UVB-INDUCED DNA BREAKS INTERFERE WITH TRANSCRIPTIONAL INDUCTION OF C-FOS

Oxidative stress may play an important role in the carcinogenic action of UVB light (290 to 320 nm). UVB light induces the growth-related immediate-early gene c-fos in JB6 mouse epidermal cells, but at the same time it causes structural damage to DNA, in particular DNA strand breakage. We have studied the effect of the modulation of the frequencies of DNA breaks on the transcriptional induction of c-fos by changing the cellular antioxidant defense or by inhibiting break repair. Reduction of UVB-induced DNA breakage in a stable transfectant with an increased complement of glutathione peroxidase enhanced the induction of c-fos. In contrast, c-fos induction was diminished in stable transfectants with Cu,Zn-superoxide dismutase. Increasing the stationary concentration of UVB-induced DNA breaks by inhibition of repair in the presence of the adenosine diphosphoribose (ADPR)-transferase inhibitor 3-amino-benzamide suppressed the induction of c-fos. We conclude that DNA breaks which are induced by UVB via oxidative processes interfere with the transcriptional induction of c-fos. DNA breaks appear to exert a long-range effect on chromatin conformation which is incompatible with efficient transcription. This notion is supported by the observation that inhibition of break rejoining by 3-amino-benzamide suppressed the UVB induction of the endogenous c-fos gene and of a stably integrated construct containing the c-fos regulatory sequences linked to a reporter gene. In contrast, the induction of the same construct was not inhibited when it remained extrachromosomal in transient transfection experiments.