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Immunoglobulin heavy chain (IgH) class switch recombination (CSR) occurs through the deliberate introduction of AID-instigated DNA double strand breaks (DSBs) into the IgH loci. Since DSBs are generally highly toxic, mechanisms that regulate AID expression are of much relevance to both CSR and genomic integrity; however, effectors of such regulatory processes are still poorly understood. Here we show that the transcription factor Sox2 is expressed in activated B cells but almost exclusively in those that have undergone CSR. We demonstrate that enforced expression of Sox2 in splenic B cells severely inhibits AID expression and CSR, while deletion of Sox2 increases the frequency of IgH;c-Myc translocations. These results suggest that Sox2 may regulate AID expression in class-switched B cells to suppress genomic instability associated with CSR.

Upon encountering antigens, mature IgM-positive B lymphocytes undergo class-switch recombination (CSR) wherein exons encoding the default Cμ constant coding gene segment of the immunoglobulin (Ig) heavy-chain (Igh) locus are excised and replaced with a new constant gene segment (referred to as "Ch genes", e.g., Cγ, Cɛ, or Cα). The B cell thereby changes from expressing IgM to one producing IgG, IgE, or IgA, with each antibody isotype having a different effector function during an immune reaction. CSR is a DNA deletional-recombination reaction that proceeds through the generation of DNA double-strand breaks (DSBs) in repetitive switch (S) sequences preceding each Ch gene and is completed by end-joining between donor Sμ and acceptor S regions. CSR is a multistep reaction requiring transcription through S regions, the DNA cytidine deaminase AID, and the participation of several general DNA repair pathways including base excision repair, mismatch repair, and classical nonhomologous end-joining. In this review, we discuss our current understanding of how transcription through S regions generates substrates for AID-mediated deamination and how AID participates not only in the initiation of CSR but also in the conversion of deaminated residues into DSBs. Additionally, we review the multiple processes that regulate AID expression and facilitate its recruitment specifically to the Ig loci, and how deregulation of AID specificity leads to oncogenic translocations. Finally, we summarize recent data on the potential role of AID in the maintenance of the pluripotent stem cell state during epigenetic reprogramming.