Efficient AID targeting of switch regions is not sufficient for optimal class switch recombination

Amélie Bonaud, Fabien Lechouane, Sandrine Le Noir, Olivier Monestier, Michel Cogné () and Christophe Sirac ()
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Amélie Bonaud: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges
Fabien Lechouane: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges
Sandrine Le Noir: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges
Olivier Monestier: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges
Michel Cogné: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges
Christophe Sirac: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: Abstract Antibody affinity maturation relies on activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM) of immunoglobulin (Ig) loci. Class switch recombination (CSR) can in parallel occur between AID-targeted, transcribed, spliced and repetitive switch (S) regions. AID thus initiates not only mutations but also double-strand breaks (DSBs). What governs the choice between those two outcomes remains uncertain. Here we explore whether insertion of transcribed intronic S regions in a locus (Igκ) strongly recruiting AID is sufficient for efficient CSR. Although strongly targeted by AID and carrying internal deletions, the knocked-in S regions only undergo rare CSR-like events. This model confirms S regions as exquisite SHM targets, extending AID activity far from transcription initiation sites, and shows that such spliced and repetitive AID targets are not sufficient by themselves for CSR. Beyond transcription and AID recruitment, additional IgH elements are thus needed for CSR, restricting this hazardous gene remodelling to IgH loci.

Date: 2015
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DOI: 10.1038/ncomms8613

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