eLife (Nov 2015)
Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing
- Li Zhang,
- Ngoc-Tung Tran,
- Hairui Su,
- Rui Wang,
- Yuheng Lu,
- Haiping Tang,
- Sayura Aoyagi,
- Ailan Guo,
- Alireza Khodadadi-Jamayran,
- Dewang Zhou,
- Kun Qian,
- Todd Hricik,
- Jocelyn Côté,
- Xiaosi Han,
- Wenping Zhou,
- Suparna Laha,
- Omar Abdel-Wahab,
- Ross L Levine,
- Glen Raffel,
- Yanyan Liu,
- Dongquan Chen,
- Haitao Li,
- Tim Townes,
- Hengbin Wang,
- Haiteng Deng,
- Y George Zheng,
- Christina Leslie,
- Minkui Luo,
- Xinyang Zhao
Affiliations
- Li Zhang
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
- Ngoc-Tung Tran
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
- Hairui Su
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
- Rui Wang
- Program of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
- Yuheng Lu
- Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
- Haiping Tang
- School of Life Sciences, Tsinghua University, Beijing, China
- Sayura Aoyagi
- Cell Signaling Technology, Inc., Danvers, United States
- Ailan Guo
- Cell Signaling Technology, Inc., Danvers, United States
- Alireza Khodadadi-Jamayran
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
- Dewang Zhou
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
- Kun Qian
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, United States
- Todd Hricik
- Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
- Jocelyn Côté
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
- Xiaosi Han
- Department of Neurology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, United States
- Wenping Zhou
- Department of Internal Medicine, Zhengzhou - Henan Cancer Hospital, Zhengzhou, China
- Suparna Laha
- Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, United States
- Omar Abdel-Wahab
- Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
- Ross L Levine
- Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
- Glen Raffel
- Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, United States
- Yanyan Liu
- Department of Internal Medicine, Zhengzhou - Henan Cancer Hospital, Zhengzhou, China
- Dongquan Chen
- Division of Preventive Medicine, The University of Alabama at Birmingham, Birmingham, United States
- Haitao Li
- School of Life Sciences, Tsinghua University, Beijing, China
- Tim Townes
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
- Hengbin Wang
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
- Haiteng Deng
- School of Life Sciences, Tsinghua University, Beijing, China
- Y George Zheng
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, United States
- Christina Leslie
- Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
- Minkui Luo
- Program of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
- Xinyang Zhao
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
- DOI
- https://doi.org/10.7554/eLife.07938
- Journal volume & issue
-
Vol. 4
Abstract
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.
Keywords
