title: Parp3 negatively regulates immunoglobulin class switch recombination.
abstract: To generate highly specific and adapted immune responses, B cells diversify their antibody repertoire through mechanisms involving the generation of programmed DNA damage. Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by the recruitment of activation-induced cytidine deaminase (AID) to immunoglobulin loci and by the subsequent generation of DNA lesions, which are differentially processed to mutations during SHM or to double-stranded DNA break intermediates during CSR. The latter activate the DNA damage response and mobilize multiple DNA repair factors, including Parp1 and Parp2, to promote DNA repair and long-range recombination. We examined the contribution of Parp3 in CSR and SHM. We find that deficiency in Parp3 results in enhanced CSR, while SHM remains unaffected. Mechanistically, this is due to increased occupancy of AID at the donor (Sμ) switch region. We also find evidence of increased levels of DNA damage at switch region junctions and a bias towards alternative end joining in the absence of Parp3. We propose that Parp3 plays a CSR-specific role by controlling AID levels at switch regions during CSR.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Centre National de Recherche Scientifique, UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Robert
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Centre National de Recherche Scientifique, UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Gaudot
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Centre National de Recherche Scientifique, UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Rogier
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Centre National de Recherche Scientifique, UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Heyer
authors.affiliation: Centre National de Recherche Scientifique, UMR7242, Illkirch, France; Université de Strasbourg, Laboratoire d'Excellence Medalis, Illkirch, France; Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, Illkirch, France; Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Noll
authors.affiliation: Centre National de Recherche Scientifique, UMR7242, Illkirch, France; Université de Strasbourg, Laboratoire d'Excellence Medalis, Illkirch, France; Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, Illkirch, France; Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Dantzer
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Centre National de Recherche Scientifique, UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Reina-San-Martin
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005786:Gene Expression Regulation; D056426:Genetic Loci; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007134:Immunoglobulin Switch Region / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics
chemical_list: D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse; D003564:Cytidine Deaminase