RAG1RAG2

RAG1 and RAG2 are genes that encode the recombination-activating proteins RAG1 and RAG2, which together form a core complex essential for V(D)J recombination. This process generates the diverse antigen receptors used by B cells and T cells, enabling the adaptive immune response.

The RAG1–RAG2 complex recognizes recombination signal sequences flanking variable (V), diversity (D), and joining (J) gene segments. It introduces DNA double-strand breaks at these sites and initiates rearrangement that creates diverse variable regions of immunoglobulin and T-cell receptor genes. In the coding segments, the breaks are processed into hairpin structures, while the ends associated with the signal sequences are joined. The joining steps rely on the non-homologous end joining pathway.

RAG1 is the catalytic subunit responsible for DNA cleavage, while RAG2 acts as a regulatory partner and enhances activity. RAG2 contains a plant homeodomain (PHD) finger that binds histone H3 trimethylated at lysine 4 (H3K4me3), linking recombination to chromatin state and accessibility. RAG activity is developmentally restricted to early B and T cell precursors and is coordinated with other signaling pathways that govern lymphoid maturation.

Clinical significance is marked by defects in RAG1 or RAG2, which can cause severe combined immunodeficiency (SCID). Hypomorphic mutations may lead to Omenn syndrome or leaky SCID, characterized by partial immune function and autoimmune features. Evolutionarily, RAG1 and RAG2 are derived from a transposable element and are conserved in jawed vertebrates as the engine of adaptive immune receptor diversification.