title: Efficient AID targeting of switch regions is not sufficient for optimal class switch recombination.
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.
authors.affiliation: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges, Limoges 87025, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonaud
authors.affiliation: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges, Limoges 87025, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lechouane
authors.affiliation: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges, Limoges 87025, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Le Noir
authors.affiliation: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges, Limoges 87025, France.
authors.forename: Olivier
authors.identifier: 0000000232360807
authors.initials: O
authors.lastname: Monestier
authors.affiliation: 1] Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges, Limoges 87025, France. [2] Institut Universitaire de France, Paris 75000, France.
authors.forename: Michel
authors.identifier: 0000000285194427
authors.initials: M
authors.lastname: Cogné
authors.affiliation: Immunology, CNRS UMR 7276, Centre Nationale de la Recherche Scientifique, Université de Limoges, Limoges 87025, France.
authors.forename: Christophe
authors.identifier: 0000000211834989
authors.initials: C
authors.lastname: Sirac
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000502:physiology*; D000916:Antibody Diversity; D001402:B-Lymphocytes / Q000502:physiology*; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D055879:Gene Knock-In Techniques; D017578:Immunoglobulin Class Switching; D051379:Mice; D013154:Spleen / Q000166:cytology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase