Molecular Mechanism of Activation-Induced Cytidine Deaminase

Activation-induced cytidine deaminase (AID) is specifically expressed in the activated B cells upon cytokine stimulation and essential in both somatic hypermutation (SHM) and class switch recombination. Models of the molecular mechanism of AID should explain its target specificity and its domain-specific functions, which various AID mutants have revealed. The RNA-editing hypothesis proposes that AID has multiple RNA-editing targets, which enable both of AID's N-terminus-dependent DNA cleavage and C-terminus-dependent DNA repair. This hypothesis suggests that the target specificity is determined by the DNA sequences that are prone to taking non-B DNA structures and cleaved by topoisomerase1 (TOP1). In contrast, the DNA deamination hypothesis postulates that the numerous cofactors support AID recruitment to specific loci, and AID exerts its catalytic capacity only for DNA deamination. However, accumulating results over the past two decades indicate that AID has at least two distinct functions for single-strand breaks (SSBs) in the immunoglobulin (Ig) locus and for the repair of the breaks. Evidence for and against the two models suggests that the RNA-editing hypothesis can explain many AID functions better than the DNA deamination model.