Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing

eLife - Tập 4
Li Zhang1, Ngoc Tung Tran1, Hairui Su1, Rui Wang2, Yuheng Lu3, Haiping Tang4, Sayura Aoyagi5, Ailan Guo5, Alireza Khodadadi‐Jamayran1, Dewang Zhou1, Kun Qian6, Todd Hricik7, Jocelyn Côté8, Xiaosi Han9, Wenping Zhou10, Suparna Laha11, Omar Abdel‐Wahab7, Ross L. Levine7, Glen Raffel11, Yanyan Liu10, Dongquan Chen12, Haitao Li4, Tim M. Townes1, Hengbin Wang1, Haiteng Deng4, Y. George Zheng6, Christina Leslie3, Minkui Luo2, Xinyang Zhao1
1Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
2Program of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
3Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
4School of Life Sciences, Tsinghua University, Beijing, China
5Cell Signaling Technology, Inc., Danvers, United States
6Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, United States
7Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
8Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
9Department of Neurology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, United States
10Department of Internal Medicine, Zhengzhou - Henan Cancer Hospital, Zhengzhou, China
11Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, United States
12Division of Preventive Medicine, The University of Alabama at Birmingham, Birmingham, United States

Tóm tắt

RBM15, an RNA binding protein, determines cell-fate specification of many tissues including blood. We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578, leading to its degradation via ubiquitylation by an E3 ligase (CNOT4). Overexpression of PRMT1 in acute megakaryocytic leukemia cell lines blocks megakaryocyte terminal differentiation by downregulation of RBM15 protein level. Restoring RBM15 protein level rescues megakaryocyte terminal differentiation blocked by PRMT1 overexpression. At the molecular level, RBM15 binds to pre-messenger RNA intronic regions of genes important for megakaryopoiesis such as GATA1, RUNX1, TAL1 and c-MPL. Furthermore, preferential binding of RBM15 to specific intronic regions recruits the splicing factor SF3B1 to the same sites for alternative splicing. Therefore, PRMT1 regulates alternative RNA splicing via reducing RBM15 protein concentration. Targeting PRMT1 may be a curative therapy to restore megakaryocyte differentiation for acute megakaryocytic leukemia.

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