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Function of poly(ADP-ribose) polymerase in response to DNA damage: Gene-disruption study in mice

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Abstract

To elucidate the biological functions of poly(ADP-ribose) polymerase (PARP, [EC 2.4.2.30]) in DNA damage responses, genetic and biochemical approaches were undertaken. By disrupting exon 1 of the mouse PARP gene by a homologous recombination, PARP-deficient mouse embryonic stem (ES) cell lines and mice could be produced without demonstrating lethality. PARP-/- ES cells showed complete loss of PARP activity and increased sensitivity to γ-irradiation and an alkylating agents, indicating a physiological role for PARP in the response to DNA damage. p53, a key molecule in cellular DNA damage response, was found to stimulate PARP activity and became poly(ADP-ribosyl)ated in the presence of damaged DNA. However, PARP-/- ES cells showed p21 and Mdm-2 mRNA induction following γ-irradiation, indicating that PARP activity is not indispensable for p21 and Mdm-2 mRNA induction in the established p53-cascade. On the other hand, in a reconstituted reaction system, purified PARP from human placenta suppressed the pRB-phosphorylation activity in the presence of NAD and damaged DNA. Human PARP expressed in E. coli showed a similar effect on pRB-phosphorylation activity of cdk2. These findings suggest a direct involvement of PARP in the regulation of cdk activity for cell-cycle arrest.

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Authors and Affiliations

  1. Biochemistry Division, National Cancer Center Research Institute, Tokyo, Japan

    Mitsuko Matsutani, Tadashige Nozaki, Eiko Nishiyama, Takashi Shimokawa, Yumiko Tachi, Hitoshi Nakagama & Takashi Sugimura

  2. Cancer Prevention Division, National Cancer Center Research Institute, Tokyo, Japan

    Keiji Wakabayashi

  3. Chugai Pharmaceutical Co., Shizuoka, Japan

    Hiroshi Suzuki

Authors
  1. Mitsuko Matsutani
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  2. Tadashige Nozaki
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  3. Eiko Nishiyama
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  4. Takashi Shimokawa
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  5. Yumiko Tachi
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  6. Hiroshi Suzuki
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  7. Hitoshi Nakagama
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  8. Keiji Wakabayashi
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  9. Takashi Sugimura
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Matsutani, M., Nozaki, T., Nishiyama, E. et al. Function of poly(ADP-ribose) polymerase in response to DNA damage: Gene-disruption study in mice. Mol Cell Biochem 193, 149–152 (1999). https://doi.org/10.1023/A:1006941016799

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  • DOI: https://doi.org/10.1023/A:1006941016799

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