A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination.
A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination.
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DNA 断裂和磷酸化依赖性正反馈环路促进免疫球蛋白类别转换重组。
DOI：
10.1038/ni.2732
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发表时间：
2013
影响因子：
30.5
通讯作者：
Chaudhuri,Jayanta
中科院分区：
文献类型：
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作者：
Vuong,BaoQ;Herrick-Reynolds,Kayleigh;Vaidyanathan,Bharat;Pucella,JosephN;Ucher,AnnaJ;Donghia,NinaM;Gu,Xiwen;Nicolas,Laura;Nowak,Urszula;Rahman,Numa;Strout,MatthewP;Mills,KevinD;Stavnezer,Janet;Chaudhuri,Jayanta
激活诱导的胞苷脱氨酶（AID）有效介导类别转换重组（CSR）的能力取决于其在Ser 38的磷酸化;然而，诱导AID磷酸化的触发因素以及磷酸化AID驱动CSR的机制尚未阐明。在这里，我们发现AID在Ser 38的磷酸化是由DNA断裂诱导的。相反，在缺乏AID磷酸化的情况下，在免疫球蛋白重链基因座（Igh）中的开关（S）区域不能有效地产生DNA断裂，这与AID不能与核酸内切酶APE 1相互作用一致。此外，DNA损伤传感器ATM的缺陷损害了AID在Ser 38的磷酸化以及AID与APE 1的相互作用。我们的研究结果确定了一个正反馈环的扩增DNA断裂在S区通过磷酸化和ATM依赖的相互作用的AID与APE 1。
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.