FIGURE 1 | Rearrangement at the immunoglobulin heavy-chain locus.

From the following article:

Class-switch recombination: interplay of transcription, DNA deamination and DNA repair

Jayanta Chaudhuri & Frederick W. Alt

Nature Reviews Immunology 4, 541-552 (July 2004)

doi:10.1038/nri1395

Class-switch recombination: interplay of transcription, DNA deamination and DNA repair

The variable region of the immunoglobulin heavy chain is assembled from component variable (VH), diversity (DH), and joining (JH) gene segments by V(D)J recombination. The process of rearrangement involves cleavage of the recombination signal sequences in the DNA, which flank the rearranging gene segments, which is carried out by the recombination-activating gene 1 (RAG1)–RAG2 complex. Joining of the DNA ends requires non-homologous end-joining (NHEJ) proteins, including Ku70, Ku80, ARTEMIS, X-ray repair cross-complementing protein 4 (XRCC4), DNA ligase IV and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Transcription across the locus is driven by a promoter upstream of the rearranged VDJ segment (blue arrow), which facilitates the synthesis of a mu heavy chain. This then associates with a light chain, thereby forming an IgM molecule, which is displayed on the cell-surface of a B cell. Subsequently, secondary isotypes are produced by class-switch recombination (CSR), a process that exchanges the constant region of the heavy chain (CH) with a set of downstream constant-region genes (CSR to IgE is shown). This deletional-recombination reaction, which requires the enzyme activation-induced cytidine deaminase (AID), involves the generation of DNA breaks at switch (S) regions, which precede the constant-region genes, followed by the repair of DNA. This leads to a rearranged CH locus and deletion of the intervening sequence as an episomal circle. Cytokines stimulate transcription (red arrows) through the CH gene and determine the immunoglobulin isotype that the B cell will switch to. The rearranged variable regions of both the heavy and light chains also undergo a high rate of point mutation through the process of somatic hypermutation (SHM) (not shown). The Emu and 3'-regulatory-region (3' RR) enhancers influence V(D)J recombination and CSR, respectively.

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