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Chk1 has an essential role in the survival of differentiated cortical neurons in the absence of DNA damage

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Abstract

Neuronal death in the central nervous system contributes to the development of age-related neurodegeneration. The ATR/Chk1 pathway appears to function neuroprotectively to prevent DNA damage induced by cytotoxic agents. Here, we examine the function of Chk1 on cell viability of cortical neurons in the absence of additional DNA damaging stimuli. The Chk1-specific inhibitor, UCN-01, and the ATR inhibitor, Caffeine, cause neuronal apoptosis in differentiated neurons in the absence of additional treatment, whereas inhibition of ATM or Chk2, does not. UCN-01 treatment increased the detection of γ-H2AX phosphorylation, DNA strand breaks, and an activated p53-dependent DNA damage response (DDR), suggesting that Chk1 normally helps to maintain genomic stability. UCN-01 treatment also enhanced the apoptosis seen in neurons treated with DNA damaging agents, such as camptothecin (CPT). Our results indicate that Chk1 is essential for neuronal survival, and perturbation of this pathway increases a cell’s sensitivity to naturally accumulating DNA damage.

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Acknowledgments

We thank Dr. William Oxberry for help with confocal microscopy techniques. This work was supported by a grant from the American Cancer Society to S.W.B.

Conflict of interest

The authors declare no conflict of interest.

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Author notes

  1. Weizhen Ye

    Present address: Department of Research, Hackensack University Medical Center, 30 Prospect Avenue, Hackensack, NJ, 07601, USA

Authors and Affiliations

  1. Department of Pediatrics, State University of New York, Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY, 12003, USA

    Weizhen Ye & Stacy W. Blain

  2. Department of Cell Biology, State University of New York, Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY, 12003, USA

    Weizhen Ye & Stacy W. Blain

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  1. Weizhen Ye
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Correspondence to Stacy W. Blain.

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Ye, W., Blain, S.W. Chk1 has an essential role in the survival of differentiated cortical neurons in the absence of DNA damage. Apoptosis 16, 449–459 (2011). https://doi.org/10.1007/s10495-011-0579-z

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