Key Points
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Immunoglobulin class-switch recombination (CSR) is a B-cell specific DNA-rearrangement reaction that exchanges the expressed Ig heavy-chain constant-region gene (CH) from Cμ to another downstream CH gene. This results in the generation of antibodies of secondary isotypes (IgG, IgA or IgE), which have different effector functions.
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CSR occurs between repetitive DNA elements called switch (S) regions that precede each of the constant-region genes. The reaction probably proceeds through the introduction of double-strand breaks (DSBs) in the DNA of two participating S regions, followed by their fusion. During this process, the DNA between the participating S regions is lost as an extrachromosomal circle.
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Transcription through the participating S regions is a prerequisite for CSR. The germline transcripts do not encode proteins but might have direct mechanistic roles in CSR, by forming RNA–DNA hybrids, thereby generating higher-order secondary structures. One such structure, the R loop, in which the non-template strand remains single stranded, has been demonstrated to form both in vitro and in vivo following the transcription of S regions. Other transcription-generated structures might also have roles in CSR.
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Somatic hypermutation (SHM) is another B cell-specific reaction that introduces point mutations into the antigen-binding segment of immunoglobulin genes to allow the generation of higher-affinity antibodies.
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Activation-induced cytidine deaminase (AID), recently identified as an enzyme expressed specifically by activated B cells, is essential for CSR and SHM. In mice and humans, inactivating mutations of AID lead to an absolute block in CSR and SHM. Ectopic expression of AID in fibroblasts can induce SHM and CSR in artificial substrates.
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The role of AID in CSR has been intensely debated since its discovery : it has been speculated to be an mRNA-editing enzyme and also to be a DNA-cytidine deaminase. There are now strong genetic and biochemical data to support the latter possibility.
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Recent work has provided evidence that single-stranded DNA that is generated during the transcription of S regions provides DNA substrates for AID deaminase activity. The deaminated DNA might be processed by components of the base-excision repair and mismatch-repair machineries to generate DSBs. The fusion of the two S region DSBs is probably mediated by non-homologous DNA end joining.
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Although the discovery of AID has considerably advanced our understanding of CSR and SHM, many issues remain unresolved, including the specificity of AID activity, the mechanism by which AID recognizes its targets, and the process that converts the deaminated DNA into DSBs and ultimately resolves the DNA lesions to complete CSR. A combination of in vivo and in vitro biochemical approaches should help address these issues.
Abstract
Class-switch recombination (CSR) of immunoglobulin heavy chains is the genetic process by which a B cell switches from the production of IgM to the production of IgG, IgE or IgA. Although the general characteristics of CSR have been known for some time, the detailed molecular mechanism of this process is only now emerging. CSR is unique, in that it seems to involve transcription-generated, higher-order RNA–DNA structures, specific DNA deamination and several DNA-repair pathways. In this review, we discuss our current knowledge of the mechanism of CSR and highlight the important unanswered questions.
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Acknowledgements
We thank John Manis, Ming Tian, Ali Zarrin, Sheila Ranganath, Craig Bassing and Chan Khuong and other members of the laboratory for careful evaluation of this manuscript. Work on CSR in the Alt laboratory is supported in part by the National Institutes of Health. F.W.A. is an Investigator of the Howard Hughes Medical Institute.
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Glossary
- NON-HOMOLOGOUS END JOINING
-
(NHEJ). The process that joins broken DNA ends without depending on extended homology. Components of this pathway include the DNA-end-binding proteins Ku70 and Ku80, the endonuclease ARTEMIS, X-ray repair cross-complementing protein 4 (XRCC4), DNA ligase IV and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).
- CYTOKINES
-
Biologically active molecules that are released by cells and affect the function of other cells.
- RGYW MOTIFS
-
The nucleotide sequence RGYW (where R denotes A or G, Y denotes C or T, and W denotes A or T) is considered a 'hot spot' for somatic hypermutation, as it is considerably more mutable than other random sequences.
- LIGATION-MEDIATED PCR
-
(lm-pcr). This method, which involves the ligation of unphosphorylated adaptors to broken DNA followed by PCR, can detect DNA double-stranded breaks in defined regions of the genome. It has been used extensively to analyse recombination-activating gene (RAG)-dependent breaks during V(D)J recombination, and more recently, in variable (V) gene segments and switch (S) regions during somatic hypermutation and class-switch recombination, respectively.
- SYNAPSIS
-
Non-covalent juxtaposition of two non-adjacent stretches of DNA.
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Chaudhuri, J., Alt, F. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat Rev Immunol 4, 541–552 (2004). https://doi.org/10.1038/nri1395
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DOI: https://doi.org/10.1038/nri1395
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