The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.
By A. Bracken, D. Kleine-Kohlbrecher, Nikolaj Dietrich, Diego Pasini, G. Gargiulo, C. Beekman, K. Theilgaard-Mönch, S. Minucci, B. Porse, J. Marine and 2 more. Genes & Development, 2007
930 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/acaf4b091309bd9722bcf224dc5c252ae9db84bf
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Molecular Biology
- S. Morrison
- Jesús Gil
- N. Sharpless
- J. Simon
- Irving L. Weissman
- Domhnall McHugh
- Robert E. Kingston
- Shenghui He
In Physiology
- Jesús Gil
- Domhnall McHugh
- S. Morrison
- Stuart H. Orkin
- Shenghui He
- Derrick J. Rossi
- N. Sharpless
- W. Mooi
Citations in the corpus
- Stems cells and the pathways to aging and cancer. (2008, background): “Intriguingly, Bmi-1-mediated suppression of the p16-p19 locus is dependent upon the presence of Ezh2 (Bracken et al., 2007), suggesting a mechanism through which reduced expression of Ezh2 in aged HSCs (Rossi et al.”
- Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. (2008, background): “Moreover, a recent study has provided a direct mechanistic link between PcG activity, H3K27 methylation, and the transcription of the INK4A–ARF locus in senescence (Bracken et al. 2007).”
- EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. (2008, background): “It has been reported that decreased Ezh2 levels in senescent cells and aged stem cells lead to the activation of the Ink4f-Arf locus encoding Cdkn2a, a negative regulator of the cell cycle, and subsequent decreases in proliferation and stem cell self-renewal (Bracken et al., 2007).”
- The essence of senescence. (2010, background): “Whereas polycomb group proteins have been shown to repress the INK4A/ARF locus (Jacobs et al. 1999; Gil et al. 2004; Bracken et al. 2007), the histone H3-Lys 27 demethylase JMJD3 contributes to its transcriptional activation (Agger et al.”
- Mechanisms of stem cell self-renewal. (2009, background): “Bmi-1 is one component of polycomb repressor complex 1 that appears to repress p16Ink4a/p19Arf by binding to trimethylated H3K27 at this locus (Bracken et al. 2007, Jacobs et al. 1999, Kotake et al. 2007).”
- Hmga2 promotes neural stem cell self-renewal in young, but not old, mice by reducing p16Ink4a and p19Arf expression (2008, background): “Recent data raised the possibility that loss of Ezh2 function in aging stem cells may contribute to increasing p16/p19 expression (Bracken et al., 2007).”
- Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition (2010, background): “PRC1 recognizes trimethylated H3K27 (H3K27me3) and maintains the repression of target gene”