Effect of Atm disruption on spontaneously arising and radiation-induced deletion mutations in mouse liver.
Deletion mutations were efficiently recovered in mouse liver after total-body irradiation with X rays by using a transgenic mouse "gpt-delta" system that harbored a lambda EG10 shuttle vector with the red and gam genes for Spi- (sensitive to P2 lysogen interference) selection. We incorporated this system into homozygous Atm-knockout mice as a model of the radiosensitive hereditary disease ataxia telangiectasia (AT). Lambda phages recovered from the livers of X-irradiated mice with the Atm+/+ genotype showed a dose-dependent increase in the Spi- mutant frequency up to sixfold at 50 Gy over the unirradiated control of 2.8x10(-6). The livers from Atm-/- mice yielded a virtually identical dose-response curve for X rays with a background fraction of 2.4x10(-6). Structural analyses revealed no significant difference in the proportion of -1 frameshifts and larger deletions between Atm+/+ and Atm-/- mice, although larger deletions prevailed in X-ray-induced Spi- mutants irrespective of Atm status. While a possible defect in DNA repair after irradiation has been strongly indicated in the literature for nondividing cultured cells in vitro from AT patients, the Atm disruption does not significantly affect radiation mutagenesis in the stationary mouse liver in vivo.
Furuno-Fukushi
Ikuko
I
Research Center for Radiation Safety, National Institute of Radiological Sciences, Anagawa, Inage-ku, Chiba 263-8555, Japan.
Masumura
Ken-ichi
K
Furuse
Takeshi
T
Noda
Yuko
Y
Takahagi
Masahiko
M
Saito
Toshiyuki
T
Hoki
Yuko
Y
Suzuki
Hiroshi
H
Wynshaw-Boris
Anthony
A
Nohmi
Takehiko
T
Tatsumi
Kouichi
K
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004307:Dose-Response Relationship, Radiation; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000528:radiation effects*; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011829:Radiation Dosage; D011836:Radiation Tolerance; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases