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A novel ATM-dependent pathway regulates protein phosphatase 1 in response to DNA damage

Xi Tang1, Zhou-Guang Hui, Xiao-Li Cui

  • 1Department of Biochemistry and Molecular Biology, Southern Research Institute, 2000 9th Ave. South, Birmingham, AL 35205, USA.

Molecular and Cellular Biology
|February 6, 2008
PubMed

Insights

Ionizing radiation (IR) activates Protein Phosphatase 1 (PP1) by causing its dissociation from inhibitor-2 (I-2), a process regulated by ATM kinase. This ATM-mediated pathway impacts DNA damage response and cell cycle checkpoints.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Protein Phosphatase 1 (PP1) is crucial for cellular responses.
  • PP1 activation is observed following DNA damage induced by ionizing radiation (IR).

Purpose of the Study:

  • To elucidate the mechanism by which IR activates PP1.
  • To identify the role of ataxia-telangiectasia mutated (ATM) kinase in PP1 regulation after IR.

Main Methods:

  • Investigated the dissociation of PP1 from its regulatory subunit inhibitor-2 (I-2) post-IR.
  • Utilized phosphorylation site analysis to determine ATM's role.
  • Assessed the impact on Aurora-B kinase activity and histone H3 phosphorylation.
  • Monitored G(2)/M checkpoint activation.

Main Results:

  • IR induces rapid dissociation of the PP1-I-2 complex.
  • ATM kinase phosphorylates I-2 at serine 43 in response to IR, triggering PP1 release and activation.
  • ATM-mediated I-2 phosphorylation inhibits Aurora-B kinase and down-regulates histone H3 serine 10 phosphorylation.
  • The pathway leads to the activation of the G(2)/M cell cycle checkpoint.

Conclusions:

  • A novel signaling pathway linking ATM, PP1, and I-2 in response to DNA damage has been identified.
  • This pathway is critical for regulating cellular responses to IR, including checkpoint activation.

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