Precise targeting of activation-induced cytidine deaminase (AID) to immunoglobulin (Ig) loci promotes antibody class switch recombination (CSR) and somatic hypermutation (SHM), whereas AID targeting of non-Ig loci can generate oncogenic DNA lesions. Here, we examined the contribution of G-quadruplex (G4) nucleic acid structures to AID targeting in vivo. Mice bearing a mutation in Aicda (AID^G133V) that disrupts AID-G4 binding modeled the pathology of hyper-IgM syndrome patients with an orthologous mutation, lacked CSR and SHM, and had broad defects in genome-wide AID^G133V chromatin localization. Genome-wide analyses also revealed that wild-type AID localized to MHCII genes, and AID expression correlated with decreased MHCII expression in germinal center B cells and diffuse large B cell lymphoma. Our findings indicate a crucial role for G4 binding in AID targeting and suggest that AID activity may extend beyond Ig loci to regulate the expression of genes relevant to the physiology and pathology of activated B cells.

将激活诱导的胞苷脱氨酶 (AID) 精确靶向免疫球蛋白 (Ig) 位点可促进抗体类别转换重组 (CSR) 和体细胞超突变 (SHM)，而针对非 Ig 位点的 AID 可产生致癌 DNA 损伤。在这里，我们检测了 G-四链体 (G4) 核酸结构对体内AID 靶向的作用。携带Aicda突变（AID ^G133V）的小鼠会破坏 AID-G4 结合，模拟了具有直系同源突变的高 IgM 综合征患者的病理学，缺乏 CSR 和 SHM，并且在全基因组 AID G133V 中存在广泛^缺陷染色质定位。全基因组分析还显示，野生型 AID 定位于 MHCII 基因，并且 AID 表达与生发中心 B 细胞和弥漫性大 B 细胞淋巴瘤中 MHCII 表达降低相关。我们的研究结果表明 G4 结合在 AID 靶向中起着至关重要的作用，并表明 AID 活性可能超出 Ig 基因座以调节与活化 B 细胞的生理学和病理学相关的基因表达。