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DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1

Oncogene volume 24, pages 7135–7144 (2005)Cite this article

Abstract

The nucleotide excision repair (NER) system consists of two subpathways, global genome repair (GGR) and transcription-coupled repair (TCR), which exhibit distinct functions in the cellular response to genotoxic stress. Defects in TCR result in prolonged UV light-induced stalling of RNA polymerase II and hypersensitivity to apoptosis induced by UV and certain chemotherapeutic drugs. Here, we show that low doses of UV trigger delayed activation of the stress-induced MAPkinase JNK and its proapoptotic targets c-Jun and ATF-3 in TCR-deficient primary human fibroblasts from Xeroderma Pigmentosum (XP) and Cockayne syndrome (CS) patients. This delayed activation of the JNK pathway is not observed in GGR-deficient TCR-proficient XP cells, is independent of functional p53, and is established through repression of the JNK-phosphatase MKP-1 rather than by activation of the JNK kinases MKK4 and 7. Enzymatic reversal of UV-induced cyclobutane pyrimidine dimers (CPDs) by CPD photolyase abrogated JNK activation, MKP-1 repression, and apoptosis in TCR-deficient XPA cells. Ectopic expression of MKP-1 inhibited DNA-damage-induced JNK activity and apoptosis. These results identify both MKP-1 and JNK as sensors and downstream effectors of persistent DNA damage in transcribed genes and suggest a link between the JNK pathway and UV-induced stalling of RNApol II.

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Acknowledgements

We thank Martijn Rabelink for assisting with lentivirus production, Axel Behrens for kindly providing the anti-phospho-Thr91-cJun antibody, and Jan Hoeijmakers, Harry Vrieling, Bert van Zeeland, Davy Rockx, Marcel Volker, Merlijn Bazuine, Peter Abrahams, and Lex van der Eb for helpful discussions. This work was supported by grants from the Netherlands Organisation for Scientific Research (NWO), the Dutch Cancer Society (KWF), and the Radiation Protection, Biomed, TMR, and RTN Programs of the European Community.

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  1. Jaap Kool

    Present address: Netherlands Cancer Institute, Division of Molecular Genetics, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

  2. Mohamed Hamdi and Jaap Kool: These authors contributed equally to this paper

Authors and Affiliations

  1. Department of Molecular Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, Leiden, 2333AL, The Netherlands

    Mohamed Hamdi, Jaap Kool, Paulien Cornelissen-Steijger, Francoise Carlotti, Herman E Popeijus, Corina van der Burgt, Josephine M Janssen, Rob C Hoeben, Carrol Terleth & Hans van Dam

  2. Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, Leiden, 2333AL, The Netherlands

    Jaap Kool, Paulien Cornelissen-Steijger, Carrol Terleth & Leon H Mullenders

  3. Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan

    Akira Yasui

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Correspondence to Hans van Dam.

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Hamdi, M., Kool, J., Cornelissen-Steijger, P. et al. DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1. Oncogene 24, 7135–7144 (2005). https://doi.org/10.1038/sj.onc.1208875

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