Stochastic properties of processive cytidine DNA deaminases AID and APOBEC3G

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Abstract
Activation-induced (cytidine) deaminase (AID) efficiently introduces multiple and diversified deaminations in immunoglobulin (Ig) variable and switch regions. Here, we review studies of AID, and the APOBEC family member, APOBEC3G, demonstrating that both enzymes introduce multiple deaminations by processive action on single-stranded DNA and that deaminations occur stochastically at hot- and cold-spot targets. In a more detailed analysis of AID, we examine phosphorylation-null mutants, particularly, S38A and S43P. S43P mutant AID has been identified in a patient with hyper-IgM immunodeficiency syndrome. The phosphorylation-null mutants have essentially the same specific activity, processivity and ability to undergo transcription-dependent deamination compared with wild-type (WT) AID. Although the phosphorylation-null mutants still deaminate 5′-WR C hot spots, the mutant deamination spectra differ from WT AID. The mutants strongly prefer two motifs, 5′AG C and 5′GG C , which are disfavoured by WT AID. Differences in deamination specificities can be attributed primarily to the replacement of Ser rather than to the absence of phosphorylation. The 5′GGC motif occurs with exceptionally high frequency on the non-transcribed strand of human switch regions, IgG 4 and IgE. The potential for S43P to catalyse large numbers of aberrant deaminations in switch region sequences suggests a possible relationship between non-canonical AID deamination specificity and a loss of antibody diversification.