Mechanism and control of V(D)J recombination versus class switch recombination: Similarities and differences

V(D)J recombination is the process by which the variable region exons encoding the antigen recognition sites of receptors expressed on B and T lymphocytes are generated during early development via somatic assembly of component gene segments. In response to antigen, somatic hypermutation (SHM) and class switch recombination (CSR) induce further modifications of immunoglobulin genes in B cells. CSR changes the IgH constant region for an alternate set that confers distinct antibody effector functions. SHM introduces imitations, at a high rate, into variable region exons, ultimately allowing affinity maturation. All of these genomic alteration processes require tight regulatory control mechanisms, both to ensure development of a normal immune system and to prevent potentially oncogenic processes, such as translocations, caused by errors in the recombination/mutation processes. In this regard, transcription of substrate sequences plays a significant role in target specificity, and transcription is mechanistically coupled to CSR and SHM. However there are many mechanistic differences in these reactions. V(D)J recombination proceeds, via precise DNA cleavage initiated by the RAG proteins at short conserved signal sequences, whereas CSR and SHM are initiated over large target regions via activation-induced cytidine deaminase (AID)-mediated DNA deamination of transcribed the context of CSR via a general anchoring mechanism proposed to hold DSBs together in chromatin before their joining via NHEJ. In contrast, RAG-generated DSBs appear to be held together in a postcleavage synaptic complex by the RAGs themselves, which then recruit the NHEJ factors to complete the reaction. In both V(D)J recombination and CSR, however, we still know little about the actual process of synapsis and how the involved proteins contribute to it.