Evolution of Phosphorylation-Dependent Regulation of Activation-Induced Cytidine Deaminase

被引:36
作者
Basu, Uttiya [1 ,2 ]
Wang, Yabin [1 ,2 ]
Alt, Frederick W. [1 ,2 ]
机构
[1] Harvard Univ, Sch Med, Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA
[2] Immune Dis Inst, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1016/j.molcel.2008.08.019
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Interaction of activation-induced cytidine deaminase (AID) with replication protein A (RPA) has been proposed to promote AID access to transcribed double-stranded (ds) DNA during immunoglobulin light chain and heavy chain class switch recombination (CSR). Mouse AID (mAID) interaction with RPA and transcription-dependent dsDNA deamination in vitro requires protein kinase A (PKA) phosphorylation at serine 38 (S38), and normal mAID CSR activity depends on S38. However, zebrafish AID (zAID) catalyzes robust CSR in mouse cells despite lacking an S38-equivalent PKA site. Here, we show that aspartate 44 (D44) in zAID provides similar in vitro and in vivo functionality as mAID S38 phosphorylation. Moreover, introduction of a PKA site into a zAID D44 mutant made it PKA dependent for in vitro activities and restored normal CSR activity. Based on these findings, we generated mAID mutants that similarly function independently of S38 phosphorylation. Comparison of bony fish versus amphibian and mammalian AlDs suggests evolutionary divergence from constitutive to PKA-regulated RPA/AID interaction.
引用
收藏
页码:285 / 291
页数:7
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