Delayed c-Fos activation in human cells triggers XPF induction and an adaptive response to UVC-induced DNA damage and cytotoxicity.
The oncoprotein c-Fos has been commonly found differently expressed in cancer cells. Our previous work showed that mouse cells lacking the immediate-early gene c-fos are hypersensitive to ultraviolet (UVC) light. Here, we demonstrate that in human diploid fibroblasts UV-triggered induction of c-Fos protein is a delayed and long-lasting event. Sustained upregulation of c-Fos goes along with transcriptional stimulation of the NER gene xpf, which harbors an AP-1 binding site in the promoter. Data gained on c-Fos knockdown and c-Fos overexpressing human cells provide evidence that c-Fos/AP-1 stimulates upregulation of XPF, thereby increasing the cellular repair capacity protecting from UVC-induced DNA damage. When these cells are pre-exposed to a low non-toxic UVC dose and challenged with a subsequent high dose of UVC irradiation, they show accelerated repair of UVC-induced DNA adducts and reduced cell kill. The data indicate a protective role of c-Fos induction by triggering an adaptive response pathway.
Department of Toxicology, University Medical Center Mainz, Obere Zahlbacher Str. 67, 55131, Mainz, Germany.
Maja T
MT
Tomicic
Patricia
P
Reischmann
Birgit
B
Rasenberger
Ruth
R
Meise
Bernd
B
Kaina
Markus
M
Christmann
D002460:Cell Line; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; C095888:xeroderma pigmentosum group F protein