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Fen1 is induced p53 dependently and involved in the recovery from UV-light-induced replication inhibition

Oncogene volume 24, pages 8304–8313 (2005)Cite this article

Abstract

Mouse embryonic fibroblasts (MEFs) that lack p53 are hypersensitive to the cytotoxic and genotoxic effect of ultraviolet (UV-C) light. They also display a defect in the recovery from UV-C-induced DNA replication inhibition. An enzyme involved in processing stalled DNA replication forks is flap endonuclease 1 (Fen1). Gene expression profiling of UV-C-irradiated MEFs revealed fen1 to be upregulated, which was confirmed by RT–PCR and Western blot experiments. Increased Fen1 levels upon UV-C exposure are due to transcriptional activation, as revealed by inhibitor studies. Fen1 induction was dose- and time-dependent; it occurred on protein level already 3 h after irradiation. Induction of Fen1 by UV-C requires p53 since it was observed in p53 wild-type (wt) but not in p53 null (p53−/−) fibroblasts. Fen1 upregulation paralleled the increase in p53 protein level in replicating wt cells, whereas in nonreplicating cells both Fen1 and p53 were not induced by UV-C. The mouse fen1 promoter was cloned and shown to harbor a p53 consensus sequence to which p53 binds. In cotransfection experiments, p53 stimulated the expression of a fen1 promoter–reporter construct. Transgenic expression of Fen1 in p53 null cells attenuated UV-C light-induced DNA replication inhibition, supporting the hypothesis that Fen1 induction is involved in the recovery of cells from DNA damage.

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Acknowledgements

This work was supported by Deutsche Forschungsgemeinschaft (KA724 and SFB 432).

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  1. Department of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, Mainz, D-55131, Germany

    Markus Christmann, Maja T Tomicic, Judith Origer & Bernd Kaina

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  1. Markus Christmann
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  2. Maja T Tomicic
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Correspondence to Bernd Kaina.

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Christmann, M., Tomicic, M., Origer, J. et al. Fen1 is induced p53 dependently and involved in the recovery from UV-light-induced replication inhibition. Oncogene 24, 8304–8313 (2005). https://doi.org/10.1038/sj.onc.1208994

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