The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells
Bracken, Adrian P Kleine-Kohlbrecher, Daniela Dietrich, Nikolaj Pasini, Diego Gargiulo, Gaetano Beekman, Chantal Theilgaard-Monch, Kim Minucci, Saverio Porse, Bo T Marine, Chris Hansen, Klaus H Helin, Kristian # ×
Cold Spring Harbor Laboratory Press
Genes & Development vol:21 issue:5 pages:525-530
The p16(INK4A) and p14(ARF) 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.