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Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer

Nature Structural & Molecular Biology volume 23, pages 522530 (2016) | Download Citation

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Abstract

Long noncoding RNAs (lncRNAs) play critical roles during tumorigenesis by functioning as scaffolds that regulate protein-protein, protein-DNA or protein-RNA interactions. Using a clinically guided genetic screening approach, we identified lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1), which is overexpressed in human triple-negative breast cancer. We found that LINP1 enhances repair of DNA double-strand breaks by serving as a scaffold linking Ku80 and DNA-PKcs, thereby coordinating the NHEJ pathway. Importantly, blocking LINP1, which is regulated by p53 and epidermal growth factor receptor (EGFR) signaling, increases the sensitivity of the tumor-cell response to radiotherapy in breast cancer.

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Acknowledgements

We thank the TCGA and CCLE project teams. We thank Dr. B. Vogelstein (Johns Hopkins University) for providing HCT116 WT and HCT116 TP53 cell lines. This work was supported, in whole or in part, by the Basser Center for BRCA (L.Z.), the US National Institutes of Health (R01CA142776 to L.Z., R01CA190415 to L.Z., P50CA083638 to L.Z., P50CA174523 to L.Z., R01CA148759 to Q.H., and R01NS094533 to Y.F.), the Breast Cancer Alliance (L.Z. and C.V.D.), the Ovarian Cancer Research Fund (X.H.), the Foundation for Women's Cancer (X.H.), and the Marsha Rivkin Center for Ovarian Cancer Research (L.Z.). S.W. was supported by the China Scholarship Council.

Author information

Author notes

    • Youyou Zhang
    •  & Qun He

    These authors contributed equally to this work.

Affiliations

  1. Center for Research on Reproduction & Women's Health, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Youyou Zhang
    • , Qun He
    • , Zhongyi Hu
    • , Yi Feng
    • , Lingling Fan
    • , Zhaoqing Tang
    • , Jiao Yuan
    • , Weiwei Shan
    • , Chunsheng Li
    • , Xiaowen Hu
    •  & Lin Zhang
  2. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Yi Feng
    •  & Chi V Dang
  3. Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Chunsheng Li
    • , Xiaowen Hu
    • , Janos L Tanyi
    •  & Lin Zhang
  4. Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Yi Fan
  5. Wistar Institute, Philadelphia, Pennsylvania, USA.

    • Qihong Huang
  6. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Kathleen Montone
  7. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Chi V Dang
  8. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Chi V Dang
    •  & Lin Zhang

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Contributions

Y.Z., C.V.D. and L.Z. conceptualized and designed the experiments. Y.Z., Q. He, L.F., W.S., and C.L. performed the molecular and cellular biology experiments. Z.H., Y. Fan, Z.T. and J.Y. performed bioinformatics analysis. Y.Z., Z.H., J.Y., X.H., J.L.T., Y.F., Q. Huang, and K.M. analyzed and interpreted data. Y.Z., Y. Feng, C.V.D., and L.Z. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Chi V Dang or Lin Zhang.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6

  2. 2.

    Supplementary Data Set 2

    Raw gel images from all figures

Excel files

  1. 1.

    Supplementary Table 1

    The list of lncRNAs that were significantly enriched in expression in TNBC/basal tumors

  2. 2.

    Supplementary Table 2

    The list of siRNA sequences for the lncRNAs

  3. 3.

    Supplementary Table 3

    Mass spectrometry (MS) results of identified proteins by RNA pulldown

  4. 4.

    Supplementary Data Set 1

    The breast cancer specimens from TCGA

  5. 5.

    Supplementary Data Set 3

    Oligos and primers used in this study

  6. 6.

    Supplementary Data Set 4

    Antibody information

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DOI

https://doi.org/10.1038/nsmb.3211

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