title: Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing.
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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States.
authors.forename: Ngoc-Tung
authors.initials: NT
authors.lastname: Tran
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States.
authors.forename: Hairui
authors.initials: H
authors.lastname: Su
authors.affiliation: Program of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Yuheng
authors.initials: Y
authors.lastname: Lu
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Tang
authors.affiliation: Cell Signaling Technology, Inc., Danvers, United States.
authors.forename: Sayura
authors.initials: S
authors.lastname: Aoyagi
authors.affiliation: Cell Signaling Technology, Inc., Danvers, United States.
authors.forename: Ailan
authors.initials: A
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States.
authors.forename: Alireza
authors.initials: A
authors.lastname: Khodadadi-Jamayran
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States.
authors.forename: Dewang
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, United States.
authors.forename: Kun
authors.initials: K
authors.lastname: Qian
authors.affiliation: Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Todd
authors.initials: T
authors.lastname: Hricik
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Côté
authors.affiliation: Department of Neurology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, United States.
authors.forename: Xiaosi
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Zhengzhou - Henan Cancer Hospital, Zhengzhou, China.
authors.forename: Wenping
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Suparna
authors.initials: S
authors.lastname: Laha
authors.affiliation: Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Glen
authors.initials: G
authors.lastname: Raffel
authors.affiliation: Department of Internal Medicine, Zhengzhou - Henan Cancer Hospital, Zhengzhou, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Preventive Medicine, The University of Alabama at Birmingham, Birmingham, United States.
authors.forename: Dongquan
authors.initials: D
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States.
authors.forename: Tim
authors.initials: T
authors.lastname: Townes
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States.
authors.forename: Hengbin
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, United States.
authors.forename: Y George
authors.initials: YG
authors.lastname: Zheng
authors.affiliation: Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Christina
authors.initials: C
authors.lastname: Leslie
authors.affiliation: Program of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Minkui
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Zhao
mesh_terms: D002460:Cell Line; D006801:Humans; D008745:Methylation; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D059748:Proteolysis; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C431574:RBM15 protein, human; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: CNOT4; PRMT1; RBM15; RNA metabolism; arginine methylation; biochemistry; human; human biology; medicine; ubiquitylation