DNA Repair Mechanisms Could Be Key to Overcoming Tumor Resistance to Radiotherapy

A groundbreaking study has shed light on the crucial role of DNA repair processes in tumor resistance to radiotherapy, opening avenues for improved cancer treatments. Published in Cell Death & Differentiation, the research was led by Professor Zhao Guoping at the Hefei Institutes of Physical Science of the Chinese Academy of Sciences. The study emphasizes that tumor cells' ability to repair DNA damage significantly hampers the effectiveness of radiation therapy. When radiation induces double-strand DNA breaks, tumor cells often overexpress repair proteins, creating a resilient damage response system that contributes to clinical radioresistance.

The research team uncovered a pivotal regulatory network involving epigenetic modifications that govern DNA repair. A key focus was on ZNF451, a zinc finger protein notably overexpressed in cancers such as breast and lung, where its high levels correlate with poorer prognosis. Mechanistic experiments revealed that upon DNA damage caused by radiation, ZNF451 accumulates rapidly at the damage sites. It specifically catalyzes the SUMO2 modification of RNF168, a post-translational change that stabilizes RNF168 and enhances its recruitment to DNA damage sites. This process amplifies downstream ubiquitination of histones like H2A/H2AX, facilitating efficient DNA repair.

Furthermore, the study identified a dynamic interaction between ZNF451 and RNF8, two proteins that cooperatively regulate RNF168 activity through competitive binding. These proteins modulate the recruitment process of RNF168, with ZNF451 and RNF8 mutually inhibiting each other but jointly influencing the DNA repair pathway. Quantitative analysis demonstrated that the amounts of ZNF451 and RNF8 precisely regulate RNF168’s interaction with histone H2AX, effectively balancing DNA repair efficiency.

This research provides substantial insight into the epigenetic regulation of DNA damage repair, proposing what is called the "dynamic equilibrium regulation" model. Such understanding offers promising strategies to sensitize resistant tumors to radiotherapy by targeting these molecular regulators, potentially enhancing clinical outcomes for cancer patients.

For more details, the findings are available in the publication: Feng Xu et al, "ZNF451 collaborates with RNF8 to regulate RNF168 localization and amplify ubiquitination signaling," Cell Death & Differentiation (2025). Read the full study.