Non-homologous End Joining - V(D)J Recombination

V(D)J Recombination

NHEJ plays a critical role in V(D)J recombination, the process by which B-cell and T-cell receptor diversity is generated in the vertebrate immune system. In V(D)J recombination, hairpin-capped double-strand breaks are created by the RAG1/RAG2 nuclease, which cleaves the DNA at recombination signal sequences. These hairpins are then opened by the Artemis nuclease and joined by NHEJ. A specialized DNA polymerase called terminal deoxynucleotidyl transferase (TdT), which is only expressed in lymph tissue, adds nontemplated nucleotides to the ends before the break is joined. This process couples "variable" (V), "diversity" (D), and "joining" (J) regions, which when assembled together create the variable region of a B-cell or T-cell receptor gene. Unlike typical cellular NHEJ, in which accurate repair is the most favorable outcome, error-prone repair in V(D)J recombination is beneficial in that it maximizes diversity in the coding sequence of these genes. Patients with mutations in NHEJ genes are unable to produce functional B cells and T cells and suffer from severe combined immunodeficiency (SCID).