Regulation of activation-induced cytidine deaminase DNA deamination activity in B-cells by Ser³⁸ phosphorylation

Human and mouse Ig genes are diversified in mature B-cells by distinct processes known as Ig heavy-chain CSR (class switch recombination) and Ig variable-region exon SHM (somatic hypermutation). These DNA-modification processes are initiated by AID (activation-induced cytidine deaminase), a DNA cytidine deaminase predominantly expressed in activated B-cells. AID is post-transcriptionally regulated via multiple mechanisms, including microRNA regulation, nucleocytoplasmic shuttling, ubiquitination and phosphorylation. Among these regulatory processes, AID phosphorylation at Ser³⁸ has been a focus of particularly intense study and debate. In the present paper, we discuss recent biochemical and mouse genetic studies that begin to elucidate the functional significance of AID Ser³⁸ phosphorylation in the context of the evolution of this mode of AID regulation and the potential roles that it may play in activated B-cells during a normal immune response.