UV-induced skin carcinogenesis in xeroderma pigmentosum group A (XPA) gene-knockout mice with nucleotide excision repair-deficiency

Kiyoji Tanaka, Shinya Kamiuchi, Yan Ren, Rie Yonemasu, Minoru Ichikawa, Hiroaki Murai, Masafumi Yoshino, Seiji Takeuchi, Masafumi Saijo, Yoshimichi Nakatsu, Hiroko Miyauchi-Hashimoto, Takeshi Horio

研究成果: ジャーナルへの寄稿学術誌査読

31 被引用数 (Scopus)


Nucleotide excision repair (NER) removes a wide variety of lesions from the genome and is deficient in the genetic disorder, xeroderma pigmentosum (XP). In this paper, an in vitro analysis of the XP group A gene product (XPA protein) is reported. Results of an analysis on the pathogenesis of ultraviolet (UV)-B-induced skin cancer in the XPA gene-knockout mouse are also described: (1) contrary to wild type mice, significant bias of p53 mutations to the transcribed strand and no evident p53 mutational hot spots were detected in the skin tumors of XPA-knockout mice. (2) Skin cancer cell lines from UVB-irradiated XPA-knockout mice had a decreased mismatch repair activity and an abnormal cell cycle checkpoint, suggesting that the downregulation of mismatch repair helps cells escape killing by UVB and that mismatch repair-deficient clones are selected for during the tumorigenic transformation of XPA (-/-) cells. (3) The XPA-knockout mice showed a higher frequency of UVB-induced mutation in the rpsL transgene at a low dose of UVB-irradiation than the wild type mice. CC → TT tandem transition, a hallmark of UV-induced mutation, was detected at higher frequency in the rpsL transgene in the XPA-knockout mice than the wild type mice. This rpsL/XPA mouse system will be useful for further analysing the role of NER in the mutagenesis induced by various carcinogens. (4) The UVB-induced immunosuppression was greatly enhanced in the XPA-knockout mice. It is possible that an enhanced impairment of the immune system by UVB irradiation is involved in the high incidence of skin cancer in XP.

ジャーナルMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
出版ステータス出版済み - 6月 2 2001

!!!All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 遺伝学
  • 健康、毒物学および変異誘発


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