4.6 Article

Context-Dependent Functions of E2F1: Cell Cycle, Cell Death, and DNA Damage Repair in Cortical Neurons

期刊

MOLECULAR NEUROBIOLOGY
卷 57, 期 5, 页码 2377-2390

出版社

SPRINGER
DOI: 10.1007/s12035-020-01887-5

关键词

Camptothecin; DNA damage; Cell cycle; Neurodegeneration; ChIPseq

资金

  1. Research Grants Council (RGC) of the HongKong SAR [16101315, 660813, AoE/M-604/16]
  2. Hong Kong University of Science and Technology [R9321]

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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(Cip1). 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.

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