title: p53-Dependent suppression of genome instability in germ cells.
abstract: Radiation increases mutation frequencies at tandem repeat loci. Germline mutations in γ-ray-irradiated medaka fish (Oryzias latipes) were studied, focusing on the microsatellite loci. Mismatch-repair genes suppress microsatellite mutation by directly removing altered sequences at the nucleotide level, whereas the p53 gene suppresses genetic alterations by eliminating damaged cells. The contribution of these two defense mechanisms to radiation-induced microsatellite instability was addressed. The spontaneous mutation frequency was significantly higher in msh2(-/-) males than in wild-type fish, whereas there was no difference in the frequency of radiation-induced mutations between msh2(-/-) and wild-type fish. By contrast, irradiated p53(-/-) fish exhibited markedly increased mutation frequencies, whereas their spontaneous mutation frequency was the same as that of wild-type fish. In the spermatogonia of the testis, radiation induced a high level of apoptosis both in wild-type and msh2(-/-) fish, but negligible levels in p53(-/-) fish. The results demonstrate that the msh2 and p53 genes protect genome integrity against spontaneous and radiation-induced mutation by two different pathways: direct removal of mismatches and elimination of damaged cells.
authors.affiliation: Department of Otorhinolaryngology and Head and Neck Surgery, Osaka University School of Medicine, Osaka 565-0871, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Otozai
authors.affiliation: Department of Radiation Biology and Medical Genetics, Graduate School of Medicine, Osaka University, B4, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ishikawa-Fujiwara
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Oda
authors.affiliation: Department of Radiation Biology and Medical Genetics, Graduate School of Medicine, Osaka University, B4, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kamei
authors.affiliation: Nomura Project, National Institute of Biomedical Innovation, Osaka 565-0085, Japan.
authors.forename: Haruko
authors.initials: H
authors.lastname: Ryo
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Ayuko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Nomura Project, National Institute of Biomedical Innovation, Osaka 565-0085, Japan.
authors.forename: Taisei
authors.initials: T
authors.lastname: Nomura
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitani
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Tsujimura
authors.affiliation: Department of Otorhinolaryngology and Head and Neck Surgery, Osaka University School of Medicine, Osaka 565-0871, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Inohara
authors.affiliation: Department of Radiation Biology and Medical Genetics, Graduate School of Medicine, Osaka University, B4, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: todo@radbio.med.osaka-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Todo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005399:Fishes / Q000235:genetics*; D005720:Gamma Rays / Q000009:adverse effects; D042822:Genomic Instability / Q000235:genetics* / Q000528:radiation effects; D005854:Germ Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D008297:Male; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D051718:MutS Homolog 2 Protein
keywords: CE; DDR; DNA damage response; DSB; ESTR; HRM; MMR; MSI; Medaka fish; Microsatellite instability; Radiation; Spermatogonial stem cell; TILLING; double-strand break; expanded simple tandem repeat; fluorescent capillary electrophoresis; high-resolution melting; microsatellite instability; mismatch-repair; msh2; p53; target induced local lesion in genome