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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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References

  • Bae SH, Bae KH, Kim JA and Seo YS . (2001). Nature, 412, 456–461.

  • Bartek J, Lukas C and Lukas J . (2004). Nat. Rev. Mol. Cell Biol., 5, 792–804.

  • Chan GL, Doetsch PW and Haseltine WA . (1985). Biochemistry, 24, 5723–5728.

  • Chehab NH, Malikzay A, Stavridi ES and Halazonetis TD . (1999). Proc. Natl. Acad. Sci. USA, 96, 13777–13782.

  • Christmann M and Kaina B . (2000). J. Biol. Chem., 275, 36256–36262.

  • Christmann M, Tomicic MT and Kaina B . (2002). Nucleic. Acids Res., 30, 1959–1966.

  • Christmann M, Tomicic MT, Roos WP and Kaina B . (2003). Toxicology, 193, 3–34.

  • Cistulli CA and Kaufmann WK . (1998). Cancer Res., 58, 1993–2002.

  • el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW and Vogelstein B . (1992). Nat. Genet., 1, 45–49.

  • Gottifredi V, Shieh S, Taya Y and Prives C . (2001). Proc. Natl. Acad. Sci. USA, 98, 1036–1041.

  • Grombacher T, Eichhorn U and Kaina B . (1998). Oncogene, 17, 845–851.

  • Haas S and Kaina B . (1995). Carcinogenesis, 16, 985–991.

  • Harrington JJ and Lieber MR . (1994). EMBO J., 13, 1235–1246.

  • Hawkins DS, Demers GW and Galloway DA . (1996). Cancer Res., 56, 892–898.

  • Henneke G, Koundrioukoff S and Hubscher U . (2003). Oncogene, 22, 4301–4313.

  • Janus F, Albrechtsen N, Dornreiter I, Wiesmuller L, Grosse F and Deppert W . (1999). Cell Mol. Life Sci., 55, 12–27.

  • Kastan MB, Onyekwere O, Sidransky D, Vogelstein B and Craig RW . (1991). Cancer Res., 51, 6304–6311.

  • Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y and Shkedy D . (1999). Proc. Natl. Acad. Sci. USA, 96, 14973–14977.

  • Kim IS . (1998). Exp. Mol. Med., 30, 252–256.

  • Klungland A and Lindahl T . (1997). EMBO J., 16, 3341–3348.

  • Lackinger D, Eichhorn U and Kaina B . (2001). Mutagenesis, 16, 233–241.

  • Lackinger D and Kaina B . (2000). Mutat. Res., 457, 113–123.

  • Lakin ND and Jackson SP . (1999). Oncogene, 18, 7644–7655.

  • Larsen E, Gran C, Saether BE, Seeberg E and Klungland A . (2003). Mol. Cell. Biol., 23, 5346–5353.

  • Maltzman W and Czyzyk L . (1984). Mol. Cell. Biol., 4, 1689–1694.

  • Prasad R, Dianov GL, Bohr VA and Wilson SH . (2000). J. Biol. Chem., 275, 4460–4466.

  • Prost S, Ford JM, Taylor C, Doig J and Harrison DJ . (1998). J. Biol. Chem., 273, 33327–33332.

  • Ruggiero BL and Topal MD . (2004). J. Biol. Chem., 279, 23088–23097.

  • Rumbaugh JA, Henricksen LA, DeMott MS and Bambara RA . (1999). J. Biol. Chem., 274, 14602–14608.

  • Sharma S, Otterlei M, Sommers JA, Driscoll HC, Dianov GL, Kao HI, Bambara RA and Brosh Jr RM . (2004). Mol. Biol. Cell, 15, 734–750.

  • Shi BS, Yu YN, Cai ZN and Shen BH . (2001). Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai), 33, 309–314.

  • Shibata Y and Nakamura T . (2002). J. Biol. Chem., 277, 746–754.

  • Smith ML, Ford JM, Hollander MC, Bortnick RA, Amundson SA, Seo YR, Deng CX, Hanawalt PC and Fornace Jr AJ . (2000). Mol. Cell. Biol., 20, 3705–3714.

  • Tomicic MT, Friedrichs C, Christmann M, Wutzler P, Thust R and Kaina B . (2003). Mol. Pharmacol., 63, 439–449.

  • Warbrick E, Coates PJ and Hall PA . (1998). J. Pathol., 186, 319–324.

  • Zheng L, Zhou M, Chai Q, Parrish J, Xue D, Patrick SM, Turchi JJ, Yannone SM, Chen D and Shen B . (2005). EMBO Rep., 6, 83–89.

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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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