title: Ultraviolet light-induced DNA damage triggers apoptosis in nucleotide excision repair-deficient cells via Bcl-2 decline and caspase-3/-8 activation.
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-x(L) 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.
authors.affiliation: Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany.
authors.forename: T R
authors.initials: TR
authors.lastname: Dunkern
authors.forename: G
authors.initials: G
authors.lastname: Fritz
authors.forename: B
authors.initials: B
authors.lastname: Kaina
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D006224:Cricetinae; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D014162:Transfection; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D053200:Fas-Associated Death Domain Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases