Mus musculus strain:c57 Raw sequence reads. Mus musculus strain:c57

Activation-induced cytidine deaminase (AID) initiates somatic hyper-mutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes to produce high affinity antibodies in mature B cells. However, it has remained long enigmatic about how AID finds its targets in the genome to mediate such programmatic genomic rearrangement. Here we report that the RNA binding protein PTBP3 is required for both CSR and SHM in activated B cells. We demonstrate that PTBP3 forms a complex with AID, which together navigate through the genome via bi-directional RNAs. Strikingly, specific mutations in AID that are causal to Hyper-IgM syndrome type 2 (HIGM2) completely disrupt the complex, thereby abolishing the AID recruitment to Ig loci. These data reveal that a specific RNA binding protein functions to impart the specificity to AID, and highlight the importance of regulatory RNA in immune response.