The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence

Agger, Karl; Cloos, Paul A.C.; Rudkjær, Lise; Williams, Kristine; Andersen, Gitte; Christensen, Jesper; Helin, Kristian

doi:10.1101/gad.510809

Cited by 427Telomeres, Telomerase, and SenescenceEpigenetics and DNA MethylationGenomics and Chromatin Dynamics

The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence

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Agger, Karl, Cloos, Paul A.C., Rudkjær, Lise, Williams, Kristine, Andersen, Gitte, Christensen, Jesper, Helin, Kristian·2009·Genes & Development

DOI 10.1101/gad.510809PMC PMC2685535

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Abstract

The tumor suppressor proteins p16 INK4A and p14 ARF, encoded by the INK4A–ARF locus, are key regulators of cellular senescence. The locus is epigenetically silenced by the repressive H3K27me3 mark in normally growing cells, but becomes activated in response to oncogenic stress. Here, we show that expression of the histone H3 Lys 27 (H3K27) demethylase JMJD3 is induced upon activation of the RAS–RAF signaling pathway. JMJD3 is recruited to the INK4A–ARF locus and contributes to the transcriptional activation of p16 INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16 Ink4a and p19 Arf expression and in their immortalization.

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Oncogene activation induces JMJD3, which removes repressive H3K27 tri-methylation marks and thereby promotes p16 expression.
“For example, oncogene activation induces the expression of the histone 3 Lys27 (H3K27) demethylase, Jumonji domain-containing D3 (JMJD3), which removes the repressive H3K27 tri-methylation marks and thereby promotes p16 expression [19].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [19]
During senescence, PRC delocalization from the CDKN2A locus, transcriptional downregulation of EZH2, and recruitment of JMJD3 lead to removal of the repressive H3K27me3 mark at the CDKN2A locus and facilitate p16 transcription.
“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 [84]

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Authors: Agger, K., Cloos, P. A. C., Rudkjær, L., Williams, K., Andersen, G., Christensen, J., & Helin, K.
Affiliations: University of Copenhagen (DK)
ORCID: Cloos, Paul A.C.
Williams, Kristine
Helin, Kristian
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2009-05-15
Volume: 23
Issue: 10
Pages: 1171-1176
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.510809
PMC: PMC2685535
OpenAlex: W1970592702
Cited by: 427
References: 26
Citations by year: 2026: 10 · 2025: 8 · 2024: 13 · 2023: 13 · 2022: 10 · 2021: 24 · 2020: 23 · 2019: 22 · 2018: 23 · 2017: 21 · 2016: 33 · 2015: 23 · 2014: 36 · 2013: 36 · 2012: 48
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders: Kræftens Bekæmpelse
Sundhed og Sygdom, Det Frie Forskningsråd
National Research Foundation
Danmarks Grundforskningsfond
Lundbeckfonden
Novo Nordisk
Harboefonden
Novo Nordisk Fonden
H. Lundbeck A/S
Medical Research Council
Topics: Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: JMJD3, H3K27 demethylase, H3K27me3, INK4a/ARF locus, p16INK4a, p14ARF, cellular senescence, oncogene-induced senescence, stress-induced senescence, Ras/Raf signaling, histone demethylation, epigenetic silencing, transcriptional activation, cell immortalization, histone demethylase
MeSH terms: Animals, Cell Line, Fibroblasts, Gene Expression Regulation, Humans, Neoplasms, Oncogenes, Oxidoreductases, N-Demethylating, Stress, Physiological, Cellular Senescence, ras Proteins, Cyclin-Dependent Kinase Inhibitor p16, Genes, p16, raf Kinases, Proto-Oncogene Proteins B-raf, Cell Proliferation, Mice, Jumonji Domain-Containing Histone Demethylases

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The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence

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