Antibody class switching mediated by yeast endonuclease-generated DNA breaks

Antibody class switching in activated B cells uses class switch recombination (CSR), which joins activation-induced cytidine deaminase (AID)-dependent double-strand breaks (DSBs) within two large immunoglobulin heavy chain (IgH) locus switch (S) regions that lie up to 200 kilobases apart. To test postulated roles of S regions and AID in CSR, we generated mutant B cells in which donor S mu and accepter S gamma 1 regions were replaced with yeast 1-SceI endonuclease sites. We found that site-specific 1-SceI DSBs mediate recombinational IgH locus class switching from IgM to IgG(2) without S regions or AID. We propose that CSR evolved to exploit a general DNA repair process that promotes joining of widely separated DSBs within a chromosome.