TY - JOUR TI - Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing AU - Zhang, Li AU - Tran, Ngoc-Tung AU - Su, Hairui AU - Wang, Rui AU - Lu, Yuheng AU - Tang, Haiping AU - Aoyagi, Sayura AU - Guo, Ailan AU - Khodadadi-Jamayran, Alireza AU - Zhou, Dewang AU - Qian, Kun AU - Hricik, Todd AU - Côté, Jocelyn AU - Han, Xiaosi AU - Zhou, Wenping AU - Laha, Suparna AU - Abdel-Wahab, Omar AU - Levine, Ross L AU - Raffel, Glen AU - Liu, Yanyan AU - Chen, Dongquan AU - Li, Haitao AU - Townes, Tim AU - Wang, Hengbin AU - Deng, Haiteng AU - Zheng, Y George AU - Leslie, Christina AU - Luo, Minkui AU - Zhao, Xinyang A2 - Green, Michael R VL - 4 PY - 2015 DA - 2015/11/17 SP - e07938 C1 - eLife 2015;4:e07938 DO - 10.7554/eLife.07938 UR - https://doi.org/10.7554/eLife.07938 AB - 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. KW - PRMT1 KW - CNOT4 KW - RBM15 KW - arginine methylation KW - ubiquitylation KW - RNA metabolism JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -