RNA Helicase DDX1 Converts RNA G-Quadruplex Structures into R-Loops to Promote IgH Class Switch Recombination

Claudia Ribeiro de Almeida, Somdutta Dhir, Ashish Dhir, Amin E Moghaddam, Quentin Sattentau, Anton Meinhart, Nicholas J Proudfoot

Research output: Contribution to journalArticlepeer-review

Abstract

Class switch recombination (CSR) at the immunoglobulin heavy-chain (IgH) locus is associated with the formation of R-loop structures over switch (S) regions. While these often occur co-transcriptionally between nascent RNA and template DNA, we now show that they also form as part of a post-transcriptional mechanism targeting AID to IgH S-regions. This depends on the RNA helicase DDX1 that is also required for CSR in vivo. DDX1 binds to G-quadruplex (G4) structures present in intronic switch transcripts and converts them into S-region R-loops. This in turn targets the cytidine deaminase enzyme AID to S-regions so promoting CSR. Notably R-loop levels over S-regions are diminished by chemical stabilization of G4 RNA or by the expression of a DDX1 ATPase-deficient mutant that acts as a dominant-negative protein to reduce CSR efficiency. In effect, we provide evidence for how S-region transcripts interconvert between G4 and R-loop structures to promote CSR in the IgH locus.

Original languageEnglish
Pages (from-to)650-662.e8
JournalMolecular Cell
Volume70
Issue number4
Early online date3 May 2018
DOIs
Publication statusPublished - 17 May 2018

Keywords

  • Adenosine Triphosphatases/genetics
  • Animals
  • B-Lymphocytes/cytology
  • Cytidine Deaminase/genetics
  • DEAD-box RNA Helicases/physiology
  • DNA Replication
  • G-Quadruplexes
  • Immunoglobulin Class Switching
  • Immunoglobulin Heavy Chains/chemistry
  • Immunoglobulin Switch Region/genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA/chemistry
  • Recombination, Genetic

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