PXD062850

PXD062850 is an original dataset announced via ProteomeXchange.

Title	PRMT5 regulates splicing of detained introns from DNA damage repair genes to protect against replication stress
Description	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.
HostingRepository	PRIDE
AnnounceDate	2026-06-19
AnnouncementXML	Submission_2026-06-19_06:50:00.398.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joao Paulo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-11 06:06:37	ID requested
⏵ 1	2026-06-19 06:50:00	announced

Dataset with its publication pending

submitter keyword: detained introns,PRMT5, ATR response, splicing, Merkel cell carcinoma, DNA damage

James A DeCaprio
contact affiliation	Dana-Farber Cancer Institute Department of Medical Oncology Harvard Medical School Boston, MA USA
contact email	james_decaprio@dfci.harvard.edu
lab head
Joao Paulo
contact affiliation	Harvard Medical School
contact email	joao_paulo@post.harvard.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD062850

PRIDE project URI

• PRIDE
  1. PXD062850
     1. Label: PRIDE project
     2. Name: PRMT5 regulates splicing of detained introns from DNA damage repair genes to protect against replication stress