Splicing

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