Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, Norway.
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Aging (Albany NY). 2020 Dec 7;12(23):23578-23597. doi: 10.18632/aging.202346.
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 or in mice results in normal or mild phenotype, while combined inactivation of or / leads to late embryonic lethality. Here, we describe three new mouse models. We demonstrate that deletion of rescues embryonic lethality in mice with combined deficiencies of and . Furthermore, and mice possess reduced body weight, severely reduced mature lymphocyte counts, and accumulation of progenitor B cells. We also report that combined inactivation of results in live-born mice with modest phenotype, and combined inactivation of results in embryonic lethality. Therefore, we conclude that XLF is functionally redundant with MRI and PAXX during lymphocyte development Moreover, genetically interacts with and
非同源末端连接 (NHEJ) 是一种在整个细胞周期中检测、加工和连接 DNA 双链断裂 (DSB) 的 DNA 修复途径。NHEJ 途径对于发育中的 B 和 T 淋巴细胞中的 V(D)J 重组至关重要。在 NHEJ 过程中，Ku70 和 Ku80 形成异二聚体，识别 DSB 并促进下游因子 PAXX、MRI、DNA-PKcs、Artemis、XLF、XRCC4 和 LIG4 的募集和功能。几个已知的 NHEJ 基因的突变导致严重联合免疫缺陷 (SCID)。或 在小鼠中的失活导致正常或轻度表型，而 或 / 的联合失活导致胚胎晚期致死。在这里，我们描述了三个新的小鼠模型。我们证明，在 和 双重缺陷的小鼠中， 的缺失可挽救胚胎致死性。此外， 和 小鼠体重减轻，成熟淋巴细胞计数严重减少，祖 B 细胞积累。我们还报告说， 联合失活导致出生后具有适度表型的小鼠，而 联合失活导致胚胎致死。因此，我们得出结论，XLF 在淋巴细胞发育过程中与 MRI 和 PAXX 具有功能冗余性。此外， 与 和
