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Originally published as MBC in Press, 10.1091/mbc.01-05-0225 on December 7, 2001
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Vol. 13, Issue 1, 348-361, January 2002

Cell Proliferation and DNA Breaks Are Involved in Ultraviolet Light-induced Apoptosis in Nucleotide Excision Repair-deficient Chinese Hamster Cells

Torsten R. Dunkern, and Bernd Kaina*

Institute of Toxicology, Division of Applied Toxicology, University of Mainz, D-55131 Mainz, Germany

UV light targets both membrane receptors and nuclear DNA, thus evoking signals triggering apoptosis. Although receptor-mediated apoptosis has been extensively investigated, the role of DNA damage in apoptosis is less clear. To analyze the importance of DNA damage induced by UV-C light in apoptosis, we compared nucleotide excision repair (NER)-deficient Chinese hamster ovary cells (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 because 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 nonrepaired 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 nonrepaired DNA lesions, replication-dependent formation of DSBs, and activation of the mitochondrial damage pathway is independent of functional p53 for which the cells are mutated.

* Corresponding author. E-mail address: kaina{at}mail.uni-mainz.de.

Molecular Biology of the Cell
Vol. 13, 348-361, January 2002
Copyright © 2002 by The American Society for Cell Biology


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