학술논문
PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia
Document Type
Academic Journal
Author
Source
Nature Structural and Molecular Biology. November 2019, Vol. 26 Issue 11, p999, 14 p.
Subject
Language
English
ISSN
1545-9993
Abstract
Author(s): Aliaksandra Radzisheuskaya [sup.1] [sup.2] [sup.3], Pavel V. Shliaha [sup.4] [sup.5], Vasily Grinev [sup.6], Eugenia Lorenzini [sup.1] [sup.2], Sergey Kovalchuk [sup.4] [sup.7], Daria Shlyueva [sup.1] [sup.2], Vladimir Gorshkov [sup.4], Ronald [...]
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. The arginine methyltransferase PRMT5 modifies the splicing regulator SRSF1 and affects acute myeloid leukemia cell survival by modulating SRSF1 function.
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. The arginine methyltransferase PRMT5 modifies the splicing regulator SRSF1 and affects acute myeloid leukemia cell survival by modulating SRSF1 function.