Regulation and Evolution of the RAG Recombinase.

The modular, noncontiguous architecture of the antigen receptor genes necessitates their assembly through V(D)J recombination. This program of DNA breakage and rejoining occurs during early lymphocyte development, and depends on the RAG1 and RAG2 proteins, whose collaborative endonuclease activity targets specific DNA motifs enriched in the antigen receptor loci. This essential gene shuffling reaction requires lymphocytes to traverse several developmental stages wherein DNA breakage is tolerated, while minimizing the expense to overall genome integrity. Thus, RAG activity is subject to stringent temporal and spatial regulation. The RAG proteins themselves also contribute autoregulatory properties that coordinate their DNA cleavage activity with target chromatin structure, cell cycle status, and DNA repair pathways. Even so, lapses in regulatory restriction of RAG activity are apparent in the aberrant V(D)J recombination events that underlie many lymphomas. In this review, we discuss the current understanding of the RAG endonuclease, its widespread binding in the lymphocyte genome, its noncleavage activities that restrain its enzymatic potential, and the growing evidence of its evolution from an ancient transposase.