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

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 Saito, Shinya Sato, Junya Kobayashi, Ryoji Yao, Kanjiro Miyata, Kazunori Kataoka, Hiroshi I. Suzuki and Yutaka Kondo ()
Additional contact information
Miho M. Suzuki: Nagoya University Graduate School of Medicine
Kenta Iijima: Nagoya University Graduate 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
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
Hiroshi I. Suzuki: Nagoya University Graduate School of Medicine
Yutaka Kondo: Nagoya University Graduate School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40243-8

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