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The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells
Open accessAbstract
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.
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“The molecular mechanisms underlying this derepression are not completely understood but have been associated with loss of polycomb group of proteins but independent of p53 (Jacobs et al., 1999; Bracken et al., 2007).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Bracken et al., 2007
In the citing paper
“During senescence, PRC delocalization from the CDKN2A locus, transcriptional downregulation of EZH2 [83], and recruitment of JMJD3 [84,85], a histone lysine demethylase that catalyzes H3K27 demethylation, lead to removal of the repressive H3K27me3 mark at the CDKN2A locus and facilitate p16 transcription.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [83]
In the citing paper
“The mechanistic details of how this happens are starting to emerge, and seem in part to involve the progressive loss of repressive Polycomb complexes 7”
From The common biology of cancer and ageing (2007) · cites this paper as [7]
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Citations
Cites
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Cellular senescence: when bad things happen to good cells
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Metadata
- Authors
- Bracken, A. P., Kleine-Kohlbrecher, D., Dietrich, N., Pasini, D., Gargiulo, G., Beekman, C., Theilgaard-Mönch, K., Minucci, S., Porse, B. T., Marine, J.-C., Hansen, K. H., & Helin, K.
- Affiliations
- University of Copenhagen (DK)
- European Institute of Oncology (IT)
- Vlaams Instituut voor Biotechnologie (BE)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-03-01
- Volume
- 21
- Issue
- 5
- Pages
- 525-530
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1820894
- OpenAlex
- W2101370480
- Cited by
- 850
- References
- 40
- Citations by year
- 2026: 16 · 2025: 14 · 2024: 20 · 2023: 26 · 2022: 29 · 2021: 40 · 2020: 43 · 2019: 30 · 2018: 32 · 2017: 50 · 2016: 76 · 2015: 48 · 2014: 48 · 2013: 55 · 2012: 58
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- Kræftens Bekæmpelse
- Sundhed og Sygdom, Det Frie Forskningsråd
- Lundbeckfonden (R9-2007-978)
- Novo Nordisk
- Novo Nordisk Fonden
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Polycomb group proteins, INK4a/ARF locus, p16INK4a, p14ARF, cellular senescence, BMI1, EZH2, polycomb repressive complex 2, H3K27me3, chromatin repression, transcriptional activation, cancer
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Cell Line, DNA-Binding Proteins, Embryo, Mammalian, Fibroblasts, Histones, Humans, Methylation, Mice, Inbred C57BL, Neoplasms, Nuclear Proteins, Histone-Lysine N-Methyltransferase, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Stem Cells, Transcription Factors, Down-Regulation, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Genes, p16, Oligonucleotide Array Sequence Analysis, Tumor Suppressor Protein p14ARF, Chromatin Immunoprecipitation, Mice, Polycomb Repressive Complex 1, Polycomb Repressive Complex 2
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