The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells
- Adrian P. Bracken1,6,
- Daniela Kleine-Kohlbrecher1,
- Nikolaj Dietrich1,
- Diego Pasini1,
- Gaetano Gargiulo2,
- Chantal Beekman3,
- Kim Theilgaard-Mönch4,
- Saverio Minucci2,
- Bo T. Porse4,
- Jean-Christophe Marine3,
- Klaus H. Hansen1, and
- Kristian Helin1,5
- 1 Centre for Epigenetics, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen 2200, Denmark;
- 2 Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy;
- 3 Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, Ghent B-9052 Belgium;
- 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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Footnotes
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↵5 Corresponding authors.
↵5 E-MAIL kristian.helin{at}bric.dk; FAX 45-3532-5669.
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↵6 E-MAIL adrian.bracken{at}bric.dk; FAX 45-3532-5669.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.415507
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- Received October 23, 2006.
- Accepted January 22, 2007.
- Copyright © 2007, Cold Spring Harbor Laboratory Press