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Updated: Jun 15, 2025
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Author Spotlight: Quantitative Detection of DNA Protein Crosslinks and Their Post-Translational Modifications
Published on: April 21, 2023
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DNA damage-induced proteasome phosphorylation controls substrate recognition and facilitates DNA repair
Xiaomei Zhang1, Tianyi Zhu1, Xuemei Li1
1Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Summary
DNA damage triggers Rpn10/PSMD4 phosphorylation, a key event in the DNA damage response (DDR). This phosphorylation limits proteasome activity, sparing DNA repair proteins like BRCA1 and enhancing repair efficiency.
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- Proteasomal degradation is crucial for DNA repair.
- Regulation of the 26S proteasome during the DNA damage response (DDR) remains poorly understood.
- Ubiquitin receptors play a key role in substrate recognition by the proteasome.
Purpose of the Study:
- To investigate the regulation of the 26S proteasome in response to DNA damage.
- To determine the role of Rpn10/PSMD4 phosphorylation in the DDR.
Main Methods:
- Phosphorylation site mapping of Rpn10/PSMD4.
- In vitro and in cellulo biochemical assays.
- Proximity labeling and quantitative proteomics.
Main Results:
- Rpn10/PSMD4 is rapidly phosphorylated at Ser266 in response to DNA damage.
- Phosphorylation at Ser266 reduces Rpn10/PSMD4's ubiquitin binding affinity.
- This regulation spares essential DDR proteins, such as BRCA1, from degradation, promoting DNA repair.
Conclusions:
- Rpn10/PSMD4 phosphorylation acts as a self-limiting mechanism for the 26S proteasome during DDR.
- This fine-tunes protein degradation, optimizing cellular response to genotoxic stress.
- Targeting Rpn10 phosphorylation could be a strategy to enhance DNA repair.
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