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Autophosphorylation at serine 1981 stabilizes ATM at DNA damage sites

Sairei So1, Anthony J Davis, David J Chen

  • 1Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, 75390, USA.

The Journal of Cell Biology
|December 23, 2009
PubMed

Insights

Autophosphorylation of Ataxia telangiectasia mutated (ATM) at serine 1981 is crucial for its sustained localization to DNA double-strand breaks (DSBs). This stabilization is essential for ATM

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • Ataxia telangiectasia mutated (ATM) is a key protein kinase involved in DNA damage response pathways.
  • ATM activation, typically marked by autophosphorylation at serine 1981, is critical for cellular survival after DNA damage.
  • The precise role of ATM autophosphorylation in its localization and sustained activity at DNA double-strand breaks (DSBs) remains incompletely understood.

Purpose of the Study:

  • To investigate the requirement of ATM autophosphorylation at serine 1981 for its localization and retention at DSBs.
  • To elucidate the role of ATM autophosphorylation in the activation of its kinase activity and downstream signaling.
  • To determine the contribution of ATM autophosphorylation to cellular radioresistance.

Main Methods:

  • Utilized techniques to assess ATM localization to DSBs in response to DNA damage.
  • Investigated the interaction between ATM, the MRE11-RAD50-NBS1 complex, and MDC1.
  • Employed genetic approaches, including ablation of ATM autophosphorylation and MDC1 knockdown, to study functional consequences.

Main Results:

  • Initial ATM localization to DSBs depends on the MRE11-RAD50-NBS1 complex.
  • Sustained retention of ATM at DSBs requires autophosphorylation at serine 1981 and interaction with MDC1.
  • Impaired ATM autophosphorylation or MDC1 levels reduce ATM's ability to phosphorylate substrates and confer radioresistance.

Conclusions:

  • ATM autophosphorylation at serine 1981 is essential for its stable association with DSBs.
  • This stabilization mediated by autophosphorylation and MDC1 is critical for effective DNA damage signaling and repair.
  • ATM autophosphorylation is a key regulatory step for maintaining DNA damage response fidelity and cellular integrity.

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