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

  1. Adrian P. Bracken1,6,
  2. Daniela Kleine-Kohlbrecher1,
  3. Nikolaj Dietrich1,
  4. Diego Pasini1,
  5. Gaetano Gargiulo2,
  6. Chantal Beekman3,
  7. Kim Theilgaard-Mönch4,
  8. Saverio Minucci2,
  9. Bo T. Porse4,
  10. Jean-Christophe Marine3,
  11. Klaus H. Hansen1, and
  12. Kristian Helin1,5
  1. 1 Centre for Epigenetics, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen 2200, Denmark;
  2. 2 Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy;
  3. 3 Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, Ghent B-9052 Belgium;
  4. 4 The Laboratory for Gene Therapy Research, Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen 2100, Denmark

Abstract

The p16INK4A and p14ARF proteins, encoded by the INK4A-ARF locus, are key regulators of cellular senescence, yet the mechanisms triggering their up-regulation are not well understood. Here, we show that the ability of the oncogene BMI1 to repress the INK4A-ARF locus requires its direct association and is dependent on the continued presence of the EZH2-containing Polycomb-Repressive Complex 2 (PRC2) complex. Significantly, EZH2 is down-regulated in stressed and senescing populations of cells, coinciding with decreased levels of associated H3K27me3, displacement of BMI1, and activation of transcription. These results provide a model for how the INK4A-ARF locus is activated and how Polycombs contribute to cancer.

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