Author:
Bracken Adrian P.,Kleine-Kohlbrecher Daniela,Dietrich Nikolaj,Pasini Diego,Gargiulo Gaetano,Beekman Chantal,Theilgaard-Mönch Kim,Minucci Saverio,Porse Bo T.,Marine Jean-Christophe,Hansen Klaus H.,Helin Kristian
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.
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
760 articles.
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