Cell Cycle-Mediated Regulation of Secondary Ig Diversification

Secondary Ig diversification in B cells requires the deliberate introduction of DNA damage into the Ig genes by the enzyme activationinduced cytidine deaminase (AID) and the error-prone resolution of AID-induced lesions. These processes must be tightly regulated because they may lead to lymphomagenesis if they act on genes other than the Ig genes. Since B cells may limit secondary Ig diversification mechanisms during the cell cycle to minimize genomic instability, we restricted the activity of AID specifically to the G1 or S/G2 phase to investigate the cell cycle contribution to the regulation of somatic hypermutation, class switch recombination, and Ig gene conversion in human, murine, and avian B cells, respectively. The efficient induction of AID in different cell cycle phases allowed us for the first time, to our knowledge, to discriminate G1- from S/G2-specific events of regulation. We show that the processes of Ig gene conversion and C/G mutagenesis during somatic hypermutation can be achieved throughout the cell cycle, whereas A/T mutagenesis and class switch recombination require AID-mediated deamination in G1. Thus, AID activity in G1, but not in S/G2, leads to the efficient accomplishment of all mechanisms of secondary Ig diversification. Our findings refine the current state-of-the-art knowledge in the context of the regulation of secondary Ig diversification. The Journal of Immunology, 2023, 210: 1508-1518.

Automated summary

Secondary Ig diversification in B cells requires the enzyme activation-induced cytidine deaminase (AID) to introduce DNA damage into Ig genes. The regulation of this process is important to prevent lymphomagenesis. This study investigated the cell cycle contribution to the regulation of somatic hypermutation, class switch recombination, and Ig gene conversion in B cells. The results show that AID activity in G1 phase is essential for efficient secondary Ig diversification mechanisms.