1. A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination.
- Author
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Vuong BQ, Herrick-Reynolds K, Vaidyanathan B, Pucella JN, Ucher AJ, Donghia NM, Gu X, Nicolas L, Nowak U, Rahman N, Strout MP, Mills KD, Stavnezer J, and Chaudhuri J
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins genetics, Ataxia Telangiectasia Mutated Proteins immunology, B-Lymphocytes cytology, Cytidine Deaminase genetics, DNA Breaks, Double-Stranded, DNA-(Apurinic or Apyrimidinic Site) Lyase genetics, Gene Expression Regulation, Immunoglobulin Heavy Chains genetics, Mice, Phosphorylation, Protein Binding, Serine immunology, Serine metabolism, Signal Transduction, B-Lymphocytes immunology, Cytidine Deaminase immunology, DNA-(Apurinic or Apyrimidinic Site) Lyase immunology, Feedback, Physiological, Immunoglobulin Class Switching, Immunoglobulin Heavy Chains immunology
- Abstract
The ability of activation-induced cytidine deaminase (AID) to efficiently mediate class-switch recombination (CSR) is dependent on its phosphorylation at Ser38; however, the trigger that induces AID phosphorylation and the mechanism by which phosphorylated AID drives CSR have not been elucidated. Here we found that phosphorylation of AID at Ser38 was induced by DNA breaks. Conversely, in the absence of AID phosphorylation, DNA breaks were not efficiently generated at switch (S) regions in the immunoglobulin heavy-chain locus (Igh), consistent with a failure of AID to interact with the endonuclease APE1. Additionally, deficiency in the DNA-damage sensor ATM impaired the phosphorylation of AID at Ser38 and the interaction of AID with APE1. Our results identify a positive feedback loop for the amplification of DNA breaks at S regions through the phosphorylation- and ATM-dependent interaction of AID with APE1.
- Published
- 2013
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