A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination.
Nat Immunol
; 14(11): 1183-1189, 2013 Nov.
Article
em En
| MEDLINE
| ID: mdl-24097111
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
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Cadeias Pesadas de Imunoglobulinas
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Switching de Imunoglobulina
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Citidina Desaminase
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Retroalimentação Fisiológica
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DNA Liase (Sítios Apurínicos ou Apirimidínicos)
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article