Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University, Rome, Italy.
Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
Cell Death Dis. 2018 Feb 22;9(3):314. doi: 10.1038/s41419-018-0357-8.
Hereditary deficiencies in DNA damage signaling are invariably associated with cancer predisposition, immunodeficiency, radiation sensitivity, gonadal abnormalities, premature aging, and tissue degeneration. ATM kinase has been established as a central player in DNA double-strand break repair and its deficiency causes ataxia telangiectasia, a rare, multi-system disease with no cure. So ATM represents a highly attractive target for the development of novel types of gene therapy or transplantation strategies. Atm tamoxifen-inducible mouse models were generated to explore whether Atm reconstitution is able to restore Atm function in an Atm-deficient background. Body weight, immunodeficiency, spermatogenesis, and radioresistance were recovered in transgenic mice within 1 month from Atm induction. Notably, life span was doubled after Atm restoration, mice were protected from thymoma and no cerebellar defects were observed. Atm signaling was functional after DNA damage in vivo and in vitro. In summary, we propose a new Atm mouse model to investigate novel therapeutic strategies for ATM activation in ataxia telangiectasia disease.
遗传性 DNA 损伤信号缺陷与癌症易感性、免疫缺陷、辐射敏感性、性腺异常、早衰和组织退化等疾病密切相关。ATR 激酶已被确定为 DNA 双链断裂修复的核心分子，ATR 缺陷会导致共济失调毛细血管扩张症，这是一种罕见的多系统疾病，目前尚无治愈方法。因此，ATR 是开发新型基因治疗或移植策略的极具吸引力的靶点。为了探索 Atm 重建是否能够恢复 Atm 缺陷背景下的 Atm 功能，我们生成了 Atm 他莫昔芬诱导型小鼠模型。从 Atm 诱导后 1 个月内，转基因小鼠的体重、免疫缺陷、精子发生和辐射抗性得到恢复。值得注意的是，Atm 恢复后，小鼠的寿命延长了一倍，免受胸腺瘤的侵害，且未观察到小脑缺陷。Atm 信号在体内和体外的 DNA 损伤后仍然具有功能。总之，我们提出了一种新的 Atm 小鼠模型，用于研究共济失调毛细血管扩张症疾病中 ATM 激活的新治疗策略。
