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

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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. Ribeiro de Almeida and colleagues demonstrate that the RNA helicase DDX1 is required for IgH class switch recombination. DDX1 binds to G-quadruplex structures present in switch long non-coding RNA and promotes R-loop formation over S-region DNA, thereby targeting AID to the IgH locus.

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Ribeiro de Almeida, C., Dhir, S., Dhir, A., Moghaddam, A. E., Sattentau, Q., Meinhart, A., & Proudfoot, N. J. (2018). RNA Helicase DDX1 Converts RNA G-Quadruplex Structures into R-Loops to Promote IgH Class Switch Recombination. Molecular Cell, 70(4), 650-662.e8. https://doi.org/10.1016/j.molcel.2018.04.001

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