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E2F1 induces MRN foci formation and a cell cycle checkpoint response in human fibroblasts

F M Frame1, H A Rogoff, M T Pickering

  • 1Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, 01655, USA.

Oncogene
|January 26, 2006
PubMed

Insights

Deregulation of the Rb/E2F pathway triggers E2F1-mediated apoptosis. E2F1 causes DNA damage response foci, leading to a G1 cell cycle arrest that prevents cancer progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The Retinoblastoma (Rb)/E2F pathway controls cell cycle progression.
  • Deregulation of this pathway is implicated in human cancers.
  • E2F1 is a key transcription factor in this pathway, known to induce apoptosis.

Purpose of the Study:

  • To investigate the mechanism by which E2F1 deregulation leads to apoptosis.
  • To elucidate the role of the MRN complex and DNA damage response in E2F1-mediated effects.
  • To understand the cell cycle checkpoint and apoptosis pathways involved.

Main Methods:

  • Studied human fibroblasts with deregulated Rb/E2F pathway.
  • Analyzed E2F1 expression and its effect on MRN foci formation.
  • Assessed correlation with DNA damage markers (53BP1, gammaH2AX) and cell cycle progression.
  • Investigated checkpoint and apoptosis pathways using gene depletion (53BP1, p21).

Main Results:

  • E2F1 expression induced MRN foci formation, mimicking DNA double-strand breaks.
  • These foci formation was independent of Nbs1 interaction and E2F1 DNA-binding domains.
  • Deregulated E2F1 caused a G1 arrest via an Nbs1/53BP1/p53/p21(WAF1/CIP1) checkpoint pathway.
  • Depletion of 53BP1 or p21 enhanced apoptosis, indicating their protective role.
  • Nbs1 and p53 were crucial for both checkpoint and apoptosis.

Conclusions:

  • E2F1-induced foci activate a cell cycle checkpoint, preventing proliferation.
  • Sustained E2F1 activity eventually leads to apoptosis.
  • Cancer transformation requires Rb/E2F deregulation coupled with inactivated checkpoint and apoptosis programs.

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