UV-induced skin carcinogenesis in xeroderma pigmentosum group A (XPA) gene-knockout mice with nucleotide excision repair-deficiency.
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.
Tanaka
K
K
Institute for Molecular and Cellular Biology, Osaka University, 1-3 Yamadaoka, Suita, 565-0871, Osaka, Japan. ktanaka@imcb.osaka-u.ac.jp
Kamiuchi
S
S
Ren
Y
Y
Yonemasu
R
R
Ichikawa
M
M
Murai
H
H
Yoshino
M
M
Takeuchi
S
S
Saijo
M
M
Nakatsu
Y
Y
Miyauchi-Hashimoto
H
H
Horio
T
T
D000818:Animals; D002453:Cell Cycle; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016158:Genes, p53; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000150:complications / Q000235:genetics; D011485:Protein Binding; D012269:Ribosomal Proteins / Q000235:genetics; D012878:Skin Neoplasms / Q000150:complications / Q000209:etiology* / Q000235:genetics; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000150:complications* / Q000235:genetics; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; D012269:Ribosomal Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C034212:ribosomal protein S12