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RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression

Oncogene volume 35, pages 1363–1372 (2016)Cite this article

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Abstract

RNF126 is an E3 ubiquitin ligase. The deletion of RNF126 gene was observed in a wide range of human cancers and is correlated with improved disease-free and overall survival. These data highlight the clinical relevance of RNF126 in tumorigenesis and cancer therapy. However, the specific functions of RNF126 remain largely unknown. Homologous recombination (HR)-mediated DNA double-strand break repair is important for tumor suppression and cancer therapy resistance. Here, we demonstrate that RNF126 facilitates HR by promoting the expression of BRCA1, in a manner independent of its E3 ligase activity but depending on E2F1, a well-known transcription factor of BRCA1 promoter. In support of this result, RNF126 promotes transactivation of BRCA1 promoter by directly binding to E2F1. Most importantly, an RNF126 mutant lacking 11 amino acids that is responsible for the interaction with E2F1 has a dominant-negative effect on BRCA1 expression and HR by suppressing E2F1-mediated transactivation of BRCA1 promoter and blocking the enrichment of E2F1 on BRCA1 promoter. Lastly, RNF126 depletion leads to the increased sensitivity to ionizing radiation and poly (ADP-ribose) polymerase inhibition. Collectively, our results suggest a novel role of RNF126 in promoting HR-mediated repair through positive regulation on BRCA1 expression by direct interaction with E2F1. This study not only offers novel insights into our current understanding of the biological functions of RNF126 but also provides a potential therapeutic target for cancer treatment.

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Acknowledgements

This study was supported by a grant (R01C A154625) from the National Cancer Institute and a startup fund from the Department of Radiation Oncology, Case Western Reserve University School of Medicine to JZ; National Natural Science Foundation of China grant (31271503), Guangdong Provincial Natural Science Foundation of China grant (S2012010008368) and a startup fund from Sun Yat-sen University to ZM. This research was also supported by Radiation Resources Core Facility and Cytometry & Imaging Microscopy Core Facility of the Case Comprehensive Cancer Center (P30 CA43703). We thank Daniel Li and Mehdi Haider for the technical support.

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Author notes

  1. Y Wang and O Deng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Y Wang, O Deng, Z Feng, Z Du, X Xiong, J Lai & J Zhang

  2. Department of Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    O Deng, X Yang & Z Ma

  3. The Second Affiliated Hospital of Fujian Medical University, QuanZhou, Fujian, China

    J Lai

  4. Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    M Xu & D Taylor

  5. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA

    H Wang

  6. GRU Cancer Center, Georgia Regents University, Augusta, GA, USA

    C Yan

  7. Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    C Chen

  8. General Medical Sciences, Case Western Reserve University, Cleveland, OH, USA

    A Difeo

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Correspondence to Z Ma or J Zhang.

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Wang, Y., Deng, O., Feng, Z. et al. RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression. Oncogene 35, 1363–1372 (2016). https://doi.org/10.1038/onc.2015.198

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  • DOI: https://doi.org/10.1038/onc.2015.198

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