Lee Y, Barnes D E, Lindahl T, McKinnon P J
Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Genes Dev. 2000 Oct 15;14(20):2576-80. doi: 10.1101/gad.837100.
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.
共济失调毛细血管扩张症由ATM基因突变引起，其特征为严重的神经退行性变以及对DNA损伤的反应缺陷。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致死，这表明在神经系统发育过程中会发生内源性形成的DNA双链断裂。在此，我们报告Atm对于DNA连接酶IV缺陷的发育中神经系统所有区域的细胞凋亡是必需的。然而，Atm缺陷未能挽救DNA连接酶IV基因敲除小鼠免疫分化的缺陷。这些数据表明，ATM对内源性DNA损伤作出反应，并在发育过程中发挥作用以消除遭受基因组损伤的神经细胞。因此，ATM对于预防神经系统中DNA损伤细胞的积累可能很重要，而这些细胞的积累最终可能导致共济失调毛细血管扩张症中观察到的神经退行性变。
