Figure 1.

Transcription-coupled mutagenesis initiates class-switch recombination and somatic hypermutation. The murine immunoglobulin heavy chain locus is shown (top line) with a rearranged variable (VDJ) region juxtaposed to the Cμ constant region. AID is depicted traveling with the transcription apparatus (tailed arrows) at the expressed variable region and the activated Sμ and Sγ1 switch regions. The shaded box illustrates how AID first deaminates C to U, and then uracil-DNA glycosylase removes U, leaving an abasic site. Subsequent steps generate single-strand breaks [17], which become substrates for mutagenic repair or recombination. Somatic hypermutation alters variable region sequence, and switch recombination joins a new constant region (Cγ1) to the expressed variable region, producing an extrachromosomal DNA circle (bottom), which contains the deleted region. The final result is a heavy chain locus containing a mutated variable region (mutations are indicated by stars) and a chromosomal Sμ/Sγ1 junction (bottom).