Format

Send to

Choose Destination
Elife. 2015 Nov 17;4. pii: e07938. doi: 10.7554/eLife.07938.

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

Author information

1
Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States.
2
Program of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
3
Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
4
School of Life Sciences, Tsinghua University, Beijing, China.
5
Cell Signaling Technology, Inc., Danvers, United States.
6
Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, United States.
7
Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
8
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
9
Department of Neurology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, United States.
10
Department of Internal Medicine, Zhengzhou - Henan Cancer Hospital, Zhengzhou, China.
11
Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, United States.
12
Division of Preventive Medicine, The University of Alabama at Birmingham, Birmingham, United States.
#
Contributed equally

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:

CNOT4; PRMT1; RBM15; RNA metabolism; arginine methylation; biochemistry; human; human biology; medicine; ubiquitylation

PMID:
26575292
PMCID:
PMC4775220
DOI:
10.7554/eLife.07938
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center