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DNA mismatch repair-dependent activation of c-Abl/p73alpha/GADD45alpha-mediated apoptosis

Long Shan Li1, Julio C Morales, Arlene Hwang

  • 1Laboratory of Molecular Stress Responses, Department of Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.

The Journal of Biological Chemistry
|May 16, 2008
PubMed

Insights

Functional DNA mismatch repair (MMR) triggers cell cycle arrest and apoptosis. This study reveals MMR-dependent apoptosis is p53-independent, involving hMLH1/c-Abl/p73alpha/GADD45alpha signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Functional DNA mismatch repair (MMR) normally induces G2 cell cycle arrest and apoptosis following DNA damage.
  • MMR-deficient cells evade this response, promoting survival of cells with mutations.
  • The signaling pathway mediating MMR-dependent G2 arrest and cell death is not fully understood.

Purpose of the Study:

  • To investigate the role of p53 in MMR-dependent G2 arrest and apoptosis.
  • To identify the retrograde signaling pathway responsible for MMR-dependent cell death.
  • To elucidate the signaling cascade initiated by DNA mismatch repair.

Main Methods:

  • Utilized p53 loss-of-function models (E6 expression, dominant-negative p53, p53 knockdown).
  • Examined the impact of c-Abl tyrosine kinase inhibitor (STI571/Gleevec) on MNNG-treated cells.
  • Assessed the effects of stable knockdown of c-Abl, p73alpha, and GADD45alpha on cellular responses.

Main Results:

  • Loss of p53 function did not prevent MMR-dependent G2 arrest, apoptosis, or cell lethality.
  • MMR-dependent upregulation of p73alpha and GADD45alpha via c-Abl was observed after MNNG exposure.
  • Inhibition of c-Abl or knockdown of c-Abl, p73alpha, or GADD45alpha blocked MMR-dependent apoptosis.
  • p73alpha knockdown abrogated apoptosis but not G2 arrest, uncoupling cell death from arrest.

Conclusions:

  • MMR-dependent apoptosis is a p53-independent process.
  • Retrograde signaling involving hMLH1/c-Abl/p73alpha/GADD45alpha stimulates MMR-dependent intrinsic apoptosis.
  • The study defines a novel signaling pathway crucial for DNA damage-induced cell death in MMR-proficient cells.

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