1. Biochemistry and Chemical Biology
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Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing

  1. Li Zhang
  2. Ngoc-Tung Tung
  3. Hairui Su
  4. Rui Wang
  5. Yuheng Lu
  6. Haiping Tang
  7. Sayura Aoyagi
  8. Ailan Guo
  9. Alireza Khodadadi-Jamayran
  10. Dewang Zhou
  11. Kun Qian
  12. Todd Hricik
  13. Jocelyn Côté
  14. Xiaosi Han
  15. Wenping zhou
  16. Suparna Laha
  17. Omar Abdel-Wahab
  18. Ross L Levine
  19. Glen Raffel
  20. Yanyan Liu
  21. Dongquan Chen
  22. Haitao Li
  23. Tim Townes
  24. Hengbin Wang
  25. Haiteng Deng
  26. Yujun George Zheng
  27. Christina Leslie
  28. Minkui Luo
  29. Xinyang Zhao  Is a corresponding author
  1. The University of Alabama at Birmingham, United States
  2. Memorial Sloan Kettering Cancer Center, United States
  3. Tsinghua University, China
  4. Cell Signaling Technology, Inc., United States
  5. The University of Georgia, United States
  6. University of Ottawa, Canada
  7. Zhengzhou - Henan Cancer Hospital, China
  8. University of Massachusetts Medical School, United States
  9. Tsinghua University, United States
Research Article
  • Cited 43
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Cite this article as: eLife 2015;4:e07938 doi: 10.7554/eLife.07938

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-mRNA 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.

Article and author information

Author details

  1. Li Zhang

    Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ngoc-Tung Tung

    Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Hairui Su

    Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Rui Wang

    Program of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yuheng Lu

    Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Haiping Tang

    School of Life Sciences, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Sayura Aoyagi

    Cell Signaling Technology, Inc., Danvers, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ailan Guo

    Cell Signaling Technology, Inc., Danvers, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Alireza Khodadadi-Jamayran

    Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Dewang Zhou

    Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Kun Qian

    Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Todd Hricik

    Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Jocelyn Côté

    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Xiaosi Han

    Department of Neurology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Wenping zhou

    Department of Internal Medicine, Zhengzhou - Henan Cancer Hospital, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Suparna Laha

    Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Omar Abdel-Wahab

    Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Ross L Levine

    Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Glen Raffel

    Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Yanyan Liu

    Department of Internal Medicine, Zhengzhou - Henan Cancer Hospital, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  21. Dongquan Chen

    Division of Preventive Medicine, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Haitao Li

    School of Life Sciences, Tsinghua University, Beijing, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Tim Townes

    Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Hengbin Wang

    Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Haiteng Deng

    School of Life Sciences, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  26. Yujun George Zheng

    Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  27. Christina Leslie

    Computational Biology Program, Sloan Kettering Institute,, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  28. Minkui Luo

    Program of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  29. Xinyang Zhao

    Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
    For correspondence
    zhaox88@uab.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Publication history

  1. Received: April 4, 2015
  2. Accepted: November 16, 2015
  3. Accepted Manuscript published: November 17, 2015 (version 1)
  4. Accepted Manuscript updated: November 19, 2015 (version 2)
  5. Version of Record published: February 24, 2016 (version 3)

Copyright

© 2015, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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