Difilippantonio Simone, Celeste Arkady, Fernandez-Capetillo Oscar, Chen Hua-Tang, Reina San Martin Bernardo, Van Laethem Francois, Yang Yong-Ping, Petukhova Galina V, Eckhaus Michael, Feigenbaum Lionel, Manova Katia, Kruhlak Michael, Camerini-Otero R Daniel, Sharan Shyam, Nussenzweig Michel, Nussenzweig André
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Nat Cell Biol. 2005 Jul;7(7):675-85. doi: 10.1038/ncb1270. Epub 2005 Jun 19.
Nijmegen breakage syndrome (NBS) is a chromosomal fragility disorder that shares clinical and cellular features with ataxia telangiectasia. Here we demonstrate that Nbs1-null B cells are defective in the activation of ataxia-telangiectasia-mutated (Atm) in response to ionizing radiation, whereas ataxia-telangiectasia- and Rad3-related (Atr)-dependent signalling and Atm activation in response to ultraviolet light, inhibitors of DNA replication, or hypotonic stress are intact. Expression of the main human NBS allele rescues the lethality of Nbs1-/- mice, but leads to immunodeficiency, cancer predisposition, a defect in meiotic progression in females and cell-cycle checkpoint defects that are associated with a partial reduction in Atm activity. The Mre11 interaction domain of Nbs1 is essential for viability, whereas the Forkhead-associated (FHA) domain is required for T-cell and oocyte development and efficient DNA damage signalling. Reconstitution of Nbs1 knockout mice with various mutant isoforms demonstrates the biological impact of impaired Nbs1 function at the cellular and organismal level.
奈梅亨断裂综合征（NBS）是一种染色体脆性疾病，与共济失调毛细血管扩张症具有临床和细胞特征。我们在此证明，Nbs1基因缺失的B细胞在受到电离辐射时，共济失调毛细血管扩张症突变（Atm）的激活存在缺陷，而共济失调毛细血管扩张症及Rad3相关（Atr）依赖性信号传导以及对紫外线、DNA复制抑制剂或低渗应激的Atm激活则保持完整。主要人类NBS等位基因的表达挽救了Nbs1-/-小鼠的致死性，但导致免疫缺陷和癌症易感性，女性减数分裂进程存在缺陷以及细胞周期检查点缺陷，这些缺陷与Atm活性部分降低有关。Nbs1的Mre11相互作用结构域对生存能力至关重要，而叉头相关（FHA）结构域对T细胞和卵母细胞发育以及有效的DNA损伤信号传导是必需的。用各种突变异构体重建Nbs1基因敲除小鼠证明了Nbs1功能受损在细胞和机体水平上的生物学影响。
