UVA1 genotoxicity is mediated not by oxidative damage but by cyclobutane pyrimidine dimers in normal mouse skin.
UVA1 induces the formation of 8-hydroxy-2'-deoxyguanosines (8-OH-dGs) and cyclobutane pyrimidine dimers (CPDs) in the cellular genome. However, the relative contribution of each type of damage to the in vivo genotoxicity of UVA1 has not been clarified. We irradiated living mouse skin with 364-nm UVA1 laser light and analyzed the DNA damage formation and mutation induction in the epidermis and dermis. Although dose-dependent increases were observed for both 8-OH-dG and CPD, the mutation induction in the skin was found to result specifically from the CPD formation, based on the induced mutation spectra in the skin genome: the dominance of C --> T transition at a dipyrimidine site. Moreover, these UV-specific mutations occurred preferentially at the 5'-TCG-3' sequence, suggesting that CpG methylation and photosensitization-mediated triplet energy transfer to thymine contribute to the CPD-mediated UVA1 genotoxicity. Thus, it is the CPD formation, not the oxidative stress, that effectively brings about the genotoxicity in normal skin after UVA1 exposure. We also found differences in the responses to the UVA1 genotoxicity between the epidermis and the dermis: the mutation induction after UVA1 irradiation was suppressed in the dermis at all levels of irradiance examined, whereas it leveled off from a certain high irradiance in the epidermis.
Ikehata
Hironobu
H
Department of Cell Biology, Graduate School of Medicine, Tohoku University, Sendai, Japan. ikehata@mail.tains.tohoku.ac.jp
Kawai
Kazuaki
K
Komura
Jun-ichiro
J
Sakatsume
Ko
K
Wang
Liangcheng
L
Imai
Masaru
M
Higashi
Shoichi
S
Nikaido
Osamu
O
Yamamoto
Kazuo
K
Hieda
Kotaro
K
Watanabe
Masakatsu
M
Kasai
Hiroshi
H
Ono
Tetsuya
T
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D003596:Cytosine / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects*; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics / Q000528:radiation effects; D018384:Oxidative Stress / Q000528:radiation effects*; D011740:Pyrimidine Dimers / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects*; D013941:Thymine / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
D011740:Pyrimidine Dimers; D017382:Reactive Oxygen Species; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003596:Cytosine; D004247:DNA; D003849:Deoxyguanosine; D013941:Thymine