Abstract
Nitric-oxide synthase (NOS) activity has been detected in many human tumours, although its function is unclear. Here we show that exposure of cells to nitric oxide (NO) results in a 4–5-fold increase in expression of the DNA-dependent protein-kinase catalytic subunit (DNA-PKcs), one of the key enzymes involved in repairing double-stranded DNA breaks. This NO-mediated increase in enzymatically active DNA-PK not only protects cells from the toxic effects of NO, but also provides crossprotection against clinically important DNA-damaging agents, such as X-ray radiation, adriamycin, bleomycin and cisplatin. The NO-mediated increase in DNA-PKcs described here demonstrates the presence of a new and highly effective NO-mediated mechanism for DNA repair.
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Acknowledgements
We thank C. Jenkins and S. Jackson for discussions, C. W. Anderson (Brookhaven National Laboratory, New York) for DNA-PKcs promoter–reporter plasmids, R. Tjian (Howard Hughes Medical Institute, Berkeley, Illinois) for pPacSp1 and pPacO plasmids and M. J. Allalunis-Turner for cell lines M059J and M059K. We also thank D. Sheer for help in the use of the X-ray facility at the ICRF, London. This work was supported by a grant from the Medical Research Council.
Correspondence and requests for materials should be addressed to I.G.C.
Supplementary information is available on Nature Cell Biology’s website (http://www.nature.com/ncb) or as paper copy from the London editorial office of Nature Cell Biology.
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Xu, W., Liu, L., Smith, G. et al. Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumour agents. Nat Cell Biol 2, 339–345 (2000). https://doi.org/10.1038/35014028
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DOI: https://doi.org/10.1038/35014028
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