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.
Highlights
RNA binding proteins control post-transcriptional processing such as alternative RNA splicing, polyadenylation and protein translation, which is a prevalent part of gene regulation in normal cell differentiation and in cancer development (Cabezas-Wallscheid et al, 2014; Chen et al, 2014; de Klerk and Hoen, 2015; Shapiro et al, 2011)
We applied bio-orthogonal profiling of protein methylation (BPPM) technology (Figure 1—figure supplement 2) (Wang et al, 2011) to identify proteins methylated by protein arginine methyltransferase 1 (PRMT1) in MKs
We report here that PRMT1 V2 dimethylates RBM15 within the sequence (LYRDRDR(me2)DLY)
Summary
RNA binding proteins control post-transcriptional processing such as alternative RNA splicing, polyadenylation and protein translation, which is a prevalent part of gene regulation in normal cell differentiation and in cancer development (Cabezas-Wallscheid et al, 2014; Chen et al, 2014; de Klerk and Hoen, 2015; Shapiro et al, 2011). We demonstrate that an RNA binding protein, RBM15, is methylated by PRMT1, which triggers its ubiquitylation by an E3 ligase CNOT4. Spen proteins are evolutionally conserved RNA binding proteins, which are involved in transcriptional regulation of Notch, Wnt and mitogen-activated protein kinase signal transduction pathways (Chang et al, 2008; Chen and Rebay, 2000; Oswald et al, 2002; Rebay et al, 2000; Su et al, 2015). RBM15 is involved in the chromosome translocation t(1;22), which produces the RBM15-MKL1 fusion protein associated with acute megakaryoblastic leukemia (AMKL) (Ma et al, 2001; Mercher et al, 2001)
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