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

Abstract

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.