Immunoglobulin class-switch recombination (CSR) requires splicing of germline switch transcripts, but the reason for this has remained a puzzle. In Cell, Zheng et al. show that splicing of switch transcripts in the locus encoding the immunoglobulin heavy chain (Igh) generates molecular guide sequences to target CSR to downstream switch regions. RNA 'lariats' formed by splice excision are cleaved by the debranching enzyme DBR1, which allows the formation of guanine quartet (G4) structures from the intronic guanine-rich switch regions. Such G4 RNA is recognized at nanomolar concentrations by AID, the cytidine deaminase that directs CSR. Substitution of the conserved Gly133 residue of AID abolishes recognition of G4 RNA and CSR in vivo without altering AID's catalytic activity or transcription and splicing of the Igh downstream constant regions. These findings provide a molecular explanation for the requirement for splicing in CSR and show that AID uses G4 RNA to target recombination in a sequence-specific manner.

Cell 161, 762–773 (2015)