Inhibition of the minor spliceosome restricts the growth of a broad spectrum of cancers

Doggett, K; Morgan, KJ; Olthof, AM; Mieruszynski, S; Williams, BB; Garnham, AL; Milevskiy, MJG; Whitehead, L; Coates, J; Buchert, M; O&#39;Donoghue, RJJ; Hall, TE; Putoczki, TL; Ernst, M; Sutherland, KD; Kanadia, RN; Heath, JK

Author(s): Doggett, K; Morgan, KJ; Olthof, AM; Mieruszynski, S; Williams, BB; Garnham, AL; Milevskiy, MJG; Whitehead, L; Coates, J; Buchert, M; O'Donoghue, RJJ; Hall, TE; Putoczki, TL; Ernst, M; Sutherland, KD; Kanadia, RN; Heath, JK;
Details: Publication Year 2025-08,Volume 26,Issue #15,Page 3937-3969
Journal Title: EMBO Reports
Abstract: Minor splicing is an under-appreciated splicing system required for the correct expression of ~700 genes in the human genome. This small subset of genes (0.35%) harbours introns containing non-canonical splicing sequences that are recognised uniquely by the minor spliceosome and cannot be processed by the major spliceosome. Using in vivo zebrafish and mouse cancer models, we show that heterozygous expression of Rnpc3, encoding a unique protein component of the minor spliceosome, restricts the growth and survival of liver, lung and gastric tumours without impacting healthy cells. RNPC3 knockdown in human lung cancer-derived A549 cells also impairs cell proliferation and RNA-seq analysis reveals a robust and selective disruption to minor intron splicing and transcription-wide effects on gene expression. We further demonstrate that these perturbations are accompanied by DNA replication stress, DNA damage, accumulation of TP53 protein and activation of a Tp53-dependent transcriptional program that induces cell cycle arrest and apoptosis. Together our data reveal a vulnerability of cancer cells to minor splicing inhibition that restricts tumour growth.
Publisher: EMBO Press
Keywords: *Spliceosomes/metabolism/genetics; Humans; Animals; Mice; Cell Proliferation/genetics; *RNA Splicing; Zebrafish/genetics; Tumor Suppressor Protein p53/metabolism/genetics; *Neoplasms/genetics/pathology/metabolism; Gene Expression Regulation, Neoplastic; DNA Damage; Cell Line, Tumor; Apoptosis/genetics; Introns; RNA-Binding Proteins/genetics/metabolism; A549 Cells; Cancer; Minor Splicing; RNA Processing; Rnpc3
Research Division(s): Inflammation; Advanced Technology And Biology; Bioinformatics and Computational Biology; Cancer Biology And Stem Cells; Genetics and Gene Regulation; Personalised Oncology
PubMed ID: 40624356
Publisher's Version: https://doi.org/10.1038/s44319-025-00511-8
Open Access at Publisher's Site: https://doi.org/10.1038/s44319-025-00511-8
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-07-28 08:47:50

Last Modified: 2025-09-23 10:03:24