Laboratory "Genome Dynamics in the Immune System", INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
Laboratoire de Radiopathologie, UMR 967, DRF, CEA-INSERM-Université Paris Diderot-Université Paris Sud, Fontenay-aux-Roses, Paris, France.
Cell Death Differ. 2018 Feb;25(2):444-452. doi: 10.1038/cdd.2017.184. Epub 2017 Oct 27.
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 XlfPAXX 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.
通过非同源末端连接（NHEJ）修复 DNA 双链断裂（DNAdsb）是中枢神经系统和适应性免疫系统正常发育的前提。然而，Xlf 或 PAXX 功能丧失的小鼠具有生存能力，并且表现出非常轻微的免疫表型，尽管它们的淋巴细胞对电离辐射敏感，这证明了这些因素在 NHEJ 中的作用。相比之下，我们在这里表明，由于有丝分裂后神经元的大量凋亡，Xlf 和 PAXX 均有缺陷的小鼠在胚胎期致死，这种情况类似于 XRCC4 或 DNA 连接酶 IV KO 条件。XlfPAXX E18.5 胚胎中适应性免疫系统的发育受到严重影响，B 细胞和 T 细胞成熟分别在 IgH 和 TCRβ 基因重排阶段受阻。这种损伤表型突出了 Xlf 和 PAXX 之间的功能联系，这对于完成小鼠发育过程中依赖 NHEJ 的机制至关重要。
