Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination.
Immunoglobulin class switch recombination (CSR) is initiated by DNA breaks triggered by activation-induced cytidine deaminase (AID). These breaks activate DNA damage response proteins to promote appropriate repair and long-range recombination. Aberrant processing of these breaks, however, results in decreased CSR and/or increased frequency of illegitimate recombination between the immunoglobulin heavy chain locus and oncogenes like c-myc. Here, we have examined the contribution of the DNA damage sensors Parp1 and Parp2 in the resolution of AID-induced DNA breaks during CSR. We find that although Parp enzymatic activity is induced in an AID-dependent manner during CSR, neither Parp1 nor Parp2 are required for CSR. We find however, that Parp1 favors repair of switch regions through a microhomology-mediated pathway and that Parp2 actively suppresses IgH/c-myc translocations. Thus, we define Parp1 as facilitating alternative end-joining and Parp2 as a novel translocation suppressor during CSR.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Cancer Biology. Institut National de la Santé et de la Recherche Médicale U964-Centre National de la Recherche Scientifique UMR7104, Université de Strasbourg, Illkirch, France.
Isabelle
I
Robert
Françoise
F
Dantzer
Bernardo
B
Reina-San-Martin
D001402:B-Lymphocytes / Q000276:immunology; D003564:Cytidine Deaminase / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D016259:Genes, myc; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D007136:Immunoglobulins / Q000235:genetics; D008213:Lymphocyte Activation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000235:genetics; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D011995:Recombination, Genetic / Q000276:immunology*; D014178:Translocation, Genetic / Q000276:immunology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D007143:Immunoglobulin Heavy Chains; D007136:Immunoglobulins; D011064:Poly Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase