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Evaluating Parp1 domains as gossypol targets

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Abstract

Poly ADP-ribose Polymerase 1 (PARP1) is an important enzyme that is involved in DNA repair, replication, and transcription. Prospective anticancer drug gossypol inhibits human PARP1, but the mechanism of inhibition remains unknown. It has been shown previously that gossypol interacts with purified BRCA1 C-terminus (BRCT) domain in vitro. However, it remained unclear whether gossypol inhibits PARP1 through the BRCT domain in the context of full-length protein. Here, we report that the BRCT domain within the full-length PARP1 protein is not required for the inhibition of catalytic activity of PARP1 by gossypol. Our results, obtained using a series of PARP1 mutations and H4-dependent pathway of PARP1 activation, also show that none of the zinc fingers or other DNA binding domains of PARP1 are involved in the inhibition of the PARP1 catalytic activity by gossypol. Thus, the likely candidate target(s) for gossypol action are the other domains of PARP1, or the interdomain linkers.

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Authors and Affiliations

  1. Cancer Epigenetics Team, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    S. Gross, E. Yu. Kotova & V. M. Studitsky

  2. Department of Biology, Moscow State University, Moscow, 119234, Russia

    N. V. Maluchenko & V. M. Studitsky

  3. Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, H3C 3J7, Canada

    J. M. Pascal

Authors
  1. S. Gross
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  2. E. Yu. Kotova
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  3. N. V. Maluchenko
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  4. J. M. Pascal
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  5. V. M. Studitsky
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Corresponding author

Correspondence to N. V. Maluchenko.

Additional information

Original Russian Text © S. Gross, E.Yu. Kotova, N.V. Maluchenko, J.M. Pascal, V.M. Studitsky, 2016, published in Vestnik Moskovskogo Universiteta, Seriya 16: Biologiya, 2016, No. 4, pp. 61–65.

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Gross, S., Kotova, E.Y., Maluchenko, N.V. et al. Evaluating Parp1 domains as gossypol targets. Moscow Univ. Biol.Sci. Bull. 71, 235–239 (2016). https://doi.org/10.3103/S0096392516040106

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  • DOI: https://doi.org/10.3103/S0096392516040106

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