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

Adrian P. Bracken(University of Copenhagen), Daniela Kleine‐Kohlbrecher(University of Copenhagen), Nikolaj Dietrich(University of Copenhagen), Diego Pasini(University of Copenhagen), Gaetano Gargiulo(European Institute of Oncology), Chantal Beekman(Ghent University Hospital), Kim Theilgaard‐Mönch(University of Copenhagen), Saverio Minucci(European Institute of Oncology), Bo Porse(University of Copenhagen), Jean‐Christophe Marine(Ghent University Hospital), Klaus Hansen(University of Copenhagen), Kristian Helin(University of Copenhagen)
Genes & Development
March 1, 2007
10.1101/gad.415507
Cited by 838Open Access
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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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