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ATM specifically mediates repair of double-strand breaks with blocked DNA ends

Alejandro Álvarez-Quilón1, Almudena Serrano-Benítez1, Jenna Ariel Lieberman1

  • 1Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla (Departamento de Genética), Sevilla 41092, Spain.

Nature Communications
|February 28, 2014
PubMed

Insights

Ataxia telangiectasia (AT) is linked to DNA damage response deficiencies. This study shows ATM is crucial for repairing blocked DNA double-strand breaks (DSBs), preventing cell death and instability, suggesting blocked DNA ends trigger AT.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Ataxia telangiectasia (AT) arises from ATM mutations, linking DNA-damage response (DDR) deficiencies to cancer predisposition and neurodegeneration.
  • ATM's role in signaling after DNA double-strand breaks (DSBs) is well-studied, yet its precise impact on DSB repair remains debated.

Purpose of the Study:

  • To investigate the role of ATM in DNA double-strand break (DSB) repair.
  • To clarify ATM's function in preventing genomic instability and cell death following DSBs.
  • To explore the pathogenic mechanisms underlying ataxia telangiectasia and related disorders.

Main Methods:

  • Development of novel genetic and molecular tools to alter DNA double-strand break (DSB) end structures.
  • Experimental manipulation of DSB end structures to assess ATM's requirement for repair.
  • Assessment of cell viability and genome stability in response to modified DSBs.

Main Results:

  • ATM is essential for efficient and accurate DNA double-strand break (DSB) repair.
  • ATM's requirement for DSB repair is specifically observed when DNA ends are irreversibly blocked.
  • Failure to repair blocked DSBs leads to cell death and genomic instability.

Conclusions:

  • ATM plays a critical role in the repair of irreversibly blocked DNA double-strand breaks (DSBs).
  • Blocked DNA ends, rather than DSBs per se, may act as the pathogenic trigger in ataxia telangiectasia and related syndromes.
  • This finding elucidates ATM's function in maintaining genome integrity and preventing disease.

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