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Mol Biol Cell. 2002 Jan;13(1):348-61.

Cell proliferation and DNA breaks are involved in ultraviolet light-induced apoptosis in nucleotide excision repair-deficient Chinese hamster cells.

Author information

1
Institute of Toxicology, Division of Applied Toxicology, University of Mainz, D-55131 Mainz, Germany.

Abstract

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.

PMID:
11809844
PMCID:
PMC65093
DOI:
10.1091/mbc.01-05-0225
[Indexed for MEDLINE]
Free PMC Article

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