PXD012007

PXD012007 is an original dataset announced via ProteomeXchange.

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

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.

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]

submitter keyword: Methylation, Leukemia, PRMT1, PRMT5

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

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PRIDE project URI

• PRIDE
  1. PXD012007
     1. Label: PRIDE project
     2. Name: Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation