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PXD039283

PXD039283 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleRemodeling oncogenic transcriptomes by small molecules targeting NONO
DescriptionA large swath of the human proteome is dedicated to mRNA homeostasis, but most RNA-binding proteins lack chemical probes. 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 of 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 the compensatory action of the paralogous proteins PSPC1 and SFPQ, which were 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.
HostingRepositoryPRIDE
AnnounceDate2024-01-26
AnnouncementXMLSubmission_2024-01-26_07:19:28.518.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterStefan Kathman
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListiodoacetamide derivatized residue
InstrumentOrbitrap Fusion
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-01-05 05:55:52ID requested
12024-01-26 07:19:29announced
Publication List
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]
Keyword List
submitter keyword: proteomics,22Rv1
Contact List
Ben Cravatt
contact affiliationDepartment of Chemistry, Scripps Research La Jolla, USA
contact emailcravatt@scripps.edu
lab head
Stefan Kathman
contact affiliationThe Scripps Research Institute
contact emailskathman@scripps.edu
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
Repository Record List
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