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Phosphorylation of Daxx by ATM contributes to DNA damage-induced p53 activation.
- Source :
-
PloS one [PLoS One] 2013; Vol. 8 (2), pp. e55813. Date of Electronic Publication: 2013 Feb 06. - Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Amino Acid Sequence
Ataxia Telangiectasia Mutated Proteins
Blotting, Western
Cell Cycle Proteins genetics
Co-Repressor Proteins
DNA-Binding Proteins genetics
Humans
Immunoprecipitation
Molecular Chaperones
Molecular Sequence Data
Neoplasms genetics
Neoplasms pathology
Nuclear Proteins genetics
Phosphorylation
Protein Serine-Threonine Kinases genetics
Proto-Oncogene Proteins c-mdm2 genetics
RNA, Messenger genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Sequence Homology, Amino Acid
Serine genetics
Serine metabolism
Tumor Cells, Cultured
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Proteins genetics
Adaptor Proteins, Signal Transducing metabolism
Cell Cycle Proteins metabolism
DNA Damage genetics
DNA-Binding Proteins metabolism
Neoplasms metabolism
Nuclear Proteins metabolism
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins c-mdm2 metabolism
Tumor Suppressor Protein p53 metabolism
Tumor Suppressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23405218
- Full Text :
- https://doi.org/10.1371/journal.pone.0055813