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ZNF451 collaborates with RNF8 to regulate RNF168 localization and amplify ubiquitination signaling to promote DNA
Feng Xu1,2, Qi Xia2, Bin Chen3
1High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China.
Cell Death and Differentiation
|March 7, 2025
Summary
ZNF451 SUMOylation of RNF168 is key for DNA double-strand break (DSB) repair. This process enhances RNF168 accumulation at damage sites, promoting histone ubiquitination and DNA repair, offering a potential radiotherapy target.
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- Histone ubiquitination by RNF8/RNF168 is vital for DNA double-strand break (DSB) repair.
- The upstream regulation of RNF168 activity in DSB response remains incompletely understood.
Purpose of the Study:
- To elucidate the upstream regulatory mechanisms controlling RNF168 function in DNA damage response.
- To investigate the role of ZNF451 in the SUMOylation and ubiquitination pathways during DSB repair.
Main Methods:
- Immunofluorescence microscopy to track protein localization at DNA damage sites.
- Co-immunoprecipitation assays to study protein-protein interactions.
- Western blotting to assess protein modification and levels.
Main Results:
- ZNF451 rapidly accumulates at radiation-induced DNA damage sites.
- ZNF451 catalyzes SUMO2 modification of RNF168, stabilizing it and enhancing its recruitment to damage foci.
- ZNF451 and RNF8 exhibit complex regulatory interactions with RNF168, influencing its recruitment and downstream histone ubiquitination.
- ZNF451-mediated SUMOylation promotes RNF168-dependent histone H2A/H2AX ubiquitination, facilitating DSB repair.
Conclusions:
- ZNF451-catalyzed SUMOylation is a critical upstream regulator of RNF168 in the DNA damage response.
- The ZNF451-RNF168 axis plays a significant role in amplifying DNA damage signals and promoting DSB repair.
- ZNF451 represents a potential therapeutic target for enhancing tumor radiotherapy efficacy.
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