Non-coding RNA Generated following Lariat Debranching Mediates Targeting of AID to DNA

Transcription through immunoglobulin switch (S) regions is essential for class switch recombination (CSR), but no molecular function of the transcripts has been described. Likewise, recruitment of activation-induced cytidine deaminase (AID) to S regions is critical for CSR; however, the underlying mechanism has not been fully elucidated. Here, we demonstrate that intronic switch RNA acts in trans to target AID to S region DNA. AID binds directly to switch RNA through G-quadruplexes formed by the RNA molecules. Disruption of this interaction by mutation of a key residue in the putative RNA-binding domain of AID impairs recruitment of AID to S region DNA, thereby abolishing CSR. Additionally, inhibition of RNA lariat processing leads to loss of AID localization to S regions and compromises CSR; both defects can be rescued by exogenous expression of switch transcripts in a sequence-specific manner. These studies uncover an RNA-mediated mechanism of targeting AID to DNA. [Display omitted] •Switch RNAs can fold into G-quadruplex structures•AID binds directly to G-quadruplex structures formed by switch RNAs•Switch RNAs act as AID guides after lariat processing•Switch RNAs target AID to DNA in a sequence-specific manner Transcription through the immunoglobulin switch (S) region produces a non-coding RNA that guides the enzyme AID to DNA in a sequence-specific manner to promote antibody class switch recombination.