2. Academic Validation
  3. RNF126-Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple-Negative Breast Cancer to Radiotherapy

RNF126-Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple-Negative Breast Cancer to Radiotherapy

  • Adv Sci (Weinh). 2022 Dec 23;e2203884. doi: 10.1002/advs.202203884.
Wenjing Liu 1 2 3,  Min Zheng 1 2,  Rou Zhang 1,  Qiuyun Jiang 1 2,  Guangshi Du 1 2,  Yingying Wu 4,  Chuanyu Yang 1 2,  Fubing Li 5,  Wei Li 1 2,  Luzhen Wang 1 6,  Jiao Wu 3,  Lei Shi 7,  Wenhui Li 3,  Kai Zhang 7,  Zhongmei Zhou 1,  Rong Liu 1 8,  Yingzheng Gao 9,  Xinwei Huang 9,  Songqing Fan 10,  Xu Zhi 11,  Dewei Jiang 1 2,  Ceshi Chen 1 3 5
Affiliations

Affiliations

  • 1 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.
  • 2 Kunming College of Life Sciences, University of the Chinese Academy of Sciences, Kunming, 650204, China.
  • 3 The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China.
  • 4 Department of the Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
  • 5 Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
  • 6 School of Life Science, University of Science & Technology of China, Hefei, 230027, China.
  • 7 Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, 300070, China.
  • 8 Translational Cancer Research Center, Peking University First Hospital, Beijing, 100034, China.
  • 9 Department of the Central Laboratory, Second Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
  • 10 Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, 410000, China.
  • 11 Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China.
PMID: 36563124 DOI: 10.1002/advs.202203884
Abstract

Triple-negative breast Cancer (TNBC) has higher molecular heterogeneity and metastatic potential and the poorest prognosis. 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-dose IR. Here, the authors report that E3 ubiquitin Ligase Ring finger protein 126 (RNF126) is important for IR-induced ATR-CHK1 pathway activation to enhance DNA damage repair (DDR). Mechanistically, RNF126 physically associates with the MRE11-RAD50-NBS1 (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-prone 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-AKT-NF-κB 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-mediated MRE11 ubiquitination is a critical regulator of the DDR, which provides a promising target for improving the sensitivity of TNBC to radiotherapy.

Keywords

Meiotic recombination 11 homolog 1 (MRE11); Nuclear Factor Kappa-Β (NF-κB); Ring finger protein 126 (RNF126); ataxia telangiectasia mutated and rad-3 related protein kinase (ATR); dihydroartemisinin; homologous recombination repair; human epidermal growth factor receptor 2 (HER2).

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