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Artemis is a negative regulator of p53 in response to oxidative stress

Oncogene volume 28, pages 2196–2204 (2009)Cite this article

Abstract

Artemis is a multifunctional phospho-protein with roles in V(D)J recombination, repair of double-strand breaks by nonhomologous end-joining and regulation of cell-cycle checkpoints after DNA damage. Here, we describe a new function of Artemis as a negative regulator of p53 in response to oxidative stress in both primary cells and cancer cell lines. We show that depletion of Artemis under typical culture conditions (21% oxygen) leads to a spontaneous phosphorylation and stabilization of p53, and resulting cellular G1 arrest and apoptosis. These effects are suppressed by co-depletion of DNA-PKcs, but not ATM, indicating that Artemis is an inhibitor of DNA–PKcs-mediated stabilization of p53. Culturing of cellsat 3% oxygen or treatment with an antioxidant abrogated p53 stabilization, indicating that oxidative stress is the responsible cellular stimulus. Treatment with ionizing radiation or hydrogen peroxide did not cause activation of this signaling pathway, whereas inhibitors of mitochondrial electron transport were effective in reducing its activation. In addition, we show that p53-inducible genes involved in reducing reactive oxygen species are upregulated by Artemis depletion. These findings indicate that Artemis and DNA-PKcs participate in a new, signaling pathway to modulate p53 function in response to oxidative stress produced by mitochondrial respiration.

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Acknowledgements

We thank G Lozano for helpful discussions of the paper. This work was supported by National Cancer Institute grant CA096574 (RJL).

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Author notes

  1. L Geng

    Present address: 2Current address: Department of Oncology, and the Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.,

  2. Y Zhu

    Present address: 3Current address: Department of Ophthalmology, Sir Run Run Shaw Hospital, Zhejiang Unviersity, Hangzhou, China.,

Authors and Affiliations

  1. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    X Zhang, Y Zhu, L Geng, H Wang & R J Legerski

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  1. X Zhang
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  3. L Geng
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Correspondence to R J Legerski.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Zhang, X., Zhu, Y., Geng, L. et al. Artemis is a negative regulator of p53 in response to oxidative stress. Oncogene 28, 2196–2204 (2009). https://doi.org/10.1038/onc.2009.100

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