RBM5 promotes exon 4 skipping of AID pre-mRNA by competing with the binding of U2AF65 to the polypyrimidine tract.

Alternative splicing is involved in functional regulation of the mutagenic enzyme activation-induced cytidine deaminase (AID). However, the molecular basis for AID splicing regulation remains undefined. Using a mini-gene-based screen in HeLa cells, we found that overexpression of RNA binding motif protein 5 (RBM5, or LUCA-15/H37) significantly promoted AID exon 4 skipping by suppressing the splicing of intron 3. The inhibitive effect of RBM5 on intron 3 splicing required a weak 3'-splice site (ss). Indicative of the underlying mechanism, RBM5 interfered with the binding of U2AF65 to the polypyrimidine tract at the 3'-ss in vitro. Our findings thus not only shed lights on the regulatory mechanism of AID exon 4 skipping, but also provide new insights into how RBM5 functions in splicing regulation.