PXD012007-2
PXD012007 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation |
Description | Cancer-associated mutations in RNA splicing factors commonly occur in myeloid and lymphoid leukemias as well as a variety of solid tumors and confer dependence on wild-type (WT) splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here we identify that inhibiting symmetric (SDMA) or asymmetric dimethyl arginine methylation (ADMA), mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs) respectively, reduces splicing fidelity and results in strong preferential killing of spliceosomal mutant leukemias over WT counterparts. Consistent with this, proteomic analyses identified RNA binding proteins and splicing factors as the most enriched PRMT5 and/or PRMT Type I substrates in leukemia. Accordingly, combined PRMT5/type I PRMT inhibition resulted in synergistic cell killing and pronounced effects on splicing compared with inhibiting either enzymatic activity alone. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer. |
HostingRepository | PRIDE |
AnnounceDate | 2019-07-30 |
AnnouncementXML | Submission_2019-08-16_00:26:57.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Enrico Massignani |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | monomethylated residue; dimethylated residue |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2018-12-11 01:54:11 | ID requested | |
1 | 2019-07-30 08:04:43 | announced | |
⏵ 2 | 2019-08-16 00:26:58 | announced | Updated publication reference for PubMed record(s): 31408619. |
Publication List
Fong JY, Pignata L, Goy PA, Kawabata KC, Lee SC, Koh CM, Musiani D, Massignani E, Kotini AG, Penson A, Wun CM, Shen Y, Schwarz M, Low DH, Rialdi A, Ki M, Wollmann H, Mzoughi S, Gay F, Thompson C, Hart T, Barbash O, Luciani GM, Szewczyk MM, Wouters BJ, Delwel R, Papapetrou EP, Barsyte-Lovejoy D, Arrowsmith CH, Minden MD, Jin J, Melnick A, Bonaldi T, Abdel-Wahab O, Guccione E, Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation. Cancer Cell, 36(2):194-209.e9(2019) [pubmed] |
Keyword List
submitter keyword: Methylation, Leukemia, PRMT1, PRMT5 |
Contact List
Tiziana Bonaldi | |
---|---|
contact affiliation | Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy |
contact email | tiziana.bonaldi@ieo.it |
lab head | |
Enrico Massignani | |
contact affiliation | European Institute of Oncology (IEO) |
contact email | enrico.massignani@ieo.it |
dataset submitter |
Full Dataset Link List
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PRIDE project URI |
Repository Record List
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