PXD032087

PXD032087 is an original dataset announced via ProteomeXchange.

Title	Remodeling of oncogenic transcriptomes by small molecules targeting the RNA-binding protein NONO
Description	A large swath of the human proteome is dedicated to mRNA homeostasis, but most RNA-binding proteins lack chemical probes1,2. Here, we report the discovery through phenotypic screening of electrophilic small molecules that swiftly (within 4 h) and stereospecifically decrease transcripts encoding the androgen receptor (AR) and its major V7 splice variant in human prostate cancer cells. We show by chemical proteomics that these compounds covalently engage cysteine-145 on the RNA-binding protein NONO. Broader profiling revealed that covalent NONO ligands suppress a discrete set of transcripts and proteins, including multiple oncogenic transcription factors, and impair the proliferation of cancer cells. These effects were not observed following genetic disruption of NONO, which instead blocked ligand activity. The covalent ligands promote accumulation of NONO in nuclear foci and at the first 5’ splice site of immature transcripts, pointing to a trapping mechanism that may prevent compensatory action by the related protein PSPC1, which was found to increase in cancer cells following genetic or chemical perturbation of NONO. These findings, taken together, designate NONO as a druggable RNA-binding protein that can be co-opted by covalent small molecules to suppress pro-tumorigenic transcriptional networks.
HostingRepository	PRIDE
AnnounceDate	2024-01-26
AnnouncementXML	Submission_2024-01-26_08:51:20.441.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Stefan Kathman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-05 12:17:15	ID requested
⏵ 1	2024-01-26 08:51:21	announced

10.1038/s41589-023-01270-0;

Kathman SG, Koo SJ, Lindsey GL, Her HL, Blue SM, Li H, Jaensch S, Remsberg JR, Ahn K, Yeo GW, Ghosh B, Cravatt BF, Remodeling oncogenic transcriptomes by small molecules targeting NONO. Nat Chem Biol, 19(7):825-836(2023) [pubmed]

submitter keyword: Human, LC-MSMS, TMT, Cancer, Chemoproteomics, Thermo Fusion

Benjamin F Cravatt
contact affiliation	The Scripps Research Institute
contact email	cravatt@scripps.edu
lab head
Stefan Kathman
contact affiliation	The Scripps Research Institute
contact email	skathman@scripps.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/2024/01/PXD032087

PRIDE project URI

• PRIDE
  1. PXD032087
     1. Label: PRIDE project
     2. Name: Remodeling of oncogenic transcriptomes by small molecules targeting the RNA-binding protein NONO