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Apoptotic DNA fragmentation factor maintains chromosome stability in a P53-independent manner

B Yan1, H Wang, H Wang

  • 1Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Oncogene
|April 19, 2006
PubMed

Insights

DNA fragmentation factor (DFF)/caspase-activated DNase (CAD) inhibition increases chromosome instability and tumor growth. This suggests DFF/CAD is crucial for maintaining genomic stability and suppressing tumor development, independent of P53 status.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • DNA fragmentation, mediated by DNA fragmentation factor (DFF)/caspase-activated DNase (CAD), is a key event in apoptosis.
  • The precise biological role of DNA fragmentation across species remains incompletely understood.

Purpose of the Study:

  • To investigate the role of DFF/CAD in maintaining chromosome stability and tumor suppression.
  • To elucidate the P53-independent functions of DFF/CAD.

Main Methods:

  • Generation of cell lines expressing a caspase-resistant inhibitor of CAD (ICAD) to constitutively inhibit DFF/CAD activity.
  • Irradiation of engineered cells and parental controls to assess chromosome aberrations and aneuploidy.
  • Evaluation of clonogenic survival and tumor growth in nude mice.

Main Results:

  • Inhibition of DFF/CAD led to increased chromosome aberrations and aneuploidy following irradiation.
  • DFF/CAD inhibition enhanced clonogenic survival of irradiated cells and delayed the clearance of DNA-damaged cells, irrespective of P53 status.
  • Tumors derived from cells with inhibited DFF/CAD exhibited accelerated growth.

Conclusions:

  • DFF/CAD plays a significant role in maintaining chromosome stability.
  • DFF/CAD functions independently of P53 in suppressing tumor development.
  • Inhibiting DFF/CAD promotes genomic instability and tumor progression.

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