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Because of limited therapeutics against TNBC, irradiation (IR) therapy is still a common treatment option for patients with lymph nodes or brain metastasis. Thus, it is urgent to develop strategies to enhance the sensitivity of TNBC tumors to low\u2010dose IR. Here, the authors report that E3 ubiquitin ligase Ring finger protein 126 (RNF126) is important for IR\u2010induced ATR\u2010CHK1 pathway activation to enhance DNA damage repair (DDR). Mechanistically, RNF126 physically associates with the MRE11\u2010RAD50\u2010NBS1 (MRN) complex and ubiquitinates MRE11 at K339 and K480 to increase its DNA exonuclease activity, subsequent RPA binding, and ATR phosphorylation, promoting sustained DDR in a homologous recombination repair\u2010prone manner. Accordingly, depletion of RNF126 leads to increased genomic instability and radiation sensitivity in both TNBC cells and mice. Furthermore, it is found that RNF126 expression is induced by IR activating the HER2\u2010AKT\u2010NF\u2010<jats:italic>\u03ba<\/jats:italic>B pathway and targeting RNF126 expression with dihydroartemisinin significantly improves the sensitivity of TNBC tumors in the brain to IR treatment in vivo. Together, these results reveal that RNF126\u2010mediated MRE11 ubiquitination is a critical regulator of the DDR, which provides a promising target for improving the sensitivity of TNBC to radiotherapy.<\/jats:p>","DOI":"10.1002\/advs.202203884","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T13:46:47Z","timestamp":1671803207000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["RNF126\u2010Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple\u2010Negative Breast Cancer to Radiotherapy"],"prefix":"10.1002","volume":"10","author":[{"given":"Wenjing","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences  Kunming 650201 China"},{"name":"Kunming College of Life 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