U.v.-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle.
Induction of p53 in u.v.-irradiated primary human fibroblasts was monitored by immunostaining and Western blotting. Minimum u.v. doses required for induction of nuclear accumulation of p53 (minimum response dose: MRD) were estimated in various cells with different DNA repair capacities. The MRD in repair deficient xeroderma pigmentosum (XP) group A cells is eightfold lower than in normal cells, indicating that nuclear accumulation of p53 is related to DNA repair capacity. Cells from patients with another u.v.-sensitive disorder, Cockayne syndrome (CS), which have normal repair capacity for the overall genome but have a specific defect in preferential repair of lesions in active genes, have the same low MRD as of XP-A cells. Furthermore, the MRD in XP-C cells, which have normal preferential repair but have defects in overall genome repair, is as high as that of normal cells. DNA damage induced by X-ray is repaired at similar rates in normal, XP and CS cells. In contrast to u.v.-irradiation, the minimum dose of X-rays that induces nuclear accumulation of p53 is the same in these cells. Inhibition of transcription with alpha-amanitin evokes nuclear accumulation of p53 both in normal cells and in XP cells. These results strongly suggest that u.v.-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes. Nuclear accumulation of p53 is observed in any phase of the cell cycle at both low and high u.v. doses.
Yamaizumi
M
M
Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Japan.
Sugano
T
T
D000546:Amanitins / Q000494:pharmacology; D002453:Cell Cycle / Q000235:genetics*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003057:Cockayne Syndrome / Q000235:genetics; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics
D000546:Amanitins; D016159:Tumor Suppressor Protein p53; D004247:DNA