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08:47

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MDC1 cleavage by caspase-3: a novel mechanism for inactivating the DNA damage response during apoptosis

Stéphanie Solier1, Yves Pommier

  • 1Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.

Cancer Research
|December 15, 2010
PubMed

Insights

The apoptotic ring, marked by phosphorylated histone H2AX (γ-H2AX), does not recruit DNA damage response (DDR) factors. This occurs because caspase-3 cleaves mediator of DNA damage checkpoint protein 1 (MDC1), inactivating DNA repair during apoptosis.

Area of Science:

  • Cell biology
  • Molecular biology
  • Biochemistry

Background:

  • Phosphorylated histone H2AX (γ-H2AX) marks the "apoptotic ring" during early apoptosis.
  • γ-H2AX typically initiates the DNA damage response (DDR), recruiting factors for DNA repair and cell-cycle checkpoints.

Purpose of the Study:

  • To investigate if the apoptotic γ-H2AX response fully recruits DDR factors.
  • To elucidate the mechanism of DNA repair inactivation during apoptosis.

Main Methods:

  • Western blotting to detect protein cleavage.
  • Analysis of DDR factor recruitment to chromatin.
  • Assessment of apoptosis induction upon MDC1 downregulation.

Main Results:

  • The apoptotic γ-H2AX response does not lead to full DDR factor recruitment.
  • Caspase-3 cleaves mediator of DNA damage checkpoint protein 1 (MDC1), separating its functional domains.
  • MDC1 cleavage prevents amplification of the DDR.
  • Downregulation of MDC1 enhances apoptosis induced by TRAIL.

Conclusions:

  • MDC1 cleavage by caspase-3 is a novel mechanism for inactivating DNA repair in apoptotic cells.
  • MDC1 plays a significant role in the cellular apoptotic response.

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