Phosphorylation of Daxx by ATM contributes to DNA damage-induced p53 activation.
Open accessAbstract
p53 plays a central role in tumor suppression. It does so by inducing anti-proliferative processes as a response to various tumor-promoting stresses. p53 is regulated by the ubiquitin ligase Mdm2. The optimal function of Mdm2 requires Daxx, which stabilizes Mdm2 through the deubiquitinase Hausp/USP7 and also directly promotes Mdm2's ubiquitin ligase activity towards p53. The Daxx-Mdm2 interaction is disrupted upon DNA damage. However, both the mechanisms and the consequence of the Daxx-Mdm2 dissociation are not understood. Here we show that upon DNA damage Daxx is phosphorylated in a manner that is dependent on ATM, a member of the PI 3-kinase family that orchestrates the DNA damage response. The main phosphorylation site of Daxx is identified to be Ser564, which is a direct target of ATM. Phosphorylation of endogenous Daxx at Ser564 occurs rapidly during the DNA damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of Daxx from Mdm2, stabilizes Mdm2, and inhibits DNA damage-induced p53 activation. These results suggest that phosphorylation of Daxx by ATM upon DNA damage disrupts the Daxx-Mdm2 interaction and facilitates p53 activation.
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These phosphorylation events disrupt p53-Mdm2 and Mdm2-DAXX interactions and promote degradation of Mdm2 and Mdm4.
“These phosphorylation events contribute to disrupting the p53-Mdm2 (Chehab et al., 2000; Shieh et al., 2000), and Mdm2-DAXX (Tang et al., 2013) interactions, as well as to the degradation of Mdm2 and Mdm4 (Stommel and Wahl, 2004; Chen et al., 2005; Pereg et al., 2005, 2006; LeBron et al., 2006).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Tang et al., 2013
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References 28 · Cited by 28
- Authors
- Tang, J., Agrawal, T., Cheng, Q., Qu, L., Brewer, M. D., Chen, J., & Yang, X.
- Affiliations
- University of Pennsylvania (US)
- Moffitt Cancer Center (US)
- Corresponding author
- Yang, Xiaolu
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-02-06
- Volume
- 8
- Issue
- 2
- Pages
- e55813
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3566025
- OpenAlex
- W1978340482
- Cited by
- 28
- References
- 28
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 4 · 2013: 1
- FWCI
- 2.50
- Type
- journal article
- Language
- en
- Update notices
- correction (2013-09-19)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Defense (W81XWH)
- National Institutes of Health (W81XWH)
- National Cancer Institute (R01CA088868, T32CA009140, CA088868, P30CA016520)
- 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
- DAXX, ATM, p53 activation, DNA damage response, MDM2, protein phosphorylation, deubiquitination, tumor suppression
- MeSH terms
- Amino Acid Sequence, DNA Damage, DNA-Binding Proteins, Humans, Molecular Sequence Data, Neoplasms, Nuclear Proteins, Phosphorylation, RNA, Messenger, Serine, Tumor Cells, Cultured, Blotting, Western, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Cell Cycle Proteins, Molecular Chaperones, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-mdm2, Co-Repressor Proteins, Real-Time Polymerase Chain Reaction, Ataxia Telangiectasia Mutated Proteins
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