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CSN7B defines a variant COP9 signalosome complex with distinct function in DNA damage response
Jing Wang1, Dawadschargal Dubiel2, Yanmeng Wu1
1School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiang'an South Road, Xiamen 361102, Fujian, China.
Cell Reports
|January 27, 2021
Summary
The COP9 signalosome (CSN) complex has two variants, CSN7A and CSN7B. CSN7B uniquely senses DNA double-strand breaks (DSBs), impacting repair pathways and chemotherapy resistance in tumors.
Area of Science:
- Cellular Biology
- Molecular Biology
- Cancer Research
Background:
- Mammalian COP9 signalosome (CSN) comprises two variants, CSN7A and CSN7B, with largely unknown functional differences.
- CSN complexes regulate protein degradation via the ubiquitin-proteasome system, crucial for various cellular processes.
Purpose of the Study:
- To elucidate the distinct functional roles of CSN7A and CSN7B paralogs within the CSN complex.
- To investigate the involvement of CSN7B in DNA double-strand break (DSB) sensing and repair pathways.
- To determine the implications of CSN7B function in cancer treatment resistance.
Main Methods:
- Generation and analysis of CSN7A and CSN7B knockout cell lines.
- Assessment of DNA damage response pathways, including ATM-dependent signaling and protein deneddylation.
- Live-cell microscopy to track CSN complex recruitment to sites of DNA damage.
- Evaluation of DNA repair pathway choice (non-homologous end joining vs. homologous recombination).
- Analysis of CSN7B knockout tumors in mice for chemoresistance.
Main Results:
- CSN7A and CSN7B exhibit overlapping roles in deneddylating cullin-RING ubiquitin ligases.
- CSN7B, but not CSN7A, is essential for DNA double-strand break (DSB) sensing, including ATM-dependent NBS1 phosphorylation and γH2AX formation.
- CSN7B is rapidly recruited to DSBs, while CSN7A is not.
- CSN7B deficiency leads to impaired deneddylation of a DSB signaling component, promoting non-homologous end joining over homologous recombination.
- CSN7B knockout cells and tumors show resistance to DNA-damaging agents like mitomycin C, ionizing radiation, and chemotherapy.
Conclusions:
- CSN7B plays a unique and critical role in DNA double-strand break (DSB) sensing and DNA repair pathway regulation.
- The impaired DSB response in CSN7B-deficient cells results in resistance to DNA-damaging therapies.
- Low CSN7B expression in tumors may explain poor prognosis and resistance to DNA-damage-inducing chemotherapy.
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