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ATR dependent activation of Chk2

Xiao Qi Wang1, J Leslie Redpath, Sheung Tat Fan

  • 1Department of Radiation Oncology, University of California Irvine, California, USA.

Journal of Cellular Physiology
|June 3, 2006
PubMed

Insights

The study reveals that ATR phosphorylates Chk2, a key DNA damage response protein. This occurs even when ATM is deficient, highlighting ATR

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Genetics

Background:

  • ATM and ATR are crucial kinases regulating DNA damage checkpoints in mammalian cells.
  • ATM primarily acts through Chk2, while ATR acts through Chk1.
  • Limited cross-regulation exists between ATM-Chk2 and ATR-Chk1 pathways, despite overlapping functions.

Purpose of the Study:

  • To investigate the role of ATR in phosphorylating Chk2.
  • To explore the interplay between ATM and ATR in response to DNA damage.
  • To determine if ATR can phosphorylate Chk2 in ATM-deficient cells.

Main Methods:

  • Utilized ionizing radiation (IR) and ultraviolet (UV) radiation to induce DNA damage.
  • Employed caffeine to inhibit ATM activity.
  • Assessed ATR activation and Chk2 phosphorylation (total and Thr68) in various cell lines, including ATM-deficient and ATM-silenced cells.
  • Performed in vitro kinase assays.

Main Results:

  • ATR phosphorylates Chk2 in response to both IR and UV radiation.
  • ATR activation by IR is enhanced in the presence of caffeine (ATM inhibition), leading to Chk2 hyperphosphorylation.
  • ATR activation by UV radiation is normal in ATM-+/+ and ATM-/- cells and is caffeine-sensitive.
  • In ATM-deficient cells, ATR is activated by IR and phosphorylates Chk2 in vitro.

Conclusions:

  • ATR acts as a kinase for Chk2, particularly under conditions of DNA damage.
  • ATR-mediated Chk2 phosphorylation is evident even when ATM is deficient or inhibited.
  • These findings suggest ATR's significant role in Chk2 phosphorylation during the DNA damage response, especially in ATM-compromised scenarios.

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