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Suppression of the poly(ADP-ribose) polymerase activity by DNA-dependent protein kinase in vitro

Oncogene volume 18, pages 4616–4625 (1999)Cite this article

Abstract

It has been suggested that DNA-dependent protein kinase (DNA-PK) is a central component of DNA double-strand-break repair. The mechanism of DNA-PK action, however, has not been fully understood. Poly(ADP-ribose) polymerase (PARP) is another nuclear enzyme which has high affinity to DNA ends. In this study, we analysed the interaction between these two enzymes. First, DNA-PK was found to suppress the PARP activity and alters the pattern of poly(ADP-ribosyl)ation. Although DNA-PK phosphorylates PARP in a DNA-dependent manner, this modification is unlikely to be responsible for the suppression of PARP activity, since this suppression occurs even in the absence of ATP. Conversely, PARP was found to ADP-ribosylate DNA-PK in vitro. However, the auto-phosphorylation activity of DNA-PK was not influenced by this modification. In a competitive electrophoretic mobility shift assay, Ku 70/80 complex, the DNA binding component of DNA-PK, was found to have higher affinity to a short fragment of DNA than does PARP. Furthermore, co-immunoprecipitation analysis suggested direct or close association between Ku and PARP. Thus, DNA-PK suppresses PARP activity, probably through direct binding and/or sequestration of DNA-ends which serve as an important stimulator for both enzymes.

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Acknowledgements

We thank Dr J Turner for M059K and M059J cells, Drs T Wada and H Handa for the supply of affinity latex particles, Dr T Taniguchi for anti-PARP antibody, Dr T Hamakubo for PARP protein as well as helpful discussion. We also thank Drs M Hijikata, M Takata, C Morrison and S Takeda for advice and discussion, and Ms K Yamagami, K Yamazaki and M Shirai for technical assistance. This work was supported in part by Grants-in-Aid for Scientific Research from Ministry of Education, Science, Sports and Culture of Japan (08280102). This work was also sponsored in part by the National Cancer Institute, DHHS, under contract with ABL.

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Authors and Affiliations

  1. Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan

    Yasuo Ariumi, Kunitada Shimotohno & Masakazu Hatanaka

  2. Biochemistry Division, National Cancer Center Research Institute, 104-0045, Tokyo, Japan

    Mitsuko Masutani & Takashi Sugimura

  3. ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, Maryland, USA

    Terry D Copeland

  4. Keio University School of Medicine, Tokyo, 160-0016, Japan

    Tuneyo Mimori

  5. Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611 - 0011, Japan

    Kunihiro Ueda

  6. Department of Molecular Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan

    Makoto Noda

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  1. Yasuo Ariumi
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Ariumi, Y., Masutani, M., Copeland, T. et al. Suppression of the poly(ADP-ribose) polymerase activity by DNA-dependent protein kinase in vitro. Oncogene 18, 4616–4625 (1999). https://doi.org/10.1038/sj.onc.1202823

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