FIG 1.

IgE CSR. Before switching, the IgH locus in a B cell is in its germline configuration, with exons encoding the heavy chain constant region domains distributed over 150 kb of genomic DNA. Stimulation with IL-4 initiates ε-germline transcription through the Sε region. Clustering of Gs results in a very tight interaction between the transcribed RNA and DNA template, leaving a single nontemplate DNA strand. Secondary structures arising in the single strand cause stalling of RNAse polymerase II (Pol II), which results in recruitment of AID. AID catalyzes dC→dU conversions. The resultant dU nucleotides are deaminated by uracil N-glycosylase (UNG), generating a basic sites, which are substrates for apurinic/apyrimidinic endonuclease 1 (APE1). Single-stranded DNA breaks introduced at high density by this enzyme ultimately lead to DSBs. Breaks in Sµ and Sε are then annealed by means of classical nonhomologous end-joining (C-NHEJ), a DNA repair process involving the enzymes Ku70, Ku80, and DNA-dependent protein kinase, catalytic subunit. The products of this reaction are an episomal switch excision circle along with a functional IgE gene in which the VDJ cassette encoding the heavy chain variable regions is juxtaposed to the Cε exons encoding the constant domains.