Abstract
The repair of DNA double-stranded breaks (DNAdsb) through non-homologous end joining (NHEJ) is a prerequisite for the proper development of the central nervous system and the adaptive immune system. Yet, mice with Xlf or PAXX loss of function are viable and present with very mild immune phenotypes, although their lymphoid cells are sensitive to ionizing radiation attesting for the role of these factors in NHEJ. In contrast, we show here that mice defective for both Xlf and PAXX are embryonically lethal owing to a massive apoptosis of post-mitotic neurons, a situation reminiscent to XRCC4 or DNA Ligase IV KO conditions. The development of the adaptive immune system in Xlf−/−PAXX−/− E18.5 embryos is severely affected with the block of B- and T-cell maturation at the stage of IgH and TCRβ gene rearrangements, respectively. This damaging phenotype highlights the functional nexus between Xlf and PAXX, which is critical for the completion of NHEJ-dependent mechanisms during mouse development.
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Acknowledgements
We thank Catherine Cailleau (SEAT) for exceptional care of our mouse lines, Sophie Berissi for help in immunohistochemistry and Olivier Alibeu, Aurore Pouliet, and Christine Bole-Feyssot (Genomic facility, Imagine Institute) for their assistance in NGS. This work was supported by institutional grants from INSERM, the Institut National du Cancer (PLBIO16-280), the Agence Nationale de la Recherche ('Investissement d’Avenir' program ANR-10-IAHU-01), and by grants from La Ligue Nationale contre le Cancer (Equipe Labellisée LA LIGUE), Pasteur Institute, ANR (Program REVIVE and grant Twothyme) to AC.
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Abramowski, V., Etienne, O., Elsaid, R. et al. PAXX and Xlf interplay revealed by impaired CNS development and immunodeficiency of double KO mice. Cell Death Differ 25, 444–452 (2018). https://doi.org/10.1038/cdd.2017.184
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DOI: https://doi.org/10.1038/cdd.2017.184
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