UV-induced mutations in epidermal cells of mice defective in DNA polymerase η and/or ι.
Xeroderma pigmentosum variant (XP-V) is a human rare inherited recessive disease, predisposed to sunlight-induced skin cancer, which is caused by deficiency in DNA polymerase η (Polη). Polη catalyzes accurate translesion synthesis (TLS) past pyrimidine dimers, the most prominent UV-induced lesions. DNA polymerase ι (Polι) is a paralog of Polη that has been suggested to participate in TLS past UV-induced lesions, but its function in vivo remains uncertain. We have previously reported that Polη-deficient and Polη/Polι double-deficient mice showed increased susceptibility to UV-induced carcinogenesis. Here, we investigated UV-induced mutation frequencies and spectra in the epidermal cells of Polη- and/or Polι-deficient mice. While Polη-deficient mice showed significantly higher UV-induced mutation frequencies than wild-type mice, Polι deficiency did not influence the frequencies in the presence of Polη. Interestingly, the frequencies in Polη/Polι double-deficient mice were statistically lower than those in Polη-deficient mice, although they were still higher than those of wild-type mice. Sequence analysis revealed that most of the UV-induced mutations in Polη-deficient and Polη/Polι double-deficient mice were base substitutions at dipyrimidine sites. An increase in UV-induced mutations at both G:C and A:T pairs associated with Polη deficiency suggests that Polη contributes to accurate TLS past both thymine- and cytosine-containing dimers in vivo. A significant decrease in G:C to A:T transition in Polη/Polι double-deficient mice when compared with Polη-deficient mice suggests that Polι is involved in error-prone TLS past cytosine-containing dimers when Polη is inactivated.
Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan; Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan; Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Rie
R
Kanao
Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan; Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
Masayuki
M
Yokoi
Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan.
Tsuyoshi
T
Ohkumo
Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan; Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan.
Yasutaka
Y
Sakurai
Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan; Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan.
Kantaro
K
Dotsu
Faculty of Medical Sciences, Kyushu University, 3-1-1 Higashi-ku, Maidashi, Fukuoka 812-8582, Japan.
Shinobu
S
Kura
Faculty of Medical Sciences, Kyushu University, 3-1-1 Higashi-ku, Maidashi, Fukuoka 812-8582, Japan.
Yoshimichi
Y
Nakatsu
Faculty of Medical Sciences, Kyushu University, 3-1-1 Higashi-ku, Maidashi, Fukuoka 812-8582, Japan.
Teruhisa
T
Tsuzuki
Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan; Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
Chikahide
C
Masutani
Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan; Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Tokyo, Japan. Electronic address: fumio.hanaoka@gakushuin.ac.jp.
Fumio
F
Hanaoka
D000818:Animals; D004247:DNA / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism* / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011740:Pyrimidine Dimers / Q000378:metabolism*; D014466:Ultraviolet Rays; D000094769:DNA Polymerase iota; D000099270:Y-Family DNA Polymerases
D004247:DNA; D004259:DNA-Directed DNA Polymerase; D011740:Pyrimidine Dimers; D000094769:DNA Polymerase iota; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases
DNA polymerase η; DNA polymerase ι; Translesion synthesis; UV-induced mutagenesis; Xeroderma pigmentosum variant (XP-V)