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

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Abstract

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 p21Cip1. 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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Acknowledgments

We thank Dr. Hiu Tung Cheung and Ms. Pui Shuen Wong for the help with ChIPseq experiment.

Funding

This work is supported by grants from the Research Grants Council (RGC) of the Hong Kong SAR (16101315, 660813, AoE/M-604/16). Additional support was received from the Hong Kong University of Science and Technology (R9321).

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Authors and Affiliations

  1. 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

    Yang Zhang, Xuan Song & Karl Herrup

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  1. Yang Zhang
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  2. Xuan Song
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YZ and KH designed the study. YZ and XS conducted experiments. YZ, XS, and KH wrote and edited the manuscript. All authors read and approved the manuscript.

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Correspondence to Karl Herrup.

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All animal procedures were approved by Animal and Plant Care Facility of Hong Kong University of Science and Technology.

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Zhang, Y., Song, X. & Herrup, K. Context-Dependent Functions of E2F1: Cell Cycle, Cell Death, and DNA Damage Repair in Cortical Neurons. Mol Neurobiol 57, 2377–2390 (2020). https://doi.org/10.1007/s12035-020-01887-5

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