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H2AX is required for cell cycle arrest via the p53/p21 pathway

Michalis Fragkos1, Jaana Jurvansuu, Peter Beard

  • 1Ecole Polytechnique Federale de Lausanne, Faculty of Life Sciences, Swiss Institute for Experimental Cancer Research, 1015 Lausanne, Switzerland.

Molecular and Cellular Biology
|March 11, 2009
PubMed

Insights

Histone H2AX phosphorylation (gammaH2AX) signals DNA damage. This study reveals H2AX is crucial for preventing cell death after replication stalling by maintaining p21 levels and enabling cell cycle arrest.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Phosphorylation of H2AX (gammaH2AX) is a known early indicator of DNA damage from replication stalling.
  • The precise role of H2AX in repairing such DNA damage remains incompletely understood.

Purpose of the Study:

  • To investigate the function of gammaH2AX in DNA repair using an inactivated adeno-associated virus (AAV) model.
  • To elucidate the role of H2AX in the cellular response to replication stalling.

Main Methods:

  • Utilized inactivated adeno-associated virus (AAV) to induce replication stalling and pannuclear H2AX phosphorylation.
  • Employed RNA interference and H2AX-deficient cells to assess gammaH2AX function.
  • Analyzed protein degradation pathways (proteasome, caspase) and cell cycle regulation (p21).

Main Results:

  • Pannuclear gammaH2AX formation resulted from ATR overactivation and diffusion, independent of ATM.
  • gammaH2AX was dispensable for DNA repair foci formation and maintenance after replication stalling.
  • H2AX absence led to p21 degradation and mitotic catastrophe, whereas H2AX presence induced p21 increase and cell cycle arrest.

Conclusions:

  • Established a novel role for H2AX in the p53/p21 pathway.
  • Demonstrated that H2AX is essential for p21-mediated cell cycle arrest following replication stalling.
  • Highlighted H2AX's importance in preventing mitotic catastrophe in response to replication stress.

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