p53-mediated heterochromatin reorganization regulates its cell fate decisions.
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p53 is a major sensor of cellular stresses, and its activation influences cell fate decisions. We identified SUV39H1, a histone code 'writer' responsible for the histone H3 Lys9 trimethylation (H3K9me3) mark for 'closed' chromatin conformation, as a target of p53 repression. SUV39H1 downregulation was mediated transcriptionally by p21 and post-translationally by MDM2. The H3K9me3 repression mark was found to be associated with promoters of representative p53 target genes and was decreased upon p53 activation. Overexpression of SUV39H1 maintained higher levels of the H3K9me3 mark on these promoters and was associated with decreased p53 promoter occupancy and decreased transcriptional induction in response to p53. Conversely, SUV39H1 pre-silencing decreased H3K9me3 levels on these promoters and enhanced the p53 apoptotic response. These findings uncover a new layer of p53-mediated chromatin regulation through modulation of histone methylation at p53 target promoters.
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SUV39H1 negatively regulates p53 transcriptional activation by co-localizing with p53 at target promoters and trimethylating H3K9 to promote heterochromatin.
“As with Mdm4, SUV39H1 negatively regulates the transcriptional activation of p53. It does so by co-localizing with p53 at the promoters of target genes, where it trimethylates lysine 9 of histone H3 (H3K9me3) to promote formation of transcriptionally inactive higher-order heterochromatin (Mungamuri et al., 2012).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Mungamuri et al., 2012
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- Authors
- Mungamuri, S. K., Benson, E. K., Wang, S., Gu, W., Lee, S. W., & Aaronson, S. A.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- University of Michigan (US)
- Columbia University (US)
- Harvard University (US)
- Corresponding author
- Aaronson, Stuart A
- Venue
- Nature Structural & Molecular Biology
- Published
- 2012-04-01
- Volume
- 19
- Issue
- 5
- Pages
- 478-484
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC4009975
- OpenAlex
- W2157049798
- Cited by
- 53
- References
- 60
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 5 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 4 · 2015: 4 · 2014: 7 · 2013: 8 · 2012: 1
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2r01ca085533-16)
- National Cancer Institute (R01-CA085533, P01CA080058)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- p53, SUV39H1, H3K9me3, heterochromatin, histone methylation, p21, MDM2, chromatin regulation, cell fate determination, apoptosis, transcriptional repression
- MeSH terms
- Cell Line, Gene Expression Regulation, Heterochromatin, Histones, Humans, Methylation, Methyltransferases, Repressor Proteins, Tumor Suppressor Protein p53, Apoptosis, Cyclin-Dependent Kinase Inhibitor p21, Proto-Oncogene Proteins c-mdm2, Cell Cycle Checkpoints
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