Abstract
Ultraviolet (UV) light is a potent mutagenic and genotoxic agent. Whereas DNA damage induced by UV light is known to be responsible for UV-induced genotoxicity, its role in triggering apoptosis is still unclear. We addressed this issue by comparing nucleotide excision repair (NER) deficient 27-1 and 43-3B Chinese hamster (CHO) cells with the corresponding wild-type and ERCC-1 complemented cells. It is shown that NER deficient cells are dramatically hypersensitive to UV-C induced apoptosis, indicating that DNA damage is the major stimulus for the apoptotic response. Apoptosis triggered by UV-C induced DNA damage is related to caspase- and proteosome-dependent degradation of Bcl-2 protein. The expression of other members of the Bcl-2 family such as Bax, Bcl-xL and Bak were not affected. Bcl-2 decline is causally involved in UV-C induced apoptosis since overexpression of Bcl-2 protected NER deficient cells against apoptosis. We also demonstrate that caspase-8, caspase-9 and caspase-3 are activated and PARP is cleaved in response to unrepaired UV-C induced DNA damage. Caspase-8 activation occurred independently of CD95 receptor activation since CD95R/FasR and CD95L/FasL were not altered in expression, and transfection of transdominant negative FADD failed to block apoptosis. Overall, the data demonstrate that UV-C induced non-repaired DNA damage triggers apoptosis in NER deficient fibroblasts involving components of the intrinsic mitochondrial damage pathway.
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Acknowledgements
We gratefully acknowledge Dr V Dixit (Michigan) for providing the dnFADD expression plasmid, Dr S Dimmeler (Frankfurt) for Bcl-2 expression plasmid, Dr K Schulze-Osthoff and Dr R Jänicke (Münster) for MCF-7/Caspase3-transfected cells and Dr R Wood (London) for ERCC1 transfected 43-3B cells. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 519/B4 and Ka724/4-4), by Stiftung Rheinland Pfalz for Innovation and by a generous grant of the University of Mainz to T Dunkern.
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Dunkern, T., Fritz, G. & Kaina, B. Ultraviolet light-induced DNA damage triggers apoptosis in nucleotide excision repair-deficient cells via Bcl-2 decline and caspase-3/-8 activation. Oncogene 20, 6026–6038 (2001). https://doi.org/10.1038/sj.onc.1204754
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DOI: https://doi.org/10.1038/sj.onc.1204754
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