Molecular Mechanism of Class Switch Recombination

Stavnezer, Janet; Kinoshita, Kazuo; Muramatsu, Masamichi; Honjo, Tasuku

doi:10.1016/b978-012053641-2/50021-6

Cited by 9 publications

(11 citation statements)

References 201 publications

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“…7). The genetic loci for AID and APOBEC-1 are tightly linked on mouse and human chromosomes (2). In addition to these evolutionary conservations, AID has functional similarities with APOBEC-1, including dimer formation, requirement of cofactors, and shuttling between cytoplasm and nucleus by N-terminal nuclear localization and C-terminal nuclear export domains (8)(9)(10).…”

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DNA cleavage in immunoglobulin somatic hypermutation depends onde novoprotein synthesis but not on uracil DNA glycosylase

Nagaoka

Ito

Muramatsu

et al. 2005

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

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Activation-induced cytidine deaminase (AID) is required for the DNA cleavage step of Ig somatic hypermutation (SHM). However, its molecular mechanism is controversial. The RNA editing hypothesis postulates that AID deaminates cytosine in an unknown mRNA to generate a new mRNA encoding SHM endonuclease. On the other hand, the DNA deamination hypothesis explains DNA cleavage by cytosine deamination in DNA, followed by uracil removal by uracil DNA glycosylase (UNG). By using the protein synthesis inhibitor cycloheximide, we showed that SHM requires de novo protein synthesis in accord with predictions by the RNA editing hypothesis. In addition, we found that cycloheximide but not Ugi (the specific inhibitor of UNG) inhibited AID-dependent DNA cleavage in the Ig gene during SHM, by using histone H2AX focus formation as a marker of DNA cleavage. The results indicate the following order of events: AID expression, protein synthesis, DNA cleavage, and SHM. The requirement of protein synthesis but not of UNG for the DNA cleavage step of SHM forces us to reconsider the DNA deamination hypothesis and strengthens the RNA editing hypothesis.A ntigen stimulation induces three types of genetic alterations, namely somatic hypermutation (SHM), gene conversion (GC), and class switch recombination (CSR) in activated B cells, giving rise to antigen-specific Ig with high affinity and appropriate effector functions. SHM introduces point mutations in variable-region (V) genes without template, whereas GC does so with pseudo-V genes as template. When SHM and GC are coupled with selection by limited amounts of antigen, highaffinity antibody-producing B cells are enriched. CSR is a genetic process that switches Ig isotypes from IgM to other isotypes such as IgG and IgE, adding diverse effector functions to Ig with a given antigen specificity (1, 2).Activation-induced cytidine deaminase (AID), which is strictly expressed in activated B cells, especially in the germinal centers of lymphoid follicles, is essential for all three types of DNA alteration in B cells activated by antigen stimulation (3-6). AID has the strongest homology with apolipoprotein B mRNA editing catalytic subunit 1 (APOBEC-1) (reviewed in ref. 7). The genetic loci for AID and APOBEC-1 are tightly linked on mouse and human chromosomes (2). In addition to these evolutionary conservations, AID has functional similarities with APOBEC-1, including dimer formation, requirement of cofactors, and shuttling between cytoplasm and nucleus by N-terminal nuclear localization and C-terminal nuclear export domains (8-10).Evolutionary conservation and biochemical similarities between AID and apolipoprotein B mRNA editing catalytic subunit 1 (APOBEC-1) led us to propose the RNA editing hypothesis that AID converts unknown mRNA precursors to novel mRNAs encoding putative endonucleases to cleave target DNA (1). The alternative hypothesis (DNA deamination) explains DNA cleavage by direct deamination of cytosine (C) to uracil (U) in target DNA by AID. To generate strand breakage, U should be...

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“…When SHM and GC are coupled with selection by limited amounts of antigen, highaffinity antibody-producing B cells are enriched. CSR is a genetic process that switches Ig isotypes from IgM to other isotypes such as IgG and IgE, adding diverse effector functions to Ig with a given antigen specificity (1,2).…”

mentioning

confidence: 99%

DNA cleavage in immunoglobulin somatic hypermutation depends onde novoprotein synthesis but not on uracil DNA glycosylase

Nagaoka

Ito

Muramatsu

et al. 2005

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

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“…This enzyme deaminates cytosine (C) at nucleotide 6666 of apoB 100 mRNA encoding a cholesterol carrier protein, converting it to apoB 48 mRNA encoding a triglyceride carrier (9). The AID and APOBEC-1 loci are tightly linked on mouse and human chromosomes (2). In addition to these evolutionary conservations, AID has functional similarities with APOBEC-1, including dimer formation, requirement of cofactors for their function, and shuttling between the cytoplasm and nucleus with the N-terminal nuclear localization and C-terminal nuclear export signal (10)(11)(12).…”

mentioning

confidence: 99%

“…A ctivation-induced cytidine deaminase (AID) is essential for all three types of DNA alteration, namely somatic hypermutation, gene conversion, and class switch recombination (CSR) in B cells activated by antigen stimulation (1)(2)(3)(4)(5). AID is expressed in activated B cells, especially in germinal centers of lymphoid follicles (6).…”

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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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“…3; Ref. 2,8 ). The strand breaks essential for CSR occur within the S-regions and require transcription (but not translation) of these sequences.…”

Section: Genetic Alterations During Affinity Maturationmentioning

confidence: 99%

Evaluation of Molecular Models for the Affinity Maturation of Antibodies: Roles of Cytosine Deamination by AID and DNA Repair

et al. 2006

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Molecular Mechanism of Class Switch Recombination

Cited by 9 publications

References 201 publications

DNA cleavage in immunoglobulin somatic hypermutation depends onde novoprotein synthesis but not on uracil DNA glycosylase

DNA cleavage in immunoglobulin somatic hypermutation depends onde novoprotein synthesis but not on uracil DNA glycosylase

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

Evaluation of Molecular Models for the Affinity Maturation of Antibodies: Roles of Cytosine Deamination by AID and DNA Repair

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