RBM15B–DDX21 coordinates m6A writer assembly to regulate gene expression
N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes, with established roles in DNA damage response and cancer. m6A is deposited co-transcriptionally by the METTL3-METTL14 methyltransferase complex (MTC), yet the mechanisms governing MTC assembly and chromatin recruitment remain poorly defined. Here, we identify RBM15B as a critical regulator of MTC integrity, demonstrating that its RRM1 domain directly mediates interaction with METTL3 and promotes efficient complex formation. Interactome analysis further reveals that the RNA helicase DDX21 drives RBM15B chromatin association, placing DDX21 upstream in the regulatory cascade. Consistently, RBM15B-dependent MTC chromatin recruitment facilitates RNA Pol II occupancy, linking this axis to active transcription. Collectively, our data establish a hierarchical pathway of DDX21-RBM15B- MTC that coordinates co-transcriptional m6A deposition, uncovering a new layer of epitranscriptomic regulation with implications for cancer biology
