Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation Journal Article

   

Authors:	Fong, J. Y.; Pignata, L.; Goy, P. A.; Kawabata, K. C.; Lee, S. C. W.; Koh, C. M.; Musiani, D.; Massignani, E.; Kotini, A. G.; Penson, A.; Wun, C. M.; Shen, Y.; Schwarz, M.; Low, D. H. P.; Rialdi, A.; Ki, M.; Wollmann, H.; Mzoughi, S.; Gay, F.; Thompson, C.; Hart, T.; Barbash, O.; Luciani, G. M.; Szewczyk, M. M.; Wouters, B. J.; Delwel, R.; Papapetrou, E. P.; Barsyte-Lovejoy, D.; Arrowsmith, C. H.; Minden, M. D.; Jin, J.; Melnick, A.; Bonaldi, T.; Abdel-Wahab, O.; Guccione, E.
Article Title:	Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation
Abstract:	Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer. Fong et al. show that spliceosomal mutant leukemias are preferentially sensitive to inhibition of protein arginine methyltransferases (PRMTs), that RNA-binding proteins are enriched among substrates of PRMT5 and type I PRMTs, and that combined PRMT5 and type I PRMT inhibition synergistically kill these leukemia cells. © 2019
Keywords:	arginine methylation; aml; mds; prmt1; prmt5; sf3b1; srsf2; u2af1; splicing factor mutations; ms023
Journal Title:	Cancer Cell
Volume:	36
Issue:	2
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2019-08-12
Start Page:	194
End Page:	209.e9
Language:	English
DOI:	10.1016/j.ccell.2019.07.003
PUBMED:	31408619
PROVIDER:	scopus
PMCID:	PMC7194031
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85069824657&doi=10.1016%2fj.ccell.2019.07.003&partnerID=40&md5=350550e3cdc6dbe323b98e2861e35aba
Notes:	Article -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/151263