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Nat Struct Mol Biol. 2019 Nov;26(11):999-1012. doi: 10.1038/s41594-019-0313-z. Epub 2019 Oct 14.

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

Author information

1
Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
2
The Danish Stem Cell Center, University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
3
Cell Biology Program and Center for Epigenetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.
5
Microchemistry and Proteomics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Department of Genetics, Faculty of Biology, Belarusian State University, Minsk, Belarus.
7
Laboratory of Bioinformatic Methods for Combinatorial Chemistry and Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
8
Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. helink@mskcc.org.
9
The Danish Stem Cell Center, University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. helink@mskcc.org.
10
Cell Biology Program and Center for Epigenetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. helink@mskcc.org.

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.

PMID:
31611688
PMCID:
PMC6858565
[Available on 2020-04-14]
DOI:
10.1038/s41594-019-0313-z

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