A Combined Nuclear and Nucleolar Localization Motif in Activation-Induced Cytidine Deaminase (AID) Controls Immunoglobulin Class Switching

Hu, Yi; Ericsson, Ida; Torseth, Kathrin; Methot, Stephen P.; Sundheim, Ottar; Liabakk, Nina Beate; Slupphaug, Geir; Noia, Javier M. Di; Krokan, Hans E.; Kavli, Bodil

doi:10.1016/j.jmb.2012.11.026

Cited by 33 publications

(30 citation statements)

References 84 publications

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“…Owing to its DNA deamination activity, high levels of AID in the nucleus may cause severe genomic instability in B cells. This is a probable reason why .90% of the total AID protein is found in the cytoplasm, regulated through both nuclear export and cytoplasmic retention (28,29). Recent studies suggest that cytoplasmic AID exists as a 300-to 500-kDa protein complex, containing Hsp90, Hsp40, and eEF1A and probably also other sofar-unknown factors (30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Cortizas

Verdún

et al. 2015

The Journal of Immunology

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Ig class switching requires cell proliferation and is division linked, but the detailed mechanism is unknown. By analyzing the first switching cells early in the kinetics, our analysis suggested that proliferating B cells had a very short G1 phase (<3.5 h), a total cell cycle time of ∼11 h, and that Ig class switching preferentially occurred in the late G1 or early S phase. Inhibition of cyclin-dependent kinases (CDKs) caused dramatic reduction of switching rate within 6 h. This was associated with less targeting of activation-induced cytidine deaminase (AID) to the Igh locus. Interestingly, ectopically expressed nuclear AID in HeLa cells was preferentially found in the early S phase. Furthermore, in CDK2 hypomorphic cells there was reduced nuclear AID accumulation. Thus, our data are compatible with the idea that division-linked Ig class switching is in part due to CDK2-regulated AID nuclear access at the G1/S border.

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Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Cortizas

Verdún

et al. 2015

The Journal of Immunology

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“…Additionally, a recent study posited that CyclinD is upregulated in mantle cell lymphoma because it becomes localized to nucleoli following a characteristic translocation with IgH 44 . Moreover, the enzyme activation-induced cytidine deaminase (AID), which catalyzes class switch recombination at immunoglobulin loci and is involved in IgH : Myc translocations has been detected in nucleoli 45 , 46 . Taken together these data suggest that localization of genes, including IgH and Myc , to nucleoli does not interfere with their function.…”

Section: Discussionmentioning

confidence: 99%

Nucleolar tethering mediates pairing between theIgHandMycloci

Strongin

Groudine

Politz

2014

Nucleus

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Gene loci on different chromosomes can preferentially colocalize in the cell nucleus. However, many of the mechanisms mediating this spatial proximity remain to be elucidated. The IgH locus on Chromosome 12 and the Myc locus on Chromosome 15 are a well-studied model for gene colocalization in murine B cells, where the two loci are positioned in close proximity at a higher than expected frequency. These gene loci are also partners in the chromosomal translocation that causes murine plasmacytoma and Burkitt’s lymphoma. Because both Chromosome 12 and Chromosome 15 carry nucleolar organizer regions (NORs) in the most commonly studied mouse strains, we hypothesized that NOR-mediated tethering of the IgH and Myc loci to shared nucleoli could serve as a mechanism to drive IgH:Myc colocalization. Using mouse strains that naturally carry nucleolar organizer regions (NORs) on different sets of chromosomes, we establish that IgH and Myc are positioned proximal to nucleoli in a NOR dependent manner and show that their joint association with nucleoli significantly increases the frequency of IgH and Myc pairing. Thus we demonstrate that simple nucleolar tethering can increase the colocalization frequency of genes on NOR-bearing chromosomes.

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“…The arginine 112 histidine mutation renders AID catalytically inactive (17), thus explaining the lack of Ig class switching and SHM in AID R112H B cells. The AID R112H mutation has been observed in several unrelated HIGM patients, and it is a frequent cause of AID deficiency (12,18).…”

Section: Discussionmentioning

confidence: 99%

A Novel Mouse Model for the Hyper-IgM Syndrome: A Spontaneous Activation-Induced Cytidine Deaminase Mutation Leading to Complete Loss of Ig Class Switching and Reduced Somatic Hypermutation

Dahlberg

Visnes

et al. 2014

The Journal of Immunology

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We describe a spontaneously derived mouse line that completely failed to induce Ig class switching in vitro and in vivo. The mice inherited abolished IgG serum titers in a recessive manner caused by a spontaneous G→A transition mutation in codon 112 of the aicda gene, leading to an arginine to histidine replacement (AIDR112H). Ig class switching was completely reconstituted by expressing wild-type AID. Mice homozygous for AIDR112H had peripheral B cell hyperplasia and large germinal centers in the absence of Ag challenge. Immunization with SRBCs elicited an Ag-specific IgG1 response in wild-type mice, whereas AIDR112H mice failed to produce IgG1 and had reduced somatic hypermutation. The phenotype recapitulates the human hyper-IgM (HIGM) syndrome that is caused by point mutations in the orthologous gene in humans, and the AIDR112H mutation is frequently found in HIGM patients. The AIDR112H mouse model for HIGM provides a powerful and more precise tool than conventional knockout strategies.

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A Combined Nuclear and Nucleolar Localization Motif in Activation-Induced Cytidine Deaminase (AID) Controls Immunoglobulin Class Switching

Cited by 33 publications

References 84 publications

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Nucleolar tethering mediates pairing between theIgHandMycloci

A Novel Mouse Model for the Hyper-IgM Syndrome: A Spontaneous Activation-Induced Cytidine Deaminase Mutation Leading to Complete Loss of Ig Class Switching and Reduced Somatic Hypermutation

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