Leaky Severe Combined Immunodeficiency in Mice Lacking Non-homologous End Joining Factors XLF and MRI

• DOI: 10.20944/preprints202009.0145.v1
• Publication Date: 2020-09-07T05:38:27Z
• Authors: Sergio Castaneda-...; Qindong Zhang; Amin Alirezaylava...; Marion Fernandez-...; Rouan Yao; Valentyn Oksenych
• Keywords: Ku80; Ku70; Non-homologous end joining

Non-homologous end-joining (NHEJ) is a DNA repair pathway required to detect, process, and ligate double-stranded breaks (DSBs) throughout the cell cycle. The NHEJ necessary for V(D)J recombination in developing B T lymphocytes. During NHEJ, Ku70 Ku80 form heterodimer that recognizes DSBs promotes recruitment function of downstream factors PAXX, MRI, DNA-PKcs, Artemis, XLF, XRCC4, LIG4. Mutations several known genes result severe combined immunodeficiency (SCID). Inactivation Mri, Paxx or Xlf mice results normal mild phenotype, while inactivation Xlf/Mri, Xlf/Paxx, Xlf/Dna-pkcs leads late embryonic lethality. Here, we describe three new mouse models. We demonstrate deletion Trp53 rescues lethality with deficiencies Mri. Furthermore, Xlf-/-Mri-/-Trp53+/- Xlf-/-Paxx-/-Trp53+/- possess reduced body weight, severely mature lymphocyte counts, accumulation progenitor cells. also report Mri/Paxx live-born modest Mri/Dna-pkcs Therefore, conclude XLF functionally redundant MRI PAXX during development vivo. Moreover, Mri genetically interacts Dna-pkcs Paxx.