Search

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. DOI: http://dx.doi.org/10.7554/eLife.07938.001, eLife digest The many different cell types in an adult animal all develop from a single fertilized egg. The development of cells into more specialized cell types is called ‘differentiation’. Proteins and other molecules from both inside and outside of the cells regulate the differentiation process. RNA is a molecule that is similar to DNA, and performs several important roles inside cells. Perhaps most importantly, RNA molecules act as messengers and carry genetic instructions during gene expression. RBM15 is an RNA-binding protein that is found throughout nature, and is involved in a number of developmental processes. Previous research has linked the incorrect control of RBM15 with an increased risk of certain cancers, including megakaryocytic leukemia. However, it is not clear what role RNA-binding proteins such as RBM15 play during differentiation. Now, Zhang, Tran, Su et al. have investigated the role of RBM15 during the development of large cells found in human bone marrow (called megakaryocytes). First, the experiments demonstrated that an enzyme called PRMT1 modifies RBM15. This enzyme adds a chemical mark called a methyl group at a specific site (an arginine amino acid) on the RNA-binding protein. Next, Zhang, Tran, Su et al. showed that the addition of this methyl group earmarks RBM15 for destruction. This means that an increase in PRMT1 levels reduces the amount of RBM15 in cells, while decreases in PRMT1 have the opposite effect. Further experiments showed that RBM15 normally processes the RNA messengers that carry the genetic instructions needed for the differentiation of bone marrow cells. An excess of PRMT1 enzyme leads to a lack of this RNA-binding protein. This in turn interferes with the differentiation process, and can contribute to the development of cancers such as megakaryocytic leukemia. Future work will therefore explore whether targeting PRMT1 with drugs could represent an effective treatment for these kinds of cancers. DOI: http://dx.doi.org/10.7554/eLife.07938.002