RRC ID 75011
Author Bello A, Müller A, Hirth G, Giebeler LN, Böttcher K, Voigt S, Jungnickel B.
Title Cell Cycle-Mediated Regulation of Secondary Ig Diversification.
Journal J Immunol
Abstract Secondary Ig diversification in B cells requires the deliberate introduction of DNA damage into the Ig genes by the enzyme activation-induced 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.
Volume 210(10)
Pages 1508-1518
Published 2023-5-15
DOI 10.4049/jimmunol.2100880
PII 263580
PMID 37000470
MeSH Animals B-Lymphocytes / metabolism Cell Cycle Cytidine Deaminase / genetics Genes, Immunoglobulin* Humans Immunoglobulin Class Switching* Mice Mutagenesis Somatic Hypermutation, Immunoglobulin
IF 4.886
Mice RBRC00897