recombinationactivating

Recombination activating genes, commonly abbreviated as RAG1 and RAG2, encode the recombination-activating endonuclease that initiates V(D)J recombination in jawed vertebrates. This process is essential for generating the diverse repertoire of B cell receptors and T cell receptors that underlies adaptive immunity.

The RAG1/RAG2 complex binds to recombination signal sequences (RSS) flanking V, D, and J gene segments. It introduces site-specific double-strand breaks between a coding segment and its adjacent RSS, forming blunt signal ends and a covalently closed coding end hairpin. The system follows the 12/23 rule, in which RSSs with a 12-base-pair spacer pair with those carrying a 23-base-pair spacer to enable correct assortment of segments.

RAG1 is the catalytic component of the complex, while RAG2 serves as an essential cofactor that stabilizes DNA binding and facilitates cleavage. After cleavage, hairpins are opened and processed by the Artemis nuclease in conjunction with DNA-PK, and the resulting coding ends and signal ends are joined by the non-homologous end joining (NHEJ) pathway, generating coding and signal joints that complete V(D)J recombination.

Expression of RAG1 and RAG2 is tightly regulated and largely restricted to developing lymphocytes (pro-B/pre-B and pro-T/pre-T cells). The activity of these genes is a major contributor to receptor diversity in B and T cells.

Evolutionarily, RAG1 and RAG2 are believed to derive from domesticated transposase genes and are found in jawed vertebrates, with homologous mechanisms in other species limited or absent. Disorders of RAG function cause severe immunodeficiency, most notably RAG deficiency leading to SCID; hypomorphic mutations can result in Omenn syndrome or other immunodeficiencies. Research on recombination-activating genes informs immunology, genetics, and gene therapy approaches.