The block in immunoglobulin class switch recombination caused by activation-induced cytidine deaminase deficiency occurs prior to the generation of DNA double strand breaks in switch mu region.
Affinity maturation of the Ab repertoire in germinal centers leads to the selection of high affinity Abs with selected heavy chain constant regions. Ab maturation involves two modifications of the Ig genes, i.e., somatic hypermutation and class switch recombination. The mechanisms of these two processes are not fully understood. As shown by the somatic hypermutation and class switch recombination-deficient phenotype of activation-induced cytidine deaminase (AID)-deficient patients (hyperIgM type 2 syndrome) and mice, both processes require the AID molecule. Somatic DNA modifications require DNA breaks, which, at least for class switch recombination, lead to dsDNA breaks. By using a ligation-mediated PCR, it was found that class switch recombination-induced dsDNA breaks in S mu switch regions were less frequent in AID-deficient B cells than in AID-proficient B cells, thus indicating that AID acts upstream of DNA break induction.
Catalan
Nadia
N
Institut National de la Santé et de la Recherche Médicale, Unité 429, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.
Selz
Françoise
F
Imai
Kohsuke
K
Revy
Patrick
P
Fischer
Alain
A
Durandy
Anne
A
D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology; D001483:Base Sequence; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D004249:DNA Damage; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics*; D006801:Humans; D006942:Hypergammaglobulinemia / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000235:genetics*; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics*; D008969:Molecular Sequence Data; D027041:Somatic Hypermutation, Immunoglobulin
D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D004247:DNA; D003564:Cytidine Deaminase