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

Mohamed Hamdi, Jaap Kool, Paulien Cornelissen-Steijger, Francoise Carlotti, Herman E. Popeijus, Corina Van Der Burgt, Josephine M. Janssen, Akira Yasui, Rob C. Hoeben, Carrol Terleth, Leon H. Mullenders, Hans Van Dam

    Research output: Contribution to journalArticlepeer-review

    64 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)7135-7144
    Number of pages10
    JournalOncogene
    Volume24
    Issue number48
    DOIs
    Publication statusPublished - 2005 Nov 3

    Keywords

    • AP-1
    • DNA damage
    • JNK
    • MKP-1
    • Transcription-coupled repair

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

    Fingerprint Dive into the research topics of 'DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1'. Together they form a unique fingerprint.

    Cite this