Abstract
Activation-induced deaminase (AID) converts C to U and 5-methyl-C to T. These mutagenic activities are critical to immunoglobulin (Ig) gene diversification and epigenetic reprogramming, but they must be tightly controlled to prevent compromising cell fitness. AID acts in the nucleus but localizes predominately to the cytoplasm. To address this apparent paradox, we have carried out time-lapse imaging of AID in single living B cells and fibroblasts. We demonstrate that AID enters the nucleus in brief (30 min) pulses, evident in about 10% of cells in the course of a single cell cycle (24 hr imaging). Pulses do not depend on AID catalytic activity, but they are coordinated with nuclear accumulation of P53. Pulsing may protect cells from pathologic consequences of excess exposure to AID, or enable AID to synchronize its activity with transcription of genes that are AID targets or with nuclear entry of factors that act at sites of AID-catalyzed DNA deamination to promote Ig gene diversification or epigenetic reprogramming.
Highlights
Activation-induced deaminase (AID) is essential for the three processes that diversify immunoglobulin (Ig) gene sequence and structure: somatic hypermutation, class switch recombination, and gene conversion [1,2,3,4,5,6]
Activation-induced deaminase (AID) is a mutagenic factor that plays a critical role in immunoglobulin gene diversification and functions in early development to reprogram methylated regions of the genome
One level of regulation is known to be nuclear entry and exit, but spatiotemporal regulation of AID had not been examined at the level of single cells
Summary
Activation-induced deaminase (AID) is essential for the three processes that diversify immunoglobulin (Ig) gene sequence and structure: somatic hypermutation, class switch recombination, and gene conversion [1,2,3,4,5,6]. In B cells of the germinal center and other lymphoid tissues, AID deaminates C to U at the rearranged and transcribed Ig genes and factors from the base excision repair or mismatch repair pathways remove the U, thereby creating a DNA nick that can initiate somatic hypermutation, gene conversion or class switch recombination [7, 8]. Even though AID must act in the nucleus, it localizes primarily to the cytoplasm. Nuclear AID is potentially toxic, and mutations that impair export or proteolysis of nuclear AID can compromise cell viability [22, 27, 29]
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