Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI.

Non-homologous end-joining (NHEJ) is a DNA repair pathway required to detect, process, and ligate DNA double-stranded breaks (DSBs) throughout the cell cycle. The NHEJ pathway is necessary for V(D)J recombination in developing B and T lymphocytes. During NHEJ, Ku70 and Ku80 form a heterodimer that recognizes DSBs and promotes recruitment and function of downstream factors PAXX, MRI, DNA-PKcs, Artemis, XLF, XRCC4, and LIG4. Mutations in several known NHEJ genes result in severe combined immunodeficiency (SCID). Inactivation of or in mice results in normal or mild phenotype, while combined inactivation of or / leads to late embryonic lethality. Here, we describe three new mouse models. We demonstrate that deletion of rescues embryonic lethality in mice with combined deficiencies of and . Furthermore, and mice possess reduced body weight, severely reduced mature lymphocyte counts, and accumulation of progenitor B cells. We also report that combined inactivation of results in live-born mice with modest phenotype, and combined inactivation of results in embryonic lethality. Therefore, we conclude that XLF is functionally redundant with MRI and PAXX during lymphocyte development Moreover, genetically interacts with and