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LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair

Author

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  • Xue-Song Liu

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School
    Present address: School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China; Fels Institute for Cancer Research and Molecular Biology, Temple University, 3500N. Broad Street, Philadelphia, Pennsylvania 19140, USA; Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China; Centre for Integrative Biology, University of Trento, 38123 Trento, Italy)

  • Gurushankar Chandramouly

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Centre, Harvard Medical School
    Present address: School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China; Fels Institute for Cancer Research and Molecular Biology, Temple University, 3500N. Broad Street, Philadelphia, Pennsylvania 19140, USA; Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China; Centre for Integrative Biology, University of Trento, 38123 Trento, Italy)

  • Emilie Rass

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Centre, Harvard Medical School)

  • Yinghua Guan

    (Harvard Medical School)

  • Guocan Wang

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Robin M. Hobbs

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Anbazhagan Rajendran

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Centre, Harvard Medical School)

  • Anyong Xie

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Centre, Harvard Medical School
    Present address: School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China; Fels Institute for Cancer Research and Molecular Biology, Temple University, 3500N. Broad Street, Philadelphia, Pennsylvania 19140, USA; Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China; Centre for Integrative Biology, University of Trento, 38123 Trento, Italy)

  • Jagesh V. Shah

    (Harvard Medical School)

  • Anthony J. Davis

    (University of Texas Southwestern Medical Centre)

  • Ralph Scully

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Centre, Harvard Medical School)

  • Andrea Lunardi

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School
    Present address: School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China; Fels Institute for Cancer Research and Molecular Biology, Temple University, 3500N. Broad Street, Philadelphia, Pennsylvania 19140, USA; Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China; Centre for Integrative Biology, University of Trento, 38123 Trento, Italy)

  • Pier Paolo Pandolfi

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School)

Abstract

Leukemia/lymphoma-related factor (LRF) is a POZ/BTB and Krüppel (POK) transcriptional repressor characterized by context-dependent key roles in cell fate decision and tumorigenesis. Here we demonstrate an unexpected transcription-independent function for LRF in the classical non-homologous end joining (cNHEJ) pathway of double-strand break (DSB) repair. We find that LRF loss in cell lines and mouse tissues results in defective cNHEJ, genomic instability and hypersensitivity to ionizing radiation. Mechanistically, we show that LRF binds and stabilizes DNA-PKcs on DSBs, in turn favouring DNA-PK activity. Importantly, LRF loss restores ionizing radiation sensitivity to p53 null cells, making LRF an attractive biomarker to direct p53-null LRF-deficient tumours towards therapeutic treatments based on genotoxic agents or PARP inhibitors following a synthetic lethal strategy.

Suggested Citation

  • Xue-Song Liu & Gurushankar Chandramouly & Emilie Rass & Yinghua Guan & Guocan Wang & Robin M. Hobbs & Anbazhagan Rajendran & Anyong Xie & Jagesh V. Shah & Anthony J. Davis & Ralph Scully & Andrea Luna, 2015. "LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9325
    DOI: 10.1038/ncomms9325
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    Cited by:

    1. Shohei Takase & Takashi Hiroyama & Fumiyuki Shirai & Yuki Maemoto & Akiko Nakata & Mayumi Arata & Seiji Matsuoka & Takeshi Sonoda & Hideaki Niwa & Shin Sato & Takashi Umehara & Mikako Shirouzu & Yosuk, 2023. "A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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