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 ofMri, PaxxorXlfin mice results in normal or mild phenotype, while combined inactivation ofXlf/Mri, Xlf/Paxx, orXlf/Dna-pkcsleads to late embryonic lethality. Here, we describe three new mouse models. We demonstrate that deletion ofTrp53rescues embryonic lethality in mice with combined deficiencies ofXlfandMri. Furthermore,Xlf^-/-Mri^-/-Trp53^+/-andXlf^-/-Paxx^-/-Trp53^+/-mice possess reduced body weight, severely reduced mature lymphocyte counts, and accumulation of progenitor B cells. We also report that combined inactivation ofMri/Paxxresults in live-born mice with modest phenotype, and combined inactivation ofMri/Dna-pkcsresults in embryonic lethality. Therefore, we conclude that XLF is functionally redundant with MRI and PAXX during lymphocyte developmentin vivo. Moreover,Mrigenetically interacts withDna-pkcsandPaxx.