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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 publication

DOI

10.1016/j.molcel.2018.04.001

Type

Journal article

Journal

Mol Cell

Publication Date

17/05/2018

Volume

70

Pages

650 - 662.e8

Keywords

DEAD-box RNA helicase 1, G-quadruplexes, R-loops, activation-induced cytidine deaminase, class switch recombination, Adenosine Triphosphatases, Animals, B-Lymphocytes, Cytidine Deaminase, DEAD-box RNA Helicases, DNA Replication, G-Quadruplexes, Immunoglobulin Class Switching, Immunoglobulin Heavy Chains, Immunoglobulin Switch Region, Mice, Mice, Inbred C57BL, Mice, Knockout, RNA, Recombination, Genetic