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The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells

Adrian P Bracken1, Daniela Kleine-Kohlbrecher, Nikolaj Dietrich

  • 1Centre for Epigenetics, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen 2200, Denmark. adrian.bracken@bric.dk

Genes & Development
|March 9, 2007
PubMed

Insights

The oncogene BMI1 represses cellular senescence regulators p16INK4A and p14ARF via Polycomb-Repressive Complex 2 (PRC2). Down-regulation of EZH2 in PRC2 activates transcription, providing a model for cancer development.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • Epigenetics

Background:

  • The INK4A-ARF locus encodes p16INK4A and p14ARF proteins, crucial for cellular senescence.
  • Mechanisms controlling the upregulation of these senescence regulators are not fully understood.

Purpose of the Study:

  • To elucidate the mechanisms by which the oncogene BMI1 represses the INK4A-ARF locus.
  • To investigate the role of Polycomb-Repressive Complex 2 (PRC2) in regulating INK4A-ARF expression.

Main Methods:

  • Investigated the direct association between BMI1 and the INK4A-ARF locus.
  • Assessed the dependency of BMI1-mediated repression on the EZH2-containing PRC2 complex.
  • Monitored EZH2 levels, H3K27me3 marks, BMI1 displacement, and transcription in stressed and senescent cells.

Main Results:

  • BMI1's repression of the INK4A-ARF locus requires its direct association and the presence of PRC2.
  • EZH2 is downregulated in stressed and senescent cells.
  • Downregulation of EZH2 correlates with decreased H3K27me3, BMI1 displacement, and transcriptional activation of the INK4A-ARF locus.

Conclusions:

  • Established a model for INK4A-ARF locus activation.
  • Demonstrated how Polycomb proteins, specifically PRC2 and BMI1, contribute to cancer by regulating senescence pathways.

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