A) Organization of an expressed IgH locus with general location of V(D)J exon, iEμ, 3'IgHRR (3'RR) and CHs, S regions and I-region promoters (line/arrow). B) During SHM in GC B cells, AID targets transcribed IgH V(D)J exons leading to mutations (red circles) but does not necessarily target downstream S regions. C) During CSR, in activated B cells in culture, AID targets transcribed S regions leading to somatic mutations and DSBs (jagged gaps) but not adjacent V(D)J exons. AID-initiated DSBs in S regions can be joined to form intra-S deletions (ISDs) (truncated S region oval with black center) or CSR events (fused S region ovals). CSR is thought to occur by a deletional mechanism with intervening sequences deleted on an excision circle. D) Working model for transcriptional AID targeting (adapted from Basu et al., 2011). “U” refers to deaminated cytidines; RPA to replication protein A) and RNAP II to RNA Polymerase. See text for other details.