PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia Journal Article

   

Authors:	Radzisheuskaya, A.; Shliaha, P. V.; Grinev, V.; Lorenzini, E.; Kovalchuk, S.; Shlyueva, D.; Gorshkov, V.; Hendrickson, R. C.; Jensen, O. N.; Helin, K.
Article Title:	PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia
Abstract:	Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantitative proteomics and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5 and that loss of PRMT5 leads to changes in alternative splicing of multiple essential genes. Our study proposes a mechanism for the requirement of PRMT5 for leukemia cell survival and provides potential biomarkers for the treatment response to PRMT5 inhibitors. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords:	controlled study; treatment response; unclassified drug; human cell; nonhuman; cell proliferation; biological marker; proteome; animal cell; mouse; cell survival; enzyme substrate; proteomics; dna methylation; regulatory mechanism; messenger rna; quantitative analysis; leukemia cell; alternative rna splicing; arginine; enzyme mechanism; regulator protein; protein arginine methyltransferase; protein arginine methyltransferase 5; acute myeloid leukemia; human; priority journal; article; srsf1 protein
Journal Title:	Nature Structural and Molecular Biology
Volume:	26
Issue:	11
ISSN:	1545-9993
Publisher:	Nature Publishing Group
Date Published:	2019-11-01
Start Page:	999
End Page:	1012
Language:	English
DOI:	10.1038/s41594-019-0313-z
PUBMED:	31611688
PROVIDER:	scopus
PMCID:	PMC6858565
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85074012394&doi=10.1038%2fs41594-019-0313-z&partnerID=40&md5=409d4b38c2a99b4c320f005e7e75f942
Notes:	Article -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/156913