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Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage

Chuangui Wang1, Lihong Chen, Xinghua Hou

  • 1Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.

Nature Cell Biology
|August 8, 2006
PubMed

Insights

The cell cycle regulator E2F1 induces SirT1, a deacetylase involved in aging and stress. SirT1 then inhibits E2F1, creating a feedback loop that impacts DNA damage sensitivity.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • The NAD-dependent deacetylase Sir2 (silent information regulator 2) and its mammalian homologue SirT1 are involved in gene silencing, lifespan regulation, and stress responses.
  • SirT1 influences key transcription factors including p53, NF-kappaB, and Forkhead proteins.

Purpose of the Study:

  • To investigate the regulatory relationship between the cell-cycle and apoptosis regulator E2F1 and the deacetylase SirT1.
  • To elucidate the role of the E2F1-SirT1 interaction in cellular responses to DNA damage.

Main Methods:

  • Transcriptional analysis to determine E2F1's effect on SirT1 expression.
  • Co-immunoprecipitation to assess SirT1 binding to E2F1.
  • Small interference RNA (siRNA) to knock down SirT1 levels.
  • Assessment of E2F1 transcriptional activity and apoptosis.
  • Evaluation of cellular sensitivity to etoposide-induced DNA damage.

Main Results:

  • E2F1 was found to induce SirT1 expression at the transcriptional level.
  • SirT1 physically interacts with E2F1 and inhibits its transcriptional and apoptotic functions, establishing a negative feedback loop.
  • SirT1 knockdown potentiated E2F1's functions and increased cellular sensitivity to etoposide.
  • DNA damage induced by etoposide led to E2F1-dependent SirT1 expression.

Conclusions:

  • A mutual regulatory mechanism exists between E2F1 and SirT1.
  • This E2F1-SirT1 interplay significantly influences cellular sensitivity to DNA damage and apoptosis.

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