The RAG1 N-terminal region regulates the efficiency and pathways of synapsis for V(D)J recombination

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 (Delta 215). While few abnormalities were detected in R1.K233R mice, R1.P326G mice exhibit multiple features indicative of reduced recombination efficiency, including an increased Ig kappa(+):Ig lambda(+) B cell ratio and decreased recombination of Igh, Ig kappa, Ig lambda, 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 R1 Delta 215 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.

Automated summary

The RAG1 N-terminal region regulates V(D)J recombination and lymphocyte development through multiple pathways, including control of the balance between short- and long-range recombination, as shown in studies with different RAG1 mutant mice.