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Transcription-independent suppression of DNA synthesis by p53 in sperm-irradiated mouse zygotes

Oncogene volume 24, pages 3229–3235 (2005)Cite this article

Abstract

Cell cycle arrest in response to DNA damage is important for the maintenance of genomic integrity in higher eukaryotes. We have previously reported the novel p53-dependent S-phase checkpoint operating in mouse zygotes fertilized with irradiated sperm. In the present study, we analysed the detail of the p53 function required for this S-phase checkpoint in mouse zygotes. The results indicate that ATM kinase is likely to be indispensable for the p53-dependent S-phase checkpoint since the suppression was abrogated by inhibitors such as caffeine and wortmannin. However, ATM phosphorylation site mutant proteins were still capable of suppressing DNA synthesis when microinjected into sperm-irradiated zygotes lacking the functional p53, suggesting that the target of the phosphorylation is not p53. In addition, the suppression was not affected by α-amanitin, and p53 protein mutated at the transcriptional activation domain was also functional in the suppression of DNA synthesis. However, p53 proteins mutated at the DNA-binding domain were devoid of the suppressing activity. Taken together, the transcription-independent function of p53 associated with the DNA-binding domain is involved in the S-phase checkpoint in collaboration with yet another unidentified target protein(s).

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Acknowledgements

We thank H Nagai for the maintenance and breeding of mice used in the present study. This work is supported by Grant-in-Aid from the Ministry of Education, Science, Sports, Culture and Technology (MEXT), Japan to ON. The work is also supported by a grant from the Nuclear Safety Research Association, Tokyo.

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Authors and Affiliations

  1. Department of Late Effect Studies, Radiation Biology Center, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto, 606-8501, Japan

    Megumi Toyoshima, Tsutomu Shimura, Satish-Kumar Adiga, Masataka Taga, Kazunori Shiraishi & Ohtsura Niwa

  2. Medical Research Institute, Kanazawa Medical University, Daigaku 1-1, Uchinada-machi, Kahoku-gun, Ishikawa, 920-0293, Japan

    Masao Inoue

  3. Department of Cancer Cell Biology, Harvard School of Public Health, Boston, MA, 02115, USA

    Zhi-Min Yuan

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  1. Megumi Toyoshima
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Correspondence to Ohtsura Niwa.

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Toyoshima, M., Shimura, T., Adiga, SK. et al. Transcription-independent suppression of DNA synthesis by p53 in sperm-irradiated mouse zygotes. Oncogene 24, 3229–3235 (2005). https://doi.org/10.1038/sj.onc.1208514

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