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TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation

Author

Listed:
  • Miho M. Suzuki

    (Nagoya University Graduate School of Medicine)

  • Kenta Iijima

    (Nagoya University Graduate School of Medicine
    Hamamatsu University School of Medicine)

  • Koichi Ogami

    (Nagoya University Graduate School of Medicine)

  • Keiko Shinjo

    (Nagoya University Graduate School of Medicine)

  • Yoshiteru Murofushi

    (Nagoya University Graduate School of Medicine)

  • Jingqi Xie

    (Nagoya University Graduate School of Medicine)

  • Xuebing Wang

    (Nagoya University Graduate School of Medicine)

  • Yotaro Kitano

    (Nagoya University Graduate School of Medicine)

  • Akira Mamiya

    (Nagoya University Graduate School of Medicine)

  • Yuji Kibe

    (Nagoya University Graduate School of Medicine
    Nagoya University Graduate School of Medicine)

  • Tatsunori Nishimura

    (Nagoya University Graduate School of Medicine)

  • Fumiharu Ohka

    (Nagoya University Graduate School of Medicine)

  • Ryuta Saito

    (Nagoya University Graduate School of Medicine)

  • Shinya Sato

    (Kanagawa Cancer Center Research Institute)

  • Junya Kobayashi

    (International University of Health and Welfare)

  • Ryoji Yao

    (Japanese Foundation for Cancer Research)

  • Kanjiro Miyata

    (The University of Tokyo)

  • Kazunori Kataoka

    (Kawasaki Institute of Industrial Promotion
    The University of Tokyo)

  • Hiroshi I. Suzuki

    (Nagoya University Graduate School of Medicine
    Tokai National Higher Education and Research System)

  • Yutaka Kondo

    (Nagoya University Graduate School of Medicine
    Tokai National Higher Education and Research System)

Abstract

Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.

Suggested Citation

  • Miho M. Suzuki & Kenta Iijima & Koichi Ogami & Keiko Shinjo & Yoshiteru Murofushi & Jingqi Xie & Xuebing Wang & Yotaro Kitano & Akira Mamiya & Yuji Kibe & Tatsunori Nishimura & Fumiharu Ohka & Ryuta S, 2023. "TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40243-8
    DOI: 10.1038/s41467-023-40243-8
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