Activation-induced cytidine deaminase (AID) is a single-stranded DNA (ssDNA) cytidine deaminase that is predominantly expressed in germinal center B cells (Figure 1). AID induces point mutations or DNA double-strand breaks (DSBs) in its physiological targets, which include immunoglobulin switch (IgS) sequences during class switch recombination (CSR) and immunoglobulin variable genes (IgV or VDJ exons) during somatic hypermutation (SHM). Lack of IgV SHM can stymie antibody recognition of pathogenic antigens. Changes in IgS mutagenesis can decrease CSR efficiency and even cause oncogenic Ig heavy-chain (IgH) translocations 1•, 2.

AID is absolutely necessary for SHM and CSR in B cells 3, 4. Transcription of IgV and IgS regions by RNA polymerase II (RNAP2) is also necessary for SHM and CSR, respectively 5, 6, 7, 8, as ssDNA is readily available for AID deamination 9, 10, 11, 12. Mutations occur on non-template and template DNA strands [13], implying that both must be single-stranded at some point. AID recruitment to and subsequent mutation of IgS and IgV regions is known as ‘AID targeting’ and SHM, whereas AID recruitment to and subsequent mutation of non-Ig, potentially oncogenic regions is known as ‘AID off-targeting’ and aberrant SHM (aSHM). Hypermutation of V genes was first observed in a study analyzing amino acid sequences originating from mouse λ light chains [14], then confirmed at the DNA level [15], and again confirmed at the protein level in a study showing that IgG antibodies against phosphorylcholine had significantly more mutations than their IgM counterparts [16]. Failure of physiological AID targeting can lead to immunodeficiency syndromes, while increased AID off-targeting can drive lymphomagenesis and transformation into diffuse large B-cell lymphoma (DLBCL). Thus, a deeper understanding of the mechanisms governing AID targeting in B cells is a significant topic in adaptive immunity and lymphoma biology.