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Activation of the cellular DNA damage response in the absence of DNA lesions

Evi Soutoglou1, Tom Misteli

  • 1National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. soutogle@mail.nih.gov

Science (New York, N.Y.)
|May 17, 2008
PubMed

Insights

Stable binding of DNA repair factors to chromatin can trigger the DNA damage response (DDR) without actual DNA damage. This process involves ATM and DNA-PK, highlighting chromatin association as a key DDR activation step.

Area of Science:

  • Cellular biology
  • Molecular genetics
  • Biochemistry

Background:

  • The DNA damage response (DDR) is crucial for maintaining genomic stability.
  • The precise mechanisms by which DNA repair complexes sense DNA damage and activate the DDR are not fully understood.

Purpose of the Study:

  • To investigate whether DNA damage is strictly required for DDR activation.
  • To elucidate the role of DNA repair factor binding to chromatin in DDR initiation.

Main Methods:

  • Targeting DNA repair factors to chromatin in the absence of DNA damage.
  • Assessing DDR activation through ATM and DNA-PK dependent pathways.
  • Analyzing protein-protein interactions within the repair complex.

Main Results:

  • Prolonged binding of DNA repair factors to chromatin can induce the DDR independently of DNA damage.
  • ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase) are essential for this damage-independent DDR.
  • A hierarchy of protein interactions within the repair complex was observed, suggesting signal amplification.

Conclusions:

  • DDR activation does not necessitate DNA damage.
  • Stable association of DNA repair factors with chromatin is a critical trigger for DDR initiation, amplification, and maintenance.

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