PUBLICATION
Inhibition of the minor spliceosome restricts the growth of a broad spectrum of cancers
- Authors
- Doggett, K., Morgan, K.J., Olthof, A.M., Mieruszynski, S., Williams, B.B., Garnham, A.L., Milevskiy, M.J.G., Whitehead, L., Coates, J., Buchert, M., O'Donoghue, R.J.J., Hall, T.E., Putoczki, T.L., Ernst, M., Sutherland, K.D., Kanadia, R.N., Heath, J.K.
- ID
- ZDB-PUB-250708-5
- Date
- 2025
- Source
- EMBO reports : (Journal)
- Registered Authors
- Coates, Janine, Doggett, Karen, Hall, Thomas, Heath, Joan K.
- Keywords
- Cancer, DNA Damage, Minor Splicing, RNA Processing, RNPC3
- MeSH Terms
-
- Spliceosomes*/genetics
- Spliceosomes*/metabolism
- Zebrafish/genetics
- Cell Proliferation/genetics
- Neoplasms*/genetics
- Neoplasms*/metabolism
- Neoplasms*/pathology
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Apoptosis/genetics
- RNA Splicing*
- DNA Damage
- Humans
- Introns
- Animals
- Gene Expression Regulation, Neoplastic
- Cell Line, Tumor
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Mice
- A549 Cells
- PubMed
- 40624356 Full text @ EMBO Rep.
Citation
Doggett, K., Morgan, K.J., Olthof, A.M., Mieruszynski, S., Williams, B.B., Garnham, A.L., Milevskiy, M.J.G., Whitehead, L., Coates, J., Buchert, M., O'Donoghue, R.J.J., Hall, T.E., Putoczki, T.L., Ernst, M., Sutherland, K.D., Kanadia, R.N., Heath, J.K. (2025) Inhibition of the minor spliceosome restricts the growth of a broad spectrum of cancers. 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping