TY - JOUR
T1 - DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1
AU - Hamdi, Mohamed
AU - Kool, Jaap
AU - Cornelissen-Steijger, Paulien
AU - Carlotti, Francoise
AU - Popeijus, Herman E.
AU - Van Der Burgt, Corina
AU - Janssen, Josephine M.
AU - Yasui, Akira
AU - Hoeben, Rob C.
AU - Terleth, Carrol
AU - Mullenders, Leon H.
AU - Van Dam, Hans
N1 - Funding Information:
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.
PY - 2005/11/3
Y1 - 2005/11/3
N2 - 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.
AB - 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.
KW - AP-1
KW - DNA damage
KW - JNK
KW - MKP-1
KW - Transcription-coupled repair
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U2 - 10.1038/sj.onc.1208875
DO - 10.1038/sj.onc.1208875
M3 - Article
C2 - 16044158
AN - SCOPUS:27944469638
VL - 24
SP - 7135
EP - 7144
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 48
ER -
