Lee Youngsoo, Katyal Sachin, Li Yang, El-Khamisy Sherif F, Russell Helen R, Caldecott Keith W, McKinnon Peter J
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Nat Neurosci. 2009 Aug;12(8):973-80. doi: 10.1038/nn.2375. Epub 2009 Jul 26.
Defective responses to DNA single strand breaks underlie various neurodegenerative diseases. However, the exact role of this repair pathway during the development and maintenance of the nervous system is unclear. Using murine neural-specific inactivation of Xrcc1, a factor that is critical for the repair of DNA single strand breaks, we found a profound neuropathology that is characterized by the loss of cerebellar interneurons. This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation. Loss of Xrcc1 also led to the persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function. Collectively, these data detail the in vivo link between DNA single strand break repair and neurogenesis and highlight the diverse consequences of specific types of genotoxic stress in the nervous system.
对DNA单链断裂的缺陷反应是多种神经退行性疾病的基础。然而，这种修复途径在神经系统发育和维持过程中的确切作用尚不清楚。通过对Xrcc1进行小鼠神经特异性失活（Xrcc1是DNA单链断裂修复的关键因子），我们发现了一种严重的神经病理学特征，即小脑中间神经元的丧失。这种细胞损失与p53依赖性细胞周期停滞有关，并且发生在中间神经元祖细胞开始分化时。Xrcc1的缺失还导致整个神经系统中DNA链断裂的持续存在以及海马功能异常。总体而言，这些数据详细阐述了DNA单链断裂修复与神经发生之间的体内联系，并突出了神经系统中特定类型的基因毒性应激的多种后果。
