Activation-induced cytidine deaminase (AID) is a mutator enzyme that targets immunoglobulin (Ig) genes to initiate antibody somatic hypermutation (SHM) and class switch recombination (CSR). Off-target AID association also occurs, which causes oncogenic mutations and chromosome rearrangements. However, AID occupancy does not directly correlate with DNA damage, suggesting that factors beyond AID association contribute to mutation targeting. CSR and SHM are regulated by phosphorylation on AID serine38 (pS38), but the role of pS38 in off-target activity has not been evaluated. We determined that lithium, a clinically used therapeutic, induced high AID pS38 levels. Using lithium and an AID-S38 phospho mutant, we compared the role of pS38 in AID activity at the Ig switch region and off-target Myc gene. We found that deficient pS38 abated AID chromatin association and CSR but not mutation at Myc. Enhanced pS38 elevated Myc translocation and mutation frequency but not CSR or Ig switch region mutation. Thus, AID activity can be differentially targeted by phosphorylation to induce oncogenic lesions.

激活诱导的胞苷脱氨酶（AID）是一种突变酶，其靶向免疫球蛋白（Ig）基因以启动抗体体细胞超突变（SHM）和类别开关重组（CSR）。脱靶AID关联也会发生，这会导致致癌突变和染色体重排。但是，AID的占用与DNA损伤不直接相关，这表明AID关联以外的因素有助于突变靶向。CSR和SHM受AID丝氨酸38（pS38）磷酸化的调节，但尚未评估pS38在脱靶活性中的作用。我们确定锂，一种临床上使用的治疗药物，可诱导高AID pS38水平。使用锂和AID-S38磷酸突变体，我们比较了pS38在Ig开关区域和脱靶Myc基因在AID活性中的作用。我们发现缺陷的pS38减弱了AID染色质的缔合和CSR，但在Myc处没有突变。增强的pS38升高了Myc易位和突变频率，但不提高CSR或Ig开关区突变。因此，可以通过磷酸化来区别地靶向AID活性以诱导致癌性病变。