Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI
Autor: | Rouan Yao, Valentyn Oksenych, Qindong Zhang, Sergio Castañeda-Zegarra, Amin Alirezaylavasani, Marion Fernandez-Berrocal |
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Rok vydání: | 2020 |
Předmět: |
Aging
DNA End-Joining Repair Ku80 DNA repair T cell VDP::Mathematics and natural science: 400::Basic biosciences: 470::Cell biology: 471 DNA-Activated Protein Kinase lymphocyte LIG4 Biology medicine Animals Genetic Predisposition to Disease genetics Lymphocytes NHEJ Mice Knockout Ku70 Severe combined immunodeficiency cyren Body Weight fungi Cell Biology Cell cycle DNA repair protein XRCC4 medicine.disease Phenotype Cell biology DNA-Binding Proteins Non-homologous end joining enzymes and coenzymes (carbohydrates) cernunnos medicine.anatomical_structure pro-B cells Severe Combined Immunodeficiency Tumor Suppressor Protein p53 Research Paper VDP::Matematikk og Naturvitenskap: 400::Basale biofag: 470::Cellebiologi: 471 |
Zdroj: | 23578-23597 Aging Aging (Albany NY) |
ISSN: | 1945-4589 |
Popis: | 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 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 describe three new mouse models. We demonstrate that deletion of Trp53 rescues embryonic lethality in mice with combined deficiencies of Xlf and Mri. Furthermore, Xlf-/-Mri-/-Trp53+/- and Xlf-/-Paxx-/-Trp53+/- mice possess reduced body weight, severely reduced mature lymphocyte counts, and accumulation of progenitor B cells. We also report that combined inactivation of Mri/Paxx results in live-born mice with modest phenotype, and combined inactivation of Mri/Dna-pkcs results in embryonic lethality. Therefore, we conclude that XLF is functionally redundant with MRI and PAXX during lymphocyte development in vivo. Moreover, Mri genetically interacts with Dna-pkcs and Paxx. |
Databáze: | OpenAIRE |
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