Immunoglobulin and T cell receptor gene assembly depends on V(D)J recombination initiated by the RAG1-RAG2 recombinase. The RAG1 N-terminal region (NTR; aa 1–383) has been implicated in regulatory functions whose influence on V(D)J recombination and lymphocyte development in vivo is poorly understood. We generated mice in which RAG1 lacks ubiquitin ligase activity (P326G), the major site of autoubiquitination (K233R), or its first 215 residues (Δ215). While few abnormalities were detected in R1.K233R mice, R1.P326G mice exhibit multiple features indicative of reduced recombination efficiency, including an increased Igκ+:Igλ+ B cell ratio and decreased recombination of Igh, Igκ, Igλ, and Tcrb loci. Previous studies indicate that synapsis of recombining partners during Igh recombination occurs through two pathways: long-range scanning and short-range collision. We find that R1Δ215 mice exhibit reduced short-range Igh and Tcrb D-to-J recombination. Our findings indicate that the RAG1 NTR regulates V(D)J recombination and lymphocyte development by multiple pathways, including control of the balance between short- and long-range recombination.

中文翻译：

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RAG1 N 末端区域调节 V(D)J 重组突触的效率和途径

免疫球蛋白和 T 细胞受体基因组装取决于 RAG1-RAG2 重组酶引发的 V(D)J 重组。RAG1 N 末端区域（NTR；aa 1-383）与调节功能有关，其对 V(D)J 重组和体内淋巴细胞发育的影响知之甚少。我们生成的小鼠中，RAG1 缺乏泛素连接酶活性 (P326G)、自动泛素化的主要位点 (K233R) 或其前 215 个残基 (Δ215)。虽然在 R1.K233R 小鼠中检测到很少的异常，但 R1.P326G 小鼠表现出多种重组效率降低的特征，包括 Igκ+:Igλ+ B 细胞比率增加以及 Igh、Igκ、Igλ 和 Tcrb 位点重组减少。先前的研究表明，Igh 重组过程中重组伙伴的突触通过两种途径发生：长程扫描和短程碰撞。我们发现 R1Δ215 小鼠表现出短程 Igh 和 Tcrb D-to-J 重组减少。我们的研究结果表明，RAG1 NTR 通过多种途径调节 V(D)J 重组和淋巴细胞发育，包括控制短程重组和长程重组之间的平衡。