The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.
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.
Bracken
Adrian P
AP
Centre for Epigenetics, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen 2200, Denmark. adrian.bracken@bric.dk
Kleine-Kohlbrecher
Daniela
D
Dietrich
Nikolaj
N
Pasini
Diego
D
Gargiulo
Gaetano
G
Beekman
Chantal
C
Theilgaard-Mönch
Kim
K
Minucci
Saverio
S
Porse
Bo T
BT
Marine
Jean-Christophe
JC
Hansen
Klaus H
KH
Helin
Kristian
K
D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence; D047369:Chromatin Immunoprecipitation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology; D000071221:Enhancer of Zeste Homolog 2 Protein; D005347:Fibroblasts / Q000166:cytology; D019942:Genes, p16; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D063150:Polycomb Repressive Complex 1; D063151:Polycomb Repressive Complex 2; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics
C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1