Division of Life Science and the State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
Mol Neurobiol. 2020 May;57(5):2377-2390. doi: 10.1007/s12035-020-01887-5. Epub 2020 Feb 15.
DNA damage has been reported to induce cell cycle-related neuronal death. This is significant as aberrant cell cycle re-entry of mature, post-mitotic neurons contributes to neurodegeneration. In this study, we investigate how DNA damage elicited by exposure to the topoisomerase I inhibitor camptothecin (CPT) leads to cycle-related death of cultured cortical neurons and examine the function of E2F1 in this process. CPT treatment induced cell cycle initiation of cortical neurons and elevated the expression of certain cell cycle components (e.g., cyclin D1, CDK4, E2F1) but failed to drive S phase entry or DNA synthesis. The arrest in the cell cycle is explained by the elevated expression of the CDK inhibitor p21. Though its level was increased after CPT treatment, E2F1 did not drive treated neurons into the G1-S phase transition. E2F1 overexpression led to cell cycle activation and acute neuronal apoptosis without detectable entry of the neurons into S phase. ChIPseq analysis demonstrated that E2F1 predominantly occupies positions on or near the promoters of cell cycle related genes. Instead, in CPT-treated neurons, E2F1 preferentially regulated DNA repair related genes. Our study reveals that the functions of E2F1 in postmitotic neurons are context-dependent and offers novel insights into the role of E2F1 in DNA damage induced cycle-related neuronal death.
DNA 损伤已被报道可诱导与细胞周期相关的神经元死亡。这是重要的，因为成熟的、有丝分裂后的神经元的异常细胞周期再进入导致神经退行性变。在这项研究中，我们研究了拓扑异构酶 I 抑制剂喜树碱 (CPT) 引起的 DNA 损伤如何导致培养的皮质神经元与细胞周期相关的死亡，并研究了 E2F1 在这一过程中的功能。CPT 处理诱导皮质神经元的细胞周期起始，并提高某些细胞周期成分（如周期蛋白 D1、CDK4、E2F1）的表达，但未能驱动 S 期进入或 DNA 合成。细胞周期的阻滞可以通过 CDK 抑制剂 p21 的表达上调来解释。尽管其水平在 CPT 处理后增加，但 E2F1 并没有将处理后的神经元驱动进入 G1-S 期过渡。E2F1 的过表达导致细胞周期激活和急性神经元凋亡，而神经元没有进入 S 期的可检测。ChIPseq 分析表明，E2F1 主要占据细胞周期相关基因的启动子或其附近的位置。相反，在 CPT 处理的神经元中，E2F1 优先调节 DNA 修复相关基因。我们的研究揭示了 E2F1 在有丝分裂后神经元中的功能是上下文依赖的，并为 E2F1 在 DNA 损伤诱导的与细胞周期相关的神经元死亡中的作用提供了新的见解。
