RAG2 abolishes RAG1 aggregation to facilitate V(D)J recombination

RAG1 and RAG2 form a tetramer nuclease to initiate V(D)J recombination in developing T and B lymphocytes. The RAG1 protein evolves from a transposon ancestor and possesses nuclease activity that requires interaction with RAG2. Here, we show that the human RAG1 protein aggregates in the nucleus in the absence of RAG2, exhibiting a extremely low V(D)J recombination activity. In contrast, RAG2 does not aggregate by itself, but it interacts with RAG1 to disrupt RAG1 aggregates and thereby to activate robust V(D)J recombination. Moreover, RAG2 from mouse and zebrafish could not disrupt the aggregation of human RAG1 as efficiently as human RAG2 did, indicating a species-specific regulatory mechanism for RAG1 by RAG2. Therefore, we propose that RAG2 coevolves with RAG1 to release inert RAG1 from aggregates and thereby activate V(D)J recombination to generate diverse antigen receptors in lymphocytes. PEM-seq sequencing was used for detecting the catalytic activity of human RAG complex . The Sample name and Species ,cell lines and treatment were listed at a Excell table. Qrignal sequencing and processed data were loaded at the datafiles. The processed data was used the superQ scripts as the descripted (Yin et al., 2019; Liu et al., 2021).