Severe immunodeficiency in mice lacking DNA repair factors XLF and Mri

Non-homologous end joining (NHEJ) is a DNA repair pathway that is 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, core factors Ku70 and Ku80 form a heterodimer called Ku, which 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 can result in immunodeficient phenotypes, including severe combined immunodeficiency (SCID). Inactivation of Mri, Paxx or Xlf in mice results in normal or mild phenotype, while combined inactivation of Xlf/Mri, Xlf/Paxx, or Xlf/Dna-pkcs leads to late embryonic lethality. Here, we demonstrated that deletion of pro-apoptotic factor Trp53 rescues embryonic lethality in mice with combined deficiency of Xlf and Mri. Furthermore, Xlf-/-Mri-/-Trp53+/- mice possessed reduced body weight, severely reduced mature B and T cell counts in the spleen and thymus, and accumulation of progenitor B cells in the bone marrow. Therefore, we conclude that Mri is functionally redundant with XLF during B and T lymphocyte development in vivo, and that Xlf-/-Mri-/-Trp53+/- mice possess a leaky SCID phenotype.