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Updated: Jul 13, 2026

Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
Published on: September 28, 2012
A p53 amino-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation
1Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, and Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, NC 27599-7295, USA.
Abstract:
The p53 protein is present in low amounts in normally growing cells and is activated in response to physiological insults. MDM2 regulates p53 either through inhibiting p53's transactivating function in the nucleus or by targeting p53 degradation in the cytoplasm. We identified a previously unknown nuclear export signal (NES) in the amino terminus of p53, spanning residues 11 to 27 and containing two serine residues phosphorylated after DNA damage, which was required for p53 nuclear export in colloboration with the carboxyl-terminal NES. Serine-15-phosphorylated p53 induced by ultraviolet irradiation was not exported. Thus, DNA damage-induced phosphorylation may achieve optimal p53 activation by inhibiting both MDM2 binding to, and the nuclear export of, p53.
Insights
The tumor suppressor p53 protein
Area of Science:
- Molecular Biology
- Cellular Biology
- Cancer Research
Background:
- The p53 protein is a crucial tumor suppressor.
- MDM2 negatively regulates p53 activity through inhibition and degradation.
- Understanding p53 regulation is vital for cancer therapy.
Purpose of the Study:
- To identify novel regulatory mechanisms of p53.
- To investigate the role of p53 phosphorylation in its regulation.
- To elucidate how DNA damage impacts p53 localization and activity.
Main Methods:
- Identification of a novel nuclear export signal (NES) in p53.
- Phosphorylation site analysis of p53 residues.
- Investigation of p53 nuclear export dynamics following DNA damage.
Main Results:
- A novel N-terminal NES (residues 11-27) in p53 was identified.
- This NES contains two serine residues phosphorylated upon DNA damage.
- Phosphorylation of Serine-15 in p53, induced by UV irradiation, inhibited nuclear export.
- DNA damage-induced phosphorylation of p53 may prevent its export and MDM2 binding.
Conclusions:
- DNA damage-induced phosphorylation of p53 inhibits its nuclear export.
- This inhibition, along with reduced MDM2 binding, contributes to optimal p53 activation.
- These findings reveal a new layer of p53 regulation critical for cellular response to DNA damage.
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