The Block in Immunoglobulin Class Switch Recombination Caused by Activation-Induced Cytidine Deaminase Deficiency Occurs Prior to the Generation of DNA Double Strand Breaks in Switch μ Region

Catalan, Nadia; Selz, Françoise; Imai, Kohsuke; Revy, Patrick; Fischer, Alain; Durandy, Anne

doi:10.4049/jimmunol.171.5.2504

Cited by 83 publications

(62 citation statements)

References 41 publications

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“…AID is expressed in activated B cells, especially in germinal centers of lymphoid follicles (6). Although AID is involved in the DNA cleavage step in CSR (7,8), its molecular mechanism is still controversial. The RNA-editing hypothesis postulates that AID converts unknown mRNA precursors to novel mRNAs encoding putative endonucleases to cleave the target DNA (6).…”

mentioning

confidence: 99%

De novo protein synthesis is required for activation-induced cytidine deaminase-dependent DNA cleavage in immunoglobulin class switch recombination

Begum

Kinoshita

Muramatsu

et al. 2004

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

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Activation-induced cytidine deaminase is required for the DNA cleavage step of Ig class switch recombination (CSR). However, its molecular mechanism is controversial. RNA-editing hypothesis postulates that activation-induced cytidine deaminase deaminates cytosine in an unknown mRNA to generate a new mRNA encoding an endonuclease for CSR and thus predicts that DNA cleavage depends on de novo protein synthesis. On the other hand, DNA deamination hypothesis proposes that DNA cleavage is initiated by cytosine deamination in DNA, followed by uracil removal by uracil DNA glycosylase. By using the chromatin immunoprecipitation assay to detect ␥-H2AX focus formation as a marker for DNA cleavage, we found that cycloheximide inhibited DNA cleavage in the Ig heavy-chain locus during CSR. Requirement of protein synthesis in the DNA cleavage step of CSR strengthens the RNAediting hypothesis.

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mentioning

confidence: 99%

De novo protein synthesis is required for activation-induced cytidine deaminase-dependent DNA cleavage in immunoglobulin class switch recombination

Begum

Kinoshita

Muramatsu

et al. 2004

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

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confidence: 99%

“…This transcription is sterile, in that the germ-line transcripts (GLT) are not translated into proteins (4, 24), and is presumably required to provide ssDNA either in the form of transcription bubbles (7) or R-loops with the nontranscribed strand being single stranded (13,14). The production of GLTs precedes the generation of AIDinduced mutations and of the DSB that are required for successful CSR (5,6,25).It has been suggested that increased accessibility contributes to the selective targeting to Ig genes and that this could be accomplished through modifications of chromatin that have been implicated in targeting transcription, replication, and other repair processes (26-28). It has been well established that modifications of histones H3 and H4 are essential for stepwise V(D)J recombination and additional steps in B cell differentiation (29,30).…”

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confidence: 99%

Differential regulation of histone acetylation and generation of mutations in switch regions is associated with Ig class switching

Luo

Scharff

2004

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

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Class switch recombination (CSR) allows B cells to make effective protective antibodies. CSR involves the replacement of the constant region with one of the downstream constant regions by recombination between the donor and recipient switch (S) regions. Although histone H3 hyperacetylation in recipient S regions was recently reported to coincide with CSR, the relative histone H3 and H4 acetylation status of the donor and recipient S regions and the relationship between the generation of mutations and histone hyperacetylation in S regions have not been addressed. Here we report that histone H3 and H4 were constitutively hyperacetylated in the donor S region before and after different mitogen and cytokine treatments. We observed an increased frequency of mutations in hyperacetylated S␥ DNA segments immunoprecipitated with anti-acetyl histone antibodies. Furthermore, time course experiments revealed that the pattern of association of RNA polymerase II with S regions was much like that of H3 hyperacetylation but not always like that of H4 hyperacetylation. Collectively, our data suggest that H3 and H4 histone hyperacetylation in different S regions is regulated differently, that RNA polymerase II distribution and H3 hyperacetylation reflect the transcriptional activity of a given S region, and that transcription, hyperacetylation, and mutation are not sufficient to guarantee CSR. These findings support the notion that there are additional modifications and͞or factors involved in the complex process of CSR.H igh-affinity IgG, IgA, and IgE antibodies protect higher organisms from infection by pathogenic organisms and other environmental threats. The generation of effective protective antibodies requires B cells to carry out somatic hypermutation (SHM) and class switch recombination (CSR), two related but quite different DNA transactions (1). SHM introduces many point mutations in the variable (V) regions of the Ig heavy and light chain genes that encode the antigen-binding site of the antibody molecule (2). In contrast to SHM, CSR is a region-specific recombinationdeletion process that requires the generation of double-stranded DNA breaks (DSB) (3). These DSB are generated in the donor switch (S) region that is just upstream of the constant (C) region gene and in a downstream recipient ␥, , or ␣ S region (4, 5). Recombination then brings one of those downstream C regions into proximity to the V region. This allows the mutated heavy chain V region to be expressed with one of the C regions so that each antigen-binding site will be able to mediate different effector functions and be distributed throughout the body.Despite the different outcomes of SHM and CSR, activationinduced cytidine deaminase (AID) is required for both processes (6) presumably because of its ability to deaminate deoxycytidine to deoxyuridine on single-stranded DNA (ssDNA) (7-11). Both SHM and CSR require transcription (12), suggesting that the ssDNA substrate for AID is created by the generation of transcription bubbles (7) and͞or perhaps triplex RNA...

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“…In addition, these studies established the mechanistic link between CSR and SHM by demonstrating that AID indeed initiates both events. DNA-dsb at IgH locus, as revealed by the formation of cH2AX and NBS1 foci or by LM-PCR, are no more detected in B cells from AID -/-mice and HIGM2 patients [66], thus indicating that AID acts upstream of the generation of DNA-dsb during CSR. Nevertheless, a dissociation of function between CSR and SHM was uncovered by the identification of HIGM patients presenting a CSR defect without alteration of SHM caused by particular mutations in the C terminus of AID.…”

Section: Higm: Csr and Shm Defectsmentioning

confidence: 93%

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

et al. 2007

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B and T lymphocytes are exposed to various genotoxic stresses during their life, which originate from programmed molecular mechanisms during their development and maturation or are secondary to cellular metabolism during acute phases of cell proliferation and activation during immune responses. How lymphocytes handle these multiple genomic assault has become a focus of interest over the years, perhaps beginning with the identification of the murine scid model in the early 80s when it was recognized that DNA repair deficiencies had profound consequences on the immune system. In this respect, the immune system represents an ideal model to study DNA damage responses (DDR) and the survey of immune deficiency conditions in humans or the development of specific animal models provided many major contributions in our understanding of the various biochemical pathways at play during DDR in general. Although the role of DNA repair in the early phases of B and T cell development has been analyzed thoroughly, the role of these functions in various aspects of the mature immune system (homeostasis, immunological memory, ageing) is less well understood. Lastly, the analysis of DNA repair in the immune system has provided many insights in the more general understanding of cancer. IntroductionAll living organisms are exposed to endogenous and environmental genotoxic stresses causing DNA injuries. Among these lesions, DNA double-strand breaks (DNAdsb) are considered as the most harmful. Unrepaired DNA damage can lead to mutation, cancer, or cell death. Several cellular responses are triggered, in what is called the DNA damage response (DDR), to handle DNA lesions (Fig. 1). The purpose of this review is not to go in the depth of the various biochemical pathways that constitute the DDR, as this aspect has been covered elsewhere [1], but rather to discuss, in an historical way, how the immune system depends on these pathways on one hand, and how studies of the immune system have been instrumental in the better understanding of some of these pathways, in particular the non-homologous end joining (NHEJ) pathway. Indeed, the immune system is the place of many genotoxic stresses that happen at various time points during the development and maturation of lymphocytes (Fig. 2). These DNA We discuss here the links that exist between the immune system and the DDR with the standpoint of the lymphocyte lifespan, from birth to ageing, and discuss the consequences of DNA repair defects on the integrity of the immune system. Development of the immune system V(D)J recombinationB and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the BCR and TCR, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Fig. 3), which assembles previously scattered variable (V), diversity (D), and joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism [2]. The reaction is initiated by the lymphoid-specific factors Rag1 and Rag2, which specifically...

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The Block in Immunoglobulin Class Switch Recombination Caused by Activation-Induced Cytidine Deaminase Deficiency Occurs Prior to the Generation of DNA Double Strand Breaks in Switch μ Region

Cited by 83 publications

References 41 publications

De novo protein synthesis is required for activation-induced cytidine deaminase-dependent DNA cleavage in immunoglobulin class switch recombination

De novo protein synthesis is required for activation-induced cytidine deaminase-dependent DNA cleavage in immunoglobulin class switch recombination

Differential regulation of histone acetylation and generation of mutations in switch regions is associated with Ig class switching

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

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