Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage
Open accessAbstract
Maintenance of genomic stability depends on the DNA damage response, an extensive signaling network that is activated by DNA lesions such as double-strand breaks (DSBs). The primary activator of the mammalian DSB response is the nuclear protein kinase ataxia–telangiectasia, mutated (ATM), which phosphorylates key players in various arms of this network. The activation and stabilization of the p53 protein play a major role in the DNA damage response and are mediated by ATM-dependent posttranslational modifications of p53 and Mdm2, a ubiquitin ligase of p53. p53's response to DNA damage also depends on Mdm2-dependent proteolysis of Mdmx, a homologue of Mdm2 that represses p53's transactivation function. Here we show that efficient damage-induced degradation of human Hdmx depends on functional ATM and at least three sites on the Hdmx that are phosphorylated in response to DSBs. One of these sites, S403, is a direct ATM target. Accordingly, each of these sites is important for Hdm2-mediated ubiquitination of Hdmx after DSB induction. These results demonstrate a sophisticated mechanism whereby ATM fine-tunes the optimal activation of p53 by simultaneously modifying each player in the process.
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Mdmx is relatively stable compared with Mdm2 and p53, presumably due to preferential ubiquitylation of the latter proteins.
“It appears that Mdmx is relatively stable compared with Mdm2 and p53 [41], presumably due to preferential ubiquitylation of the latter proteins.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [41]
Phosphorylation of Mdm2 and Mdmx at serine residues close to the RING domain by ATM or ATM-dependent kinases leads to accelerated auto-degradation of both Mdm2 and Mdmx, with consequent p53 accumulation and activation.
“Additionally, phosphorylation of Mdm2 and Mdmx at serine residues close to the RING domain by ATM or ATM-dependent kinases leads to accelerated auto-degradation of both Mdm2 [54] and Mdmx [41,55–58], with consequent p53 accumulation and activation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [41]
A recent study demonstrated phosphorylation of S403 by ATM using a phosphorylation-specific antibody.
“A recent study was able to demonstrate the phosphorylation of S403 by ATM using a phosphorylation-specific antibody (Pereg et al, 2005).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Pereg et al, 2005
S403 of MDMX is an ATM target site.
“S403 is in a favorable context for ATM and a recent study by Pereg et al (2005) provided direct evidence that it is an ATM target site.”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Pereg et al (2005)
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- Authors
- Pereg, Y., Shkedy, D., de Graaf, P., Meulmeester, E., Edelson-Averbukh, M., Salek, M., Biton, S., Teunisse, A. F. A. S., Lehmann, W. D., Jochemsen, A. G., & Shiloh, Y.
- Affiliations
- Leiden University (NL)
- The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-03-23
- Volume
- 102
- Issue
- 14
- Pages
- 5056-5061
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC555986
- OpenAlex
- W2002689109
- Semantic Scholar
- c63ebd3c151eb1c16e18c06118e0ac4a4083d45d
- Cited by
- 181
- References
- 37
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 4 · 2022: 7 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 7 · 2017: 3 · 2016: 12 · 2015: 7 · 2014: 12 · 2013: 10 · 2012: 11
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Minerva Foundation
- KWF Kankerbestrijding
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS031763, NS 31763)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- HDMX, MDM2, ATM, phosphorylation, DNA damage response, DNA double-strand breaks, p53, ubiquitination, proteolysis, genome stability, post-translational modification
- MeSH terms
- Ataxia Telangiectasia, Binding Sites, Cell Line, DNA Damage, DNA-Binding Proteins, Humans, Nuclear Proteins, Phosphorylation, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Transfection, Signal Transduction, Tumor Suppressor Protein p53, Mutagenesis, Site-Directed, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Proto-Oncogene Proteins c-mdm2, Ataxia Telangiectasia Mutated Proteins
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