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Early events in the mammalian response to DNA double-strand breaks

Lucy C Riches1, Anthony M Lynch, Nigel J Gooderham

  • 1Department of Biomolecular Medicine, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.

Mutagenesis
|July 23, 2008
PubMed

Insights

Mammalian cells detect DNA double-strand breaks (DSBs) using a complex protein network. Early response mechanisms, including the MRE11-NBS1-RAD50 complex and ATM kinase, are crucial for maintaining genetic integrity.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • DNA double-strand breaks (DSBs) are potent mutagens.
  • Cellular response involves a complex network of proteins categorized as sensors, transducers, mediators, and effectors.
  • Overlapping functions and cooperative pathways exist within the DSB response network.

Purpose of the Study:

  • To review the fundamental events in the early stages of the DNA double-strand break (DSB) response.
  • To emphasize the mechanisms maintaining genetic integrity following DSB induction.

Main Methods:

  • Literature review of protein functions in DNA double-strand break (DSB) response.
  • Analysis of signaling pathways involving key protein complexes and kinases.
  • Examination of protein modifications and sub-nuclear redistribution.

Main Results:

  • The MRE11-NBS1-RAD50 complex is essential for optimal activation of ataxia-telangiectasia-mutated (ATM) kinase.
  • ATM kinase initiates a phosphorylation cascade, affecting proteins like histone H2AX (H2AX) and nibrin (NBS1).
  • Post-translational modifications rapidly alter protein behavior and mediate damage-specific interactions.

Conclusions:

  • The early DSB response is a highly coordinated process essential for maintaining genetic integrity.
  • Overlapping functions among response proteins ensure a vigilant cellular defense against DNA damage.
  • Understanding these early events is critical for comprehending the overall cellular response to potent mutagens.

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