Ultraviolet light-induced apoptosis is associated with S-phase in primary human fibroblasts.
Transcription-coupled nucleotide excision repair (tcNER)-deficient human fibroblasts are extremely sensitive to the induction of apoptosis in response to low doses of ultraviolet light (UV light), but are less sensitive to the induction of apoptosis following exposure to high doses [J. Invest. Dermatol. 117 (2001) 1162]. This seemingly paradoxical observation led us to re-evaluate the relationship between UV dose and the induction of apoptosis. Here we report that the reduction in the extent of UV-induced apoptosis in tcNER-deficient strains following exposure to elevated doses of UV light does not result from impaired gene expression alone because neither inhibitors of transcription nor inhibitors of translation blocked UV-induced apoptosis. Furthermore, UV-induced apoptosis was greatly reduced by inhibiting S-phase progression with either mimosine or serum withdrawal. Importantly, DNA synthesis following UV-irradiation occurred only at doses that induced apoptosis in these cell lines and the apoptotic cells contained nascent DNA. Moreover, deregulation of G(1)- to S-phase transition by expression of human papillomavirus E7 sensitized cells to UV-induced apoptosis. Taken together these results suggest that the induction of apoptosis requires S-phase progression following UV-irradiation.
McKay
Bruce C
BC
Centre for Cancer Therapeutics, Ottawa Regional Cancer Centre, ON, Canada. bruce.mckay@orcc.on.ca
Becerril
Cecilia
C
Spronck
Jennifer C
JC
Ljungman
Mats
M
D017209:Apoptosis / Q000528:radiation effects*; D004265:DNA Helicases; D004260:DNA Repair / Q000528:radiation effects; D004261:DNA Replication / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D008898:Mimosine / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D016196:S Phase / Q000502:physiology*; D014158:Transcription, Genetic / Q000528:radiation effects; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C059731:oncogene protein E7, Human papillomavirus type 16; C072022:XPBC-ERCC-3 protein; C086984:XPC protein, human; D008898:Mimosine; D004265:DNA Helicases