2001 Fiscal Year Final Research Report Summary
GENOMIC INSTABILITY AND MOLECULAR MECHANISM OF DELAYED MUTAION IN Fl MICE BORN TO IRRADIATED SPERMATOZOA
| Project/Area Number |
12480156
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
環境影響評価(含放射線生物学)
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
NIWA Ohtsura RADIATION BIOLOGY CENTER, KYOTO UNIVERSITY, Professor, 放射線生物研究センター, 教授 (80093293)
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| Co-Investigator(Kenkyū-buntansha) |
KATO Tomohisa RADIATION BIOLOGY CENTER, KYOTO UNIVERSITY, Professor, 放射線生物研究センター, 助教授 (50301247)
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| Project Period (FY) |
2000 – 2001
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| Keywords | radiation / genomic instability / untargeted mutation / delayed mutation / pink-eyed unstable allele / minisatellite / genomic crosstalk / p53 dependent S checkpoint |
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| Research Abstract |
Radiation is known to induce genomic instability Which is characterized by the induction of untargeted mutation and delayed mutation. In this investigation, mutation due to genomic instability was tested in F1 mice born to irradiated father. Length change mutation at the maternally inherited allele of the mouse Ms6hm hypervariable minisatellite locus was found to increase in frequencies when born to fathers irradiated at the spermatozoa stage. Similarly, a higher frequency of somatic reversion at the maternally inherited pink-eyed unstable allele was observed in Fl mice born to irradiated spermatozoa. These demonstrated that DNA damage introduced into zygote by irradiated sperm triggers genomic instability in zygotes and in embryos of subsequent developmental stages, resulting in induction of untargeted mutation at the maternal allele of the minisatellite locus, and delayed mutation in retinal pigment epithelial cells in developing eyes.
The above study indicates that there exists a genomic crosstalk between damaged paternal genome and undamaged maternal genome. In order to investigate the molecular nature of this genomic crosstalk, we have studied radioresponses in mouse zygotes fertilized by irradiated sperm. A p53 responsive reporter was efficiently activated in female pronucleus. [3H]-Tdr labelingexperiments indicated that sperm irradiated zygotes was devoid of G1/S arrest, but pronuclear DNA synthesis was suppressed equally in male and female pronuclei. P53 -/- zygotes lacked this suppression which was corrected by microinjection of GST-p53 fusion protein. About a half of 6 Gy sperm irradiated zygotes managed to synthesize a full DNA content by prolonging S phase while the other half failed to do so. Regardless of the DNA content, all the zygotes cleaved to become 2 cell stage embryos. These results revealed the presence of p53 dependent pronuclear crosstalk and a novel function of p53 in S phase DNA-damage checkpoint of mouse zygotes.
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[Publications] Saito, Y., Y. Ochiai, Y. Kodama, Y. Togashi, H. Sato, H. Okano, T.Miyazawa, K. Hatakeyama, S. Wakana, O. Niwa and R. Kominami: "Genetic loci controlling susceptibility to g-ray-induced thymic lymphoma"Oncogen. 20. 5243-5247 (2001)
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