RT Journal Article
SR Electronic
T1 Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.04.976829
DO 10.1101/2020.03.04.976829
A1 Sergio Castañeda-Zegarra
A1 Qindong Zhang
A1 Amin Alirezaylavasani
A1 Marion Fernandez-Berrocal
A1 Rouan Yao
A1 Valentyn Oksenych
YR 2020
UL http://biorxiv.org/content/early/2020/07/18/2020.03.04.976829.abstract
AB 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, these 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. Combined inactivation of Mri and Paxx results in live-born mice with modest B cell phenotype. In contrast, combined inactivation of Mri and Dna-pkcs results in embryonic lethality. 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.Competing Interest StatementThe authors have declared no competing interest.