RAG1

RAG1, or Recombination Activating Gene 1, encodes a nuclease essential for initiating V(D)J recombination in developing B and T lymphocytes. Together with its partner RAG2, RAG1 forms a DNA-cleaving complex that recognizes recombination signal sequences flanking V, D, and J gene segments to generate diverse antigen receptor genes.

The RAG1–RAG2 complex introduces site-specific double-strand breaks at RSS, producing hairpin-sealed coding ends and blunt signal ends. This cleavage is the first step in the non-homologous end joining pathway that repairs the breaks and enables rearrangement of the immunoglobulin and T-cell receptor loci.

RAG1 is primarily expressed during specific stages of lymphoid development in the bone marrow and thymus, and its activity is tightly regulated to ensure proper timing and fidelity of recombination. The catalytic component of the complex is concentrated in RAG1, which contains a DNA-cleavage domain related to DDE-type endonucleases, while RAG2 assists with DNA binding and substrate recognition. Accessory factors such as HMGB1/2 help bend DNA to facilitate cleavage.

Mutations in RAG1 have important clinical consequences. Germline RAG1 defects can cause severe combined immunodeficiency (SCID) and related disorders; hypomorphic mutations may allow partial recombination and residual lymphocyte development, sometimes presenting as Omenn syndrome. Treatments include hematopoietic stem cell transplantation, with ongoing research into gene therapy approaches.

RAG1 and RAG2 are considered to have evolved from transposase-like enzymes and are conserved components of the vertebrate adaptive immune system. The genes are located on chromosome 11 in humans and are studied extensively in model organisms such as mice to understand their function and regulation.