title: Absence of Ku70 gene obliterates X-ray-induced lacZ mutagenesis of small deletions in mouse tissues.
abstract: With the goal of understanding the role of non-homologous end-joining repair in the maintenance of genetic information at the tissue level, we studied mutations induced by radiation and subsequent repair of DNA double-strand breaks in Ku70 gene-deficient lacZ transgenic mice. The local mutation frequencies and types of mutations were analyzed on a lacZ gene that had been chromosomally integrated, which allowed us to monitor DNA sequence alterations within this 3.1-kbp region. The mutagenic process leading to the development of the most frequently observed small deletions in wild-type mice after exposure to 20 Gy of X rays was suppressed in Ku70(-/-) mice in the three tissues examined: spleen, liver and brain. Examination of DNA break rejoining and the phosphorylation of histone H2AX in Ku70-deficient and -proficient mice revealed that Ku70 deficiency decreased the frequency of DNA rejoining, suggesting that DNA rejoining is one of the causes of radiation-induced deletion mutations. Limited but statistically significant DNA rejoining was found in the liver and brain of Ku70-deficient mice 3.5 days after irradiation, showing the presence of a DNA double-strand break repair system other than non-homologous end joining. These data indicate a predominant role of non-homologous end joining in the production of radiation-induced mutations in vivo.
authors.affiliation: Department of Cell Biology, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Uehara
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ikehata
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Komura
authors.forename: Ari
authors.initials: A
authors.lastname: Ito
authors.forename: Masaki
authors.initials: M
authors.lastname: Ogata
authors.forename: Tsunetoshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Hirayama
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Furusawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Ando
authors.forename: Tatjana
authors.initials: T
authors.lastname: Paunesku
authors.forename: Gayle E
authors.initials: GE
authors.lastname: Woloschak
authors.forename: Kenshi
authors.initials: K
authors.lastname: Komatsu
authors.forename: Shinya
authors.initials: S
authors.lastname: Matsuura
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ikura
authors.forename: Kenji
authors.initials: K
authors.lastname: Kamiya
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ono
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D017353:Gene Deletion; D000072200:Ku Autoantigen; D007763:Lac Operon / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016296:Mutagenesis / Q000235:genetics / Q000528:radiation effects*; D011829:Radiation Dosage; D014781:Viscera / Q000378:metabolism* / Q000528:radiation effects*; D014965:X-Rays
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen