Spatiotemporal regulation limits the mutagenic potential of Activation-Induced Deaminase (AID)

Activation-induced cytidine deaminase (AID) initiates immunoglobulin (Ig) gene diversification in activated B cells and participates in the erasure of methylation marks that is necessary to genome-wide reprogramming in very early development. AID belongs to the Apobec family of cytidine deaminases. In activated B cells, deamination of C to U by AID triggers repair by error-prone mechanisms, leading to somatic hypermutation, gene conversion and class switch recombination at the Ig genes.;AID has the potential for mutagenesis. Consequently, the genome accumulates off-target deaminations as collateral damage from Ig gene diversification, which are repaired to maintain genomic stability. Pathological activities of AID are evident in many B cell and non-B cell malignancies in which AID is deregulated. AID attacks only single-stranded DNA (ssDNA), raising the possibility that AID could promote genomic instability during S phase, when DNA becomes transiently single stranded for replication.;The regulation of AID is stringent to minimize pathological outcomes. The role of cell cycle in regulation of AID has not been studied extensively. Here, I sought to address the relationship between cell cycle-dependent nuclear stability of AID and the physiological vs. pathological outcomes of AID activity. I have found that nuclear stability of AID promotes Ig gene diversification in G1 phase, and that nuclear export prevents genomic instability during S/G2/M phase. These results establish the physiological importance of cell cycle-dependent regulation of AID, and show that disruption of normal cell cycle regulation can promote genomic instability and genotoxicity and may contribute to mutagenesis by AID in cancer.