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Inhibition of RNA polymerase II as a trigger for the p53 response

Oncogene volume 18, pages 583–592 (1999)Cite this article

Abstract

The mechanisms by which the p53 response is triggered following exposure to DNA-damaging agents have not yet been clearly elucidated. We and others have previously suggested that blockage of RNA polymerase II may be the trigger for induction of the p53 response following exposure to ultraviolet light. Here we report on the correlation between inhibition of mRNA synthesis and the induction of p53, p21WAF1 and apoptosis in diploid human fibroblasts treated with either UV light, cisplatin or the RNA synthesis inhibitors actinomycin D, DRB, H7 and α-amanitin. Exposure to ionizing radiation or the proteasome inhibitor LLnL, however, induced p53 and p21WAF1 without affecting mRNA synthesis. Importantly, induction of p53 by the RNA synthesis or proteasome inhibitors did not correlate with the induction of DNA strand breaks. Furthermore, cisplatin-induced accumulation of active p53 in repair-deficient XP-A cells occurred despite the lack of DNA strand break induction. Our results suggest that the induction of the p53 response by certain toxic agents is not triggered by DNA strand breaks but rather, may be linked to inhibition of mRNA synthesis either directly by the poisoning of RNA polymerase II or indirectly by the induction of elongation-blocking DNA lesions.

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Acknowledgements

We would like to thank Ted Lawrence, Al Rehemtulla and Steve Ethier for support and valuable discussions throughout this project. This work was supported by a seed grant from the Michigan Memorial-Phoenix Project (#836), by a grant from the University of Michigan Comprehensive Cancer Center's Institutional Grant from the American Cancer Society and from start-up funds supplied by the Department of Radiation Oncology, University of Michigan. AJR was supported by the National Cancer Institute of Canada.

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  1. Department of Radiation Oncology, Division of Cancer Biology, University of Michigan Comprehensive Cancer Center, Ann Arbor, 48109-0936, Michigan, USA

    Mats Ljungman, Fenfen Zhang, Feng Chen & Bruce C McKay

  2. Department of Biology, McMaster University, Hamilton, L8S 4K1, Ontario, Canada

    Andrew J Rainbow

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Ljungman, M., Zhang, F., Chen, F. et al. Inhibition of RNA polymerase II as a trigger for the p53 response. Oncogene 18, 583–592 (1999). https://doi.org/10.1038/sj.onc.1202356

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