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Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
Published on: September 28, 2012
p53 Suppresses E2F1-dependent PLK1 expression upon DNA damage by forming p53-E2F1-DNA complex.
Zhe Zhou1, Ji-Xiang Cao, Shu-Yan Li
1Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Xue Yuan Road 38, Beijing 100191, PR China.
Experimental Cell Research
|October 1, 2013
Summary
The tumor suppressor p53 interacts with E2F1 to form a complex that represses polo-like kinase-1 (PLK1) gene expression, particularly after DNA damage. This p53-E2F1 interaction suppresses PLK1, promoting apoptosis and regulating cellular stress responses.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Polo-like kinase-1 (PLK1) is crucial for cell cycle progression and its suppression is vital for DNA damage checkpoints.
- E2F1 is known to activate PLK1 transcription, but the regulatory mechanisms, especially under DNA damage, are not fully elucidated.
- Previous studies indicated p53 can suppress PLK1 gene expression via direct promoter binding.
Purpose of the Study:
- To investigate a novel mechanism by which p53 regulates E2F1-dependent PLK1 expression.
- To elucidate the role of p53-E2F1 interaction in controlling PLK1 transcription in response to DNA damage.
- To understand how this regulatory pathway contributes to apoptosis and cellular stress response.
Main Methods:
- Co-transfection and reporter enzyme assays to assess PLK1 promoter activity.
- Site-directed mutagenesis and deletion analysis of the PLK1 promoter to identify regulatory elements.
- Co-immunoprecipitation and electrophoretic mobility shift assays (EMSA) to detect protein-DNA and protein-protein interactions.
- Chromatin immunoprecipitation (ChIP) and re-ChIP assays to confirm in vivo complex formation.
Main Results:
- p53 suppressed PLK1 gene activation, while E2F1 promoted it.
- Specific E2F1 binding sites (-75/-68 and -40/-32) on the PLK1 promoter were essential for E2F1-mediated activation.
- p53-mediated suppression of PLK1 was dependent on the E2F1 binding site at -40/-32, with complete abrogation upon its mutation.
- DNA damage induced p53-E2F1 complex formation on the PLK1 promoter, confirmed by in vitro and in vivo assays.
- Suppression of PLK1 by p53 was shown to promote apoptosis.
Conclusions:
- p53 interacts with E2F1 to form a p53-E2F1-DNA complex that represses E2F1-driven PLK1 expression.
- This novel mechanism highlights a p53-dependent regulation of E2F1 activity on the PLK1 gene during DNA damage.
- The p53-E2F1-PLK1 pathway plays a significant role in mediating apoptosis and cellular response to DNA damage stress.
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