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Mutat Res. 2014 Feb;760:24-32. doi: 10.1016/j.mrfmmm.2013.12.004. Epub 2014 Jan 7.

p53-Dependent suppression of genome instability in germ cells.

Author information

1
Department of Otorhinolaryngology and Head and Neck Surgery, Osaka University School of Medicine, Osaka 565-0871, Japan.
2
Department of Radiation Biology and Medical Genetics, Graduate School of Medicine, Osaka University, B4, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
3
Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan.
4
Nomura Project, National Institute of Biomedical Innovation, Osaka 565-0085, Japan.
5
Department of Pathology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
6
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.

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.

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

PMID:
24406868
DOI:
10.1016/j.mrfmmm.2013.12.004
[Indexed for MEDLINE]

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