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PRMT5 regulates splicing of detained introns from DNA damage repair genes to protect against replication stress.

ABSTRACT: Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of symmetric dimethyl arginine on a broad range of cellular targets, and PRMT5 inhibitors (PRMT5i) show drastic anti-proliferative effects in preclinical studies. Several models have been proposed to explain and predict sensitivity to PRMT5 inhibition including through p53 activation and DNA damage response regulation. Here, we interrogate the underlying mechanisms of PRMT5i sensitivity in Merkel cell carcinoma, a high-grade neuroendocrine carcinoma of the skin that is that is highly sensitive to p53 activation. We observed that although PRMT5 inhibition activated p53, p53 loss did not impact PRMT5i sensitivity. To identify critical pathways altered by PRMT5i, we conducted a genome-wide CRISPR/Cas9 screen and found that PRMT5i-treated cells have an increased dependency on splicing factors. Furthermore, proteomic analysis found that levels of mRNA splicing factors increased after PRMT5i treatment. Characterization of the transcriptome revealed a disruption in mRNA splicing of detained introns in both PRMT5i sensitive and resistant lines. We observed that basal levels of detained introns correlated with PRMT5 inhibitor sensitivity, and that PRMT5 was required to maintain genome integrity through ATR/CHK1 signaling. Our findings support a threshold model of genome stability, in which cells can tolerate an increase in detained introns until a point where DNA damage pathways are triggered, and cells undergo apoptosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296394 | GEO | 2026/06/19

REPOSITORIES: GEO

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			Action	DRS
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	GSE296394_Counts_MKL1_4d.csv.gz	Csv
	GSE296394_Counts_MS1_4d.csv.gz	Csv
	GSE296394_Counts_WaGa_4d.csv.gz	Csv
	GSE296394_MKL1_D4_2025_DEXSeq.txt.gz	Txt

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The PRMT5-splicing axis is a critical oncogenic vulnerability that regulates detained intron splicing

Project description:Protein arginine methyltransferase 5 (PRMT5) is a promising cancer target, yet it is unclear which PRMT5 roles underlie this vulnerability. Here, we establish that PRMT5 inhibition induces a special class of unspliced introns, called detained introns (DIs). We used depletion of CLNS1A, a PRMT5 cofactor that specifically enables Sm protein methylation to interrogate the impact of DIs. We found that disruption of Sm protein methylation is sufficient to induce DI upregulation, cell cycle defects, and loss of viability. Finally, we discovered that PRMT5-regulated DIs, and the impacted genes, are highly conserved across human, and also mouse, cell lines but display little interspecies conservation. Despite this, human and mouse DIs have convergent impacts on proliferation by affecting essential components of proliferation-regulating complexes. Together, these data argue that the PRMT5-splicing axis, and particularly appropriate DI splicing, underlies cancer’s vulnerability to PRMT5 inhibitors.

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Productive mRNA chromatin escape is promoted by PRMT5 activity - Cytoplasm Nucleoplasm Chromatin Fractions

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PRMT5-mediated SRSF1 methylation promotes virus-positive Merkel cell carcinoma tumorigenesis by increasing Tip60 exon inclusion [PacBio Sequel IIe]

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