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A more recent version of this article appeared on January 1, 2002
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Submitted on May 5, 2001
Revised on October 10, 2001
Accepted on October 22, 2001
1 Institute of Toxicology, Division of Applied Toxicology, University of Mainz, Mainz, Germany
* Corresponding author. E-mail address: kaina{at}mail.uni-mainz.de.
Ultraviolet (UV) light targets both membrane receptors and nuclear DNA, thus evoking signals triggering apoptosis. Whereas receptor mediated apoptosis has been extensively investigated, the role of DNA damage in apoptosis is less clear. To analyse the importance of DNA damage induced by UV-C light in apoptosis, we compared nucleotide excision repair (NER) deficient Chinese hamster ovary cells (the lines 27-1 and 43-3B mutated for the repair genes ERCC3 and ERCC1 respectively) with the corresponding DNA repair proficient fibroblasts (CHO-9 and ERCC1 complemented 43-3B cells). NER deficient cells were hypersensitive as to the induction of apoptosis indicating that apoptosis induced by UV-C light is due to unrepaired DNA base damage. Unrepaired lesions, however, do not activate the apoptotic pathway directly since apoptosis upon UV-C irradiation requires DNA replication and cell proliferation. It is also shown that in NER deficient cells unrepaired lesions are converted into DNA double-strand breaks (DSBs) and chromosomal aberrations by a replication dependent process that precedes apoptosis. We therefore propose that DSBs arising from replication of DNA containing non-repaired lesions act as an ultimate trigger of UV-C induced apoptosis. Induction of apoptosis by UV-C light was related to decline in the expression level of Bcl-2 and activation of caspases. Decline of Bcl-2 and subsequent apoptosis might also be caused, at least in part, by UV-C induced blockage of transcription which was more pronounced in NER deficient than in wild-type cells. This is in line with experiments with actinomycin D which provoked Bcl-2 decline and apoptosis. UV-C induced apoptosis due to non-repaired DNA lesions, replication-dependent formation of DSBs and activation of the mitochondrial damage pathway appears to be independent of functional p53 for which the cells are mutated.
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