Congenital defects in V(D)J recombination

The V(D)J recombination is a DNA rearrangement process that generates the diversity of T and B lymphocyte immune repertoire. It proceeds through the generation of a DNA double-strand break (DNA-DSB) by the Rag1/2 lymphoid-specific factors, which is repaired by the non-homologous end joining (NHEJ) DNA repair pathway. V(D)J recombination also constitutes a checkpoint in the lymphoid development. V(D)J recombination defect results in severe combined immune deficiency (SCID) with a lack of T and B lymphocytes. The V(D)J recombination represents one of the few programmed molecular events leading to DNA-DSBs that strictly relies on NHEJ. Two NHEJ factors, Artemis and XLF/Cernunnos, were identified through the molecular studies of SCID patients. Mutations in PRKDC and DNA Ligase IV genes also result in SCID. Studies in mice have demonstrated that XLF/Cernunnos is dispensable for V(D)J recombination in lymphoid cells but not for the repair of genotoxic-induced DNA-DSBs, which raises the question of the implication of Rag1/2 factors in the DNA repair phase of V(D)J recombination. New factors of NHEJ, such as PAXX, are being identified. Patients with NHEJ deficiency (XRCC4) without immune deficiency were recently reported. We, therefore, may not have yet the complete picture of DNA-DSB repair in the context of V(D)J recombination.