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Published on: September 24, 2015
Speckle-type POZ protein, SPOP, is involved in the DNA damage response
Dan Zhang1, Haibo Wang2, Mianen Sun3
1Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University Medical College, Xi'An, Shaanxi 710061, China, Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA.
Abstract:
Speckle-type POZ protein (SPOP) is an adaptor of the cullin 3-based ubiquitin ligase responsible for the degradation of oncoproteins frequently overexpressed in many tumor cells. Altered expression and somatic mutations of SPOP have been observed in various tumor types with chromosomal aberrations, indicating a role of SPOP in maintaining genome stability, although a detailed mechanism remains unclear. Here, we show that SPOP is a component of the DNA damage response (DDR). SPOP is recruited to DNA double-strand break sites and it forms nuclear foci after DNA damage. SPOP foci colocalize with γ-H2AX foci and are predominantly dependent on the activity of the ataxia-telangiectasia mutated (ATM) kinase. Furthermore, SPOP interacts with ATM in response to DNA damage. Finally, we demonstrate that knocking down of SPOP resulted in an impaired DDR and a hypersensitivity to ionizing irradiation. Together, we highlight a critical role of SPOP in the DDR.
Insights
Speckle-type POZ protein (SPOP) acts in the DNA damage response (DDR). SPOP recruitment to DNA breaks and interaction with ATM kinase are crucial for genome stability and DNA repair.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Speckle-type POZ protein (SPOP) is an adaptor in the cullin 3-based ubiquitin ligase complex.
- SPOP regulates degradation of oncoproteins overexpressed in tumors.
- Altered SPOP expression and mutations suggest a role in genome stability.
Purpose of the Study:
- To investigate the role of SPOP in the DNA damage response (DDR).
- To elucidate the mechanism by which SPOP contributes to maintaining genome stability.
Main Methods:
- Immunofluorescence to detect SPOP foci at DNA double-strand break sites.
- Co-immunoprecipitation to assess SPOP-ATM interaction.
- RNA interference (RNAi) to knock down SPOP expression.
- Irradiation assays to evaluate DNA damage sensitivity.
Main Results:
- SPOP is recruited to DNA double-strand break sites and forms nuclear foci after DNA damage.
- SPOP foci colocalize with γ-H2AX and depend on ATM kinase activity.
- SPOP interacts with ATM kinase in response to DNA damage.
- Knockdown of SPOP impairs the DDR and increases sensitivity to ionizing radiation.
Conclusions:
- SPOP is a novel component of the DNA damage response (DDR).
- SPOP plays a critical role in DNA double-strand break repair and genome stability.
- SPOP's function in DDR is linked to ATM kinase signaling.
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