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Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response

Hiroshi Nishida1, Naoto Tatewaki, Yuki Nakajima

  • 1Department of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.

Nucleic Acids Research
|July 24, 2009
PubMed

Insights

Schisandrin B inhibits ATR, a key protein kinase in DNA damage response. This finding has implications for developing new anti-cancer therapies that sensitize tumors to chemotherapy and radiation.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • ATM and ATR protein kinases are vital for cellular DNA damage response.
  • Inhibiting these kinases can disrupt cell cycle checkpoints, potentially enhancing anti-cancer treatments.
  • Currently, ATR-specific inhibitors are lacking, presenting a therapeutic gap.

Purpose of the Study:

  • To investigate the inhibitory effect of schisandrin B (SchB) on ATR activity in DNA damage response.
  • To evaluate SchB's potential as a sensitizing agent for anti-cancer chemo/radiotherapy.

Main Methods:

  • Assessed SchB's effect on A549 cell viability after UV exposure.
  • Measured phosphorylation levels of ATM and ATR substrates and G2/M checkpoint activity.
  • Determined SchB's inhibitory effect on purified ATR kinase activity in vitro.
  • Evaluated SchB's impact on p53 and Chk1 phosphorylation in ATM-deficient and siATR-treated cells.

Main Results:

  • SchB significantly reduced A549 cell viability post-UV exposure.
  • SchB inhibited ATM and ATR substrate phosphorylation and G2/M checkpoint activity.
  • SchB demonstrated dose-dependent inhibition of ATR kinase activity (IC50: 7.25 μM) but not ATM, Chk1, PI3K, DNA-PK, or mTOR.
  • SchB reduced UV-induced p53 and Chk1 phosphorylation in ATM-deficient cells, but not in siATR-treated cells, confirming ATR specificity.

Conclusions:

  • Schisandrin B specifically inhibits ATR protein kinase activity following DNA damage.
  • SchB's ability to inhibit ATR has significant clinical implications for enhancing anti-cancer therapies.

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