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DNA double-strand breaks and ATM activation by transcription-blocking DNA lesions

Olivier Sordet1, Asako J Nakamura, Christophe E Redon

  • 1Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Cell Cycle (Georgetown, Tex.)
|December 22, 2009
PubMed

Insights

DNA damage response protein ATM is activated by transcription-blocking topoisomerase I complexes (TOP1cc) in neurons and lymphocytes. These complexes cause DNA double-strand breaks (DSBs) linked to R-loop formation, particularly at the IgH locus.

Area of Science:

  • Genetics
  • Molecular Biology
  • Neuroscience

Background:

  • The ATM (ataxia telangiectasia mutated) protein is essential for DNA double-strand break (DSB) repair.
  • Deficiency in ATM leads to severe neurodegenerative disorders.
  • Recent findings link transcription-blocking topoisomerase I cleavage complexes (TOP1cc) to DSB formation and ATM activation.

Purpose of the Study:

  • To elucidate the mechanism by which TOP1cc induce transcription arrest and DSBs.
  • To investigate the role of R-loop formation in this process.
  • To explore the activation of ATM by transcription-dependent DSBs and their genomic locations.

Main Methods:

  • Analysis of transcription-blocking TOP1cc formation.
  • Investigation of R-loop dynamics.
  • Assessment of DSB generation and ATM activation in relevant cell types (post-mitotic neurons, lymphocytes).
  • Genomic site analysis of DSB formation.

Main Results:

  • TOP1cc can cause transcription arrest and R-loop formation, leading to DSBs.
  • These transcription-dependent DSBs activate the ATM signaling pathway.
  • DSBs induced by TOP1cc show a tendency to occur at the IgH locus and other specific genomic regions.

Conclusions:

  • Transcription-blocking TOP1cc are a source of endogenous DSBs that activate ATM.
  • R-loop formation is implicated in the generation of these DSBs.
  • ATM plays a role in responding to TOP1cc-induced DNA damage, with potential implications for neurodegeneration and lymphocyte function.

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