| RBM15 belongs to the SPEN family of RNA-binding proteins characterized by multiple RNA recognition motifs and a conserved SPOC domain that orchestrates interactions with splicing and methylation machinery. It features an N-terminal region with RRM domains for sequence-specific pre-mRNA binding alongside a C-terminal SPOC that engages phosphorylated WTAP and RNA polymerase II CTD to anchor regulatory complexes at nascent transcripts. RBM15 recruits the WTAP-METTL3-METTL14 m6A methyltransferase complex to intronic and 3' UTR sites, installing N6-methyladenosine marks that direct alternative splicing outcomes and mRNA export through NXF1-mediated nuclear transport. Interaction with the U2 snRNP-associated SF3B1 splicing factor targets weak branch point regions, facilitating cassette exon inclusion or skipping in transcripts encoding hematopoietic regulators like GATA1, RUNX1, TAL1, and c-MPL to calibrate lineage commitment during megakaryopoiesis and myeloid differentiation. PRMT1-mediated arginine dimethylation at R578 triggers E3 ligase CNOT4 recognition, promoting K48-linked ubiquitination and proteasomal degradation that fine-tunes RBM15 steady-state levels in response to thrombopoietin signaling. RBM15 balances proliferation versus terminal maturation by modulating Mpl isoform splicing, where full-length receptors amplify self-renewal signals while truncated dominant-negative forms restrain expansion. Elevated RBM15 drives acute megakaryoblastic leukemia through fusion with MKL1, sustaining oncogenic splicing networks that evade differentiation blocks. |
Lane 1: 22Rv1, Lane 2: NIH/3T3, Lane 3: H-4-II-E, Lane 4: COS-7
