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TAO kinases mediate activation of p38 in response to DNA damage

Malavika Raman1, Svetlana Earnest, Kai Zhang

  • 1Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX 75390-9041, USA.

The EMBO Journal
|March 31, 2007
PubMed

Insights

Thousand and one amino acid (TAO) kinases regulate p38 mitogen-activated protein kinase (MAPK) activation following DNA damage. These kinases are crucial for the DNA damage-induced G2/M checkpoint and cellular response to genotoxic stress.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Thousand and one amino acid (TAO) kinases are MAP kinase kinase kinases (MAP3Ks) that activate p38 MAPK.
  • p38 MAPK plays a critical role in cellular responses to stress, including DNA damage.

Purpose of the Study:

  • To investigate the role of TAO kinases in mediating p38 MAPK activation in response to genotoxic stimuli.
  • To elucidate the upstream regulators and downstream consequences of TAO kinase activation in DNA damage response pathways.

Main Methods:

  • Utilized dominant-negative TAO constructs and siRNA to inhibit TAO kinase activity and expression.
  • Assessed p38 MAPK activation using Western blotting and other biochemical assays.
  • Investigated the role of ATM in TAO kinase phosphorylation and activation.
  • Examined the impact of TAO kinase knockdown on the DNA damage-induced G2/M checkpoint and cellular sensitivity to ionizing radiation (IR).

Main Results:

  • TAO kinases are acutely activated by genotoxic agents including ionizing radiation, UV radiation, and hydroxyurea.
  • Inhibition of TAO kinases significantly impairs p38 MAPK activation by DNA damage.
  • Knockdown of TAO kinases compromises the DNA damage-induced G2/M checkpoint and increases sensitivity to IR.
  • Ataxia telangiectasia mutated (ATM) phosphorylates TAO kinases in vitro and in cells, and TAO/p38 activation is impaired in ATM-deficient cells.

Conclusions:

  • TAO kinases are essential mediators of p38 MAPK activation in response to DNA damage.
  • TAO kinases act as intermediates in the ATM-dependent activation of p38 MAPK following genotoxic stress.
  • TAO kinases play a significant role in regulating the DNA damage response, including checkpoint control and cellular survival.

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