USP7 enforces heterochromatinization of p53 target promoters by protecting SUV39H1 from MDM2-mediated degradation.
Open accessAbstract
The H3K9me3 repressive histone conformation of p53 target promoters is abrogated in response to p53 activation by MDM2-mediated SUV39H1 degradation. Here, we present evidence that the USP7 deubiquitinase protects SUV39H1 from MDM2-mediated ubiquitination in the absence of p53 stimulus. USP7 occupies p53 target promoters in unstressed conditions, a process that is abrogated with p53 activation associated with loss of the H3K9me3 mark on these same promoters. Mechanistically, USP7 forms a trimeric complex with MDM2 and SUV39H1, independent of DNA, and modulates MDM2-dependent SUV39H1 ubiquitination. Furthermore, we show that this protective function of USP7 on SUV39H1 is independent of p53. Finally, USP7 blocking cooperates with p53 in inducing apoptosis by enhancing p53 promoter occupancy and dependent transactivation of target genes. These results uncover a layer of the p53 transcriptional program mediated by USP7, which restrains relaxation of local chromatin conformation at p53 target promoters.
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SUV39H1 is an Mdm2 substrate that is deubiquitinated and stabilized by USP7 in undamaged cells.
“The SUV39H1 methyltransferase (also known as KMT1A) is another Mdm2 substrate that is deubiquitinated and stabilized by USP7 in undamaged cells (Bosch-Presegué et al., 2011; Mungamuri et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Mungamuri et al., 2016
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References 44 · Cited by 54
- Authors
- Mungamuri, S. K., Qiao, R. F., Yao, S., Manfredi, J. J., Gu, W., & Aaronson, S. A.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Columbia University (US)
- Corresponding author
- Aaronson, Stuart A.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 14
- Issue
- 11
- Pages
- 2528-2537
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4884055
- OpenAlex
- W2293406093
- Cited by
- 54
- References
- 44
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 7 · 2023: 4 · 2022: 6 · 2021: 9 · 2020: 7 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 3
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (P01CA080058)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- USP7, SUV39H1, MDM2, heterochromatinization, H3K9me3, deubiquitination, ubiquitination, p53 transcriptional activation, apoptosis, chromatin conformation, trimeric complex
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Antineoplastic Agents, Phytogenic, DNA, Etoposide, Heterochromatin, Histones, Humans, Methyltransferases, Promoter Regions, Genetic, Protein Binding, Repressor Proteins, Blotting, Western, Tumor Suppressor Protein p53, Apoptosis, RNA Interference, RNA, Small Interfering, Ubiquitin Thiolesterase, HCT116 Cells, Immunoprecipitation, Proto-Oncogene Proteins c-mdm2, Ubiquitination, Protein Stability, Real-Time Polymerase Chain Reaction
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