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Tankyrase-1 overexpression reduces genotoxin-induced cell death by inhibiting PARP1

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Abstract

Poly(ADP-ribose) polymerases or PARPs are a family of NAD+-dependent enzymes that modify themselves and other substrate proteins with ADP-ribose polymers. The founding member PARP1 is localized predominantly in the nucleus and is activated by binding to DNA lesions. Excessive PARP1 activation following genotoxin treatment causes NAD+ depletion and cell death, whereas pharmacological PARP1 inhibition protects cells from genotoxicity. This study investigates whether cellular viability and NAD+ metabolism are regulated by tankyrase-1, a PARP member localized predominantly in the cytosol. Using a tetracycline-sensitive promoter to regulate tankyrase-1 expression in Madin–Darby canine kidney (MDCK) cells, we found that a 40-fold induction of tankyrase-1 (from 1500 to 60,000 copies per cell) lowers steady-state NAD+ levels but does not affect basal cellular viability. Moreover, the induction confers protection against the oxidative agent H2O2 and the alkylating agent MNNG, genotoxins that kill cells by activating PARP1. The cytoprotective effect of tankyrase-1 is not due to enhanced scavenging of oxidants or altered expression of Mcl-1, an anti-apoptotic molecule previously shown to be down-regulated by tankyrase-1 in CHO cells. Instead, tankyrase-1 appears to protect cells by preventing genotoxins from activating PARP1-mediated reactions such as PARP1 automodification and NAD+ consumption. Our findings therefore indicate a cytoprotective function of tankyrase-1 mediated through altered NAD+ homeostasis and inhibition of PARP1 function.

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Authors and Affiliations

  1. Department of Medicine and Cancer Center, University of California, 9500 Gilman Dr., San Diego, La Jolla, CA, 92093-0673

    Tsung-Yin J. Yeh, Juan I. Sbodio, M. T. Audrey Nguyen & Nai-Wen Chi

  2. Department of Medicine, University of Hamburg, Germany

    Tobias N. Meyer

  3. Department of Medicine, University of Utah, Salt Lake City, UT, 84112

    Ray M. Lee

  4. University of California, Department of Medicine and Cancer Center, San Diego, 9500 Gilman Dr., La Jolla, 92093-0673, CA

    Nai-Wen Chi

Authors
  1. Tsung-Yin J. Yeh
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  2. Juan I. Sbodio
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  3. M. T. Audrey Nguyen
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  4. Tobias N. Meyer
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  6. Nai-Wen Chi
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Correspondence to Nai-Wen Chi.

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Yeh, TY.J., Sbodio, J.I., Nguyen, M.T.A. et al. Tankyrase-1 overexpression reduces genotoxin-induced cell death by inhibiting PARP1. Mol Cell Biochem 276, 183–192 (2005). https://doi.org/10.1007/s11010-005-4059-z

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  • DOI: https://doi.org/10.1007/s11010-005-4059-z

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