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

Cell. 2015 May 7;161(4):762-73. doi: 10.1016/j.cell.2015.03.020.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytidine Deaminase / metabolism*
  • G-Quadruplexes
  • Immunoglobulin Class Switching*
  • Introns
  • Maltose-Binding Proteins / metabolism
  • Mice
  • RNA Processing, Post-Transcriptional
  • RNA, Guide / genetics
  • RNA, Guide / metabolism*

Substances

  • Maltose-Binding Proteins
  • RNA, Guide
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase