Cited by 181Cancer-related Molecular PathwaysDNA Repair MechanismsUbiquitin and proteasome pathways

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Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage

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Pereg, Yaron, Shkedy, Dganit, de Graaf, Petra, Meulmeester, Erik, Edelson-Averbukh, Marina, Salek, Mogjiborahman, Biton, Sharon, Teunisse, Amina F. A. S., Lehmann, Wolf D., Jochemsen, Aart G., Shiloh, Yosef·2005·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0408595102PMC PMC555986

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Abstract

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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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
ORCID: Pereg, Yaron
Salek, Mogjiborahman
Teunisse, Amina F. A. S.
Jochemsen, Aart G.
Shiloh, Yosef
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
DOI: 10.1073/pnas.0408595102
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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Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage

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