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Updated: Aug 17, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Involvement of poly(ADP-ribose) polymerase activity in regulating Chk1-dependent apoptotic cell death

Julie K Horton1, Donna F Stefanick, Samuel H Wilson

  • 1Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.

DNA Repair
|July 9, 2005
PubMed

Insights

Inhibiting poly(ADP-ribose) polymerase (PARP) with 4-AN transforms methyl methanesulfonate (MMS) cell death from necrosis to apoptosis. PARP inhibition signals cell death via a Chk1-dependent pathway, enhancing survival when combined with UCN-01.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Poly(ADP-ribose) polymerase (PARP) activity increases with DNA damage, consuming NAD+ and depleting ATP.
  • Methyl methanesulfonate (MMS) causes ATP depletion and necrosis in mouse fibroblasts.
  • PARP inhibition prevents ATP loss and alters cell death pathways.

Purpose of the Study:

  • To investigate the role of PARP inhibition in modulating cell death pathways induced by MMS.
  • To determine the effects of PARP inhibition on ATP levels and cell fate.
  • To explore the involvement of caspases and Chk1 in PARP inhibitor-mediated cell death.

Main Methods:

  • Utilizing methyl methanesulfonate (MMS) to induce DNA damage.
  • Employing the PARP inhibitor 4-amino-1,8-naphthalimide (4-AN).
  • Assessing cell death mechanisms (apoptosis vs. necrosis) using caspase inhibitors (Z-VAD) and Chk1 inhibitors (UCN-01).
  • Monitoring intracellular ATP levels.

Main Results:

  • PARP inhibition with 4-AN prevents ATP depletion caused by MMS.
  • PARP inhibition shifts MMS-induced cell death from necrosis to apoptosis.
  • Caspase inhibition redirects cell death to necrosis, indicating a caspase-dependent apoptotic component.
  • Co-inhibition of PARP and Chk1 (with UCN-01) enhances cell survival.

Conclusions:

  • PARP inhibition transforms sub-lethal MMS exposure into a cytotoxic event via apoptosis.
  • Cell death signaling involves a caspase-dependent pathway.
  • PARP inhibition, coupled with Chk1 inhibition, offers a potential strategy for enhancing cell survival following DNA damage.

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