Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm
Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm
复制标题
DOI：
10.1101/gad.837100
复制
发表时间：
2000-10-15
影响因子：
10.5
通讯作者：
McKinnon, PJ
中科院分区：
文献类型：
--
作者：
Lee, Y;Barnes, DE;McKinnon, PJ
共济失调毛细血管扩张症是由ATM突变引起的，其特征是严重的神经变性和对DNA损伤的缺陷反应。某些DNA修复基因如DNA连接酶IV的失活会导致小鼠大量神经元凋亡和胚胎死亡，这表明在神经系统发育过程中发生了内源性DNA双链断裂。在此，我们报道了在发育中的DNA连接酶IV缺陷的神经系统中，ATM对于所有区域的细胞凋亡都是必需的。然而，ATM缺乏未能挽救DNA连接酶IV缺失小鼠的免疫分化缺陷。这些数据表明，ATM对内源性DNA损伤做出反应，并在发育过程中发挥功能，以消除已引起基因组损伤的神经细胞。因此，ATM对于防止DNA损伤细胞在神经系统中积累可能最终导致共济失调毛细血管扩张所观察到的神经退行性变可能是重要的。
Ataxia telangiectasia results from mutations of ATM and is characterized by severe neurodegeneration and defective responses to DNA damage. Inactivation of certain DNA repair genes such as DNA ligase IV results in massive neuronal apoptosis and embryonic lethality in the mouse, indicating the occurrence of endogenously formed DNA double-strand breaks during nervous system development. Here we report that Atm is required for apoptosis in all areas of the DNA ligase IV-deficient developing nervous system. However, Atm deficiency failed to rescue deficits in immune differentiation in DNA ligase IV-null mice. These data indicate that ATM responds to endogenous DNA lesions and functions during development to eliminate neural cells that have incurred genomic damage. Therefore, ATM could be important for preventing accumulation of DNA-damaged cells in the nervous system that might eventually lead to the neurodegeneration observed in ataxia telangiectasia.