Schematic illustration of ZNF451 regulating DNA injury restore mechanism. Credit score: Zhao Guoping
A analysis group has unveiled an important mechanism that helps regulate DNA injury restore, with vital implications for bettering most cancers remedy outcomes.
The consequence was printed in Cell Demise & Differentiation. The group was led by Professor Zhao Guoping on the Hefei Institutes of Bodily Science of the Chinese language Academy of Sciences.
The efficacy of radiotherapy is essentially restricted by the DNA injury restore capability of tumor cells. When ionizing radiation induces DNA double-strand breaks—the first deadly injury—tumor cells typically exhibit irregular overexpression of DNA restore proteins, establishing a sturdy injury response system that drives scientific radioresistance. To handle this problem, the group deciphered the regulatory community of epigenetic modifications in DNA injury restore.
The research discovered that ZNF451, a zinc finger protein, is considerably overexpressed in breast most cancers, lung most cancers, and different malignancies, correlating with poor affected person prognosis. Mechanistic research demonstrated that upon radiation-induced DNA injury, ZNF451 quickly accumulates at injury websites and particularly catalyzes SUMO2 modification of RNF168. This post-translational modification stabilizes RNF168, enhancing its recruitment to break websites, which amplifies downstream ubiquitination of histone H2A/H2AX and in the end promotes DNA restore.
The group additional uncovered a dynamic regulatory community between ZNF451 and the canonical restore issue RNF8. These two proteins modulate RNF168 exercise by aggressive binding and cooperative interactions. Particularly, ZNF451 and RNF8 mutually inhibit one another’s recruitment of RNF168, but simultaneous depletion of each severely impairs RNF168 accumulation at injury websites. Quantitative evaluation revealed that ZNF451 and RNF8 dose-dependently fine-tune the interplay energy between RNF168 and its substrate H2AX.
This research not solely elucidates a novel mechanism by which SUMOylation regulates DNA injury restore but in addition proposes an modern “dynamic equilibrium regulation” mannequin, providing theoretical developments in understanding DNA restore mechanisms.
Extra info:
Feng Xu et al, ZNF451 collaborates with RNF8 to manage RNF168 localization and amplify ubiquitination signaling to advertise DNA injury restore and regulate radiosensitivity, Cell Demise & Differentiation (2025). DOI: 10.1038/s41418-025-01472-0
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DNA restore mechanism could maintain key to overcoming tumor resistance to radiotherapy (2025, April 22)
retrieved 22 April 2025
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