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 required for the V(D)J recombination in developing B and T lymphocytes. During the NHEJ, the core factors Ku70 and Ku80 form a heterodimer called Ku, which recognizes DSBs and promotes the recruitment of accessory factors (e.g., PAXX, Mri, Dna-pkcs, Artemis) and downstream core factors XLF, XRCC4, and Lig4. Mutations in NHEJ genes result in immunodeficiency. Deletion of individual NHEJ genes Mri, Paxx or Xlf in mice resulted in no or modest phenotype, while combined inactivation of Xlf and Mri, or Xlf and Paxx, led to late embryonic lethality. Here, we demonstrated that the deletion of pro-apoptotic factor Trp53 rescued the embryonic lethality of mice with combined deficiencies in Xlf and Mri. The Xlf-/-Mri-/-Trp53+/- mice possessed reduced body weight, severely reduced B and T cell lymphocyte counts in spleen and thymus, and accumulation of progenitor B cells in the bone marrow. To the contrary, combined inactivation of Mri and Paxx resulted in live-born mice with phenotype not distinguishable from Mri-deficient mice. We concluded that Mri is functionally redundant with XLF during the B and T lymphocyte development in vivo.