Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

Durandy, Anne; Péron, Sophie; Taubenheim, Nadine; Fischer, Alain

doi:10.1002/humu.20414

Cited by 58 publications

(47 citation statements)

References 77 publications

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“…M6A that abolished Spt6 interaction lost both SHM and CSR, although Spt6 is involved in only CSR. Human AID mutation M6T also lost both CSR and SHM (25). It is possible that M6A mutation altered the gross structure of AID to abolish the DNA cleavage function, resulting in the loss of both CSR and SHM.…”

Section: Resultsmentioning

confidence: 99%

Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation

Okazaki

Okawa²,

Kobayashi³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced cytidine deaminase (AID) is shown to be essential and sufficient to induce two genetic alterations in the Ig loci: class switch recombination (CSR) and somatic hypermutation (SHM). However, it is still unknown how a single-molecule AID differentially regulates CSR and SHM. Here we identified Spt6 as an AIDinteracting protein by yeast two-hybrid screening and immunoprecipitation followed by mass spectrometry. Knockdown of Spt6 resulted in severe reduction of CSR in both the endogenous Ig locus in B cells and an artificial substrate in fibroblast cells. Conversely, knockdown of Spt6 did not reduce but slightly enhanced SHM in an artificial substrate in B cells, indicating that Spt6 is required for AID to induce CSR but not SHM. These results suggest that Spt6 is involved in differential regulation of CSR and SHM by AID.T he Ig genes in antigen-stimulated B lymphocytes are diversified by two distinct genetic alteration mechanisms, namely somatic hypermutation (SHM) and class switch recombination (CSR) (1, 2). SHM causes the accumulation of point mutations in the rearranged variable (V) region genes, leading to generation of antibodies with higher affinity after cellular selection by a limited amount of antigen (1). CSR replaces the heavy chain constant region (C H ) gene proximal to the V H gene, namely Cμ with one of the downstream C H genes by recombination between the switch (S) regions located 5′ to each C H gene, thereby producing antibodies with diverse effector functions without changing their antigen specificity (2).Both SHM and CSR require activation-induced cytidine deaminase (AID), which is specifically expressed in activated B cells (3). It is well accepted that AID initiates single-strand DNA breaks essential for SHM and CSR through its cytidine deaminase activity. AID can also introduce mutations in such nonIg loci as c-myc, Pim1, Pax5, bcl-6, and RhoH (4, 5). The number of target loci of AID seems to be larger than expected but still limited (5). Although extensive analyses have been done to uncover the exact molecular mechanism how AID induces DNA strand breaks at restricted loci, it is unknown how a singlemolecule AID differentially regulates CSR and SHM or how the Ig genes and other target loci are preferentially targeted in the whole genome. To answer these questions, extensive studies were carried out to identify cofactor(s) that may account for the target specificity of the AID function. Several AID-interacting proteins have been reported, including RNA polymerase II (6), replication protein A (7), protein kinase A (8, 9), DNA-PKcs (10), MDM2 (11), CTNNBL1 (12), Spt5 (13), and PTBP2 (14). Unfortunately, however, none of these proteins could show any functional correlation to support the target specificity of AID. There is no clear mechanism to limit the number of target loci. Most of the proteins like RNA polymerase II, protein kinase A, Spt5, and PTBP2 are rather ubiquitous and interact with many proteins other than AID. PTBP2 is a splicing factor, and Spt5 is one of the tra...

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Section: Resultsmentioning

confidence: 99%

Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation

Okazaki

Okawa²,

Kobayashi³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The AD transmission rather suggests that AID acts in CSR at a homomultimer; however, the existence of multimeric AID complex is subject to debate. 99 Interestingly, the AID R190X mutant is found in the nucleus (and not in the cytoplasm) when transfected into a fibroblast cell line. Accumulation of the mutant protein in the nucleus might exclude the wild-type allele and thus lead to an AD effect.…”

Section: Autosomal Dominant Aid Deficiencymentioning

confidence: 98%

Class-Switch Recombination Defects

Durandy

Kracker

2014

Stiehm's Immune Deficiencies

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“…The N-terminal portion of AID is required for DNA cleavage, whereas the C-terminal portion is required for CSR, as described later (35,(37)(38)(39). Two contrasting hypotheses were put forward to explain how AID introduces DNA cleavage in the target DNA; the initially proposed RNA-editing hypothesis assumed that AID edits RNA to generate a DNA cleaving enzyme, whereas the much straightforward DNA-deamination hypothesis postulated that AID directly deaminates target DNA to initiate DNA cleavage.…”

Section: Evolution Of Acquired Immune Diversitymentioning

confidence: 99%

“…This region of AID has two activities: the nuclear export signal and the CSR-specific activity. This is because Cterminal mutants retain the in vitro DNA-deamination activity and in vivo SHM activities in both the V and S regions but lose CSR activity (35,38,39). Thus, it is likely that the CSR-specific function of the C-terminal domain of AID is independent from the DNA-deamination activity.…”

Section: Evolutionary Consideration Of the Dna-deamination Modelmentioning

confidence: 99%

An Evolutionary View of the Mechanism for Immune and Genome Diversity

Kato

Stanlie

Begum

et al. 2012

The Journal of Immunology

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An ortholog of activation-induced cytidine deaminase (AID) was, evolutionarily, the first enzyme to generate acquired immune diversity by catalyzing gene conversion and probably somatic hypermutation (SHM). AID began to mediate class switch recombination (CSR) only after the evolution of frogs. Recent studies revealed that the mechanisms for generating immune and genetic diversity share several critical features. Meiotic recombination, V(D)J recombination, CSR, and SHM all require H3K4 trimethyl histone modification to specify the target DNA. Genetic instability related to dinucleotide or triplet repeats depends on DNA cleavage by topoisomerase 1, which also initiates DNA cleavage in both SHM and CSR. These similarities suggest that AID hijacked the basic mechanism for genome instability when AID evolved in jawless fish. Thus, the risk of introducing genome instability into nonimmunoglobulin loci is unavoidable but tolerable compared with the advantage conferred on the host of being protected against pathogens by the enormous Ig diversification.

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Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

Cited by 58 publications

References 77 publications

Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation

Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation

Class-Switch Recombination Defects

An Evolutionary View of the Mechanism for Immune and Genome Diversity

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