Influences of p53 deficiency on the apoptotic response, DNA damage removal and mutagenesis in UVB-exposed mouse skin.
p53 suppresses the genomic instability provoked by genotoxic agents. Ultraviolet (UV) B induces skin cancers by producing DNA damage and mutations in the skin genome, whereas the skin tissue responds to the UVB insult with cell cycle arrest and apoptosis as well as damage exclusion by DNA repair. To address the p53 contribution to these skin responses in vivo, we analyzed the time course of DNA damage removal, apoptosis induction and hyperplasia in the skin after UVB irradiation in p53-knockout mice. We also examined UVB-induced mutations in the skin. We found that p53 deficiency does not abolish the UVB-induced apoptotic response in the epidermis but delays the process and the following hyperplasia 12-24 h. Regardless of the p53 genotype, 1 kJ/m(2) UVB induced a total replacement of the epidermal layer by destroying the damaged epidermis by apoptosis and rebuilding a new one through hyperplasia. We failed to detect a clear defect in removal of UVB-induced DNA photolesions from the genome of the p53-deficient skin except for a delay in the epidermis, which seemed to result from the delay in the apoptotic response. However, we found that p53 deficiency enhanced UVB-induced mutagenesis. Furthermore, in a genetic study using Xpa-knockout mice, we showed that the enhanced mutagenic response depends on the activity of nucleotide excision repair (NER), which was also supported by the mutation spectrum observed in the UVB-exposed p53-knockout mice. These results indicate that p53 protects the skin genome from the UVB genotoxicity by facilitating NER, whereas its contribution to the UVB-induced apoptosis is limited.
Ikehata
Hironobu
H
Department of Cell Biology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan. ikehata@mail.tains.tohoku.ac.jp
Okuyama
Ryuhei
R
Ogawa
Eisaku
E
Nakamura
Shingo
S
Usami
Atsuko
A
Mori
Toshio
T
Tanaka
Kiyoji
K
Aiba
Setsuya
S
Ono
Tetsuya
T
D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D004260:DNA Repair; D008297:Male; D051379:Mice; D016296:Mutagenesis; D009154:Mutation; D012867:Skin / Q000473:pathology / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
D016159:Tumor Suppressor Protein p53