Fig. 1.
AID-targeted deamination at V(D)J and S regions of Ig genes initiates SHM and CSR. Low affinity IgM-producing IgVH genes undergo SHM and CSR which require C → U deamination by AID at V(D)J and switch (S) regions, respectively. Transcription from the V promoter (P) is needed for AID access to V(D)J regions, whereas germline transcription from the I promoters is required for AID targeting to the donor switch (Sμ) and a downstream acceptor S (shown in this case Sε). Error-prone processing of G:U mispair by MMR, BER and replication introduces a huge number of mutations (~10−4 to 10−3 per base per generation) in the antigen-binding V(D)J region as well as the rejoining Sμ–Sε regions. CSR combines the V(D)J exon with one of the appropriate downstream constant C regions γ3, (γ1, γ2b, and γ2a not shown), ε or α, converting IgM or IgD to the other isotypes IgG3 (IgG1, IgG2b, and IgG2a not shown), IgE, or IgA. The graph on top shows a typical SHM profile. Mutations start ~150 bp downstream from the promoter (P) at the leader sequence (L) reaching a maximum frequency over the V(D)J coding exon decaying exponentially towards the 3′ end. Eμ is an intronic enhancer. E3′s are enhancers at 3′ regulatory regions (3′RR)