IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-40243-8.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-40243-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-40243-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Keisuke Katsushima & Atsushi Natsume & Fumiharu Ohka & Keiko Shinjo & Akira Hatanaka & Norihisa Ichimura & Shinya Sato & Satoru Takahashi & Hiroshi Kimura & Yasushi Totoki & Tatsuhiro Shibata & Mitsur, 2016. "Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    2. Martin Andrs & Henriette Stoy & Barbora Boleslavska & Nagaraja Chappidi & Radhakrishnan Kanagaraj & Zuzana Nascakova & Shruti Menon & Satyajeet Rao & Anna Oravetzova & Jana Dobrovolna & Kalpana Surend, 2023. "Excessive reactive oxygen species induce transcription-dependent replication stress," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Sergei M. Mirkin, 2007. "Expandable DNA repeats and human disease," Nature, Nature, vol. 447(7147), pages 932-940, June.
    4. Magdalena P. Crossley & Chenlin Song & Michael J. Bocek & Jun-Hyuk Choi & Joseph N. Kousouros & Ataya Sathirachinda & Cindy Lin & Joshua R. Brickner & Gongshi Bai & Hannes Lans & Wim Vermeulen & Month, 2023. "R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response," Nature, Nature, vol. 613(7942), pages 187-194, January.
    5. Gabrijela Dumbović & Ulrich Braunschweig & Heera K. Langner & Michael Smallegan & Josep Biayna & Evan P. Hass & Katarzyna Jastrzebska & Benjamin Blencowe & Thomas R. Cech & Marvin H. Caruthers & John , 2021. "Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    6. Gabrijela Dumbović & Ulrich Braunschweig & Heera K. Langner & Michael Smallegan & Josep Biayna & Evan P. Hass & Katarzyna Jastrzebska & Benjamin Blencowe & Thomas R. Cech & Marvin H. Caruthers & John , 2021. "Publisher Correction: Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention," Nature Communications, Nature, vol. 12(1), pages 1-1, December.
    7. Sumiyo Watanabe & Kotaro Hayashi & Kazuko Toh & Hyun Jin Kim & Xueying Liu & Hiroyuki Chaya & Shigeto Fukushima & Keisuke Katsushima & Yutaka Kondo & Satoshi Uchida & Satomi Ogura & Takahiro Nomoto & , 2019. "In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    8. Stephen P. Jackson & Jiri Bartek, 2009. "The DNA-damage response in human biology and disease," Nature, Nature, vol. 461(7267), pages 1071-1078, October.
    9. Yusuke Matsuno & Yuko Atsumi & Atsuhiro Shimizu & Kotoe Katayama & Haruka Fujimori & Mai Hyodo & Yusuke Minakawa & Yoshimichi Nakatsu & Syuzo Kaneko & Ryuji Hamamoto & Teppei Shimamura & Satoru Miyano, 2019. "Replication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Carter J. Barger & Abigail K. Suwala & Katarzyna M. Soczek & Albert S. Wang & Min Y. Kim & Chibo Hong & Jennifer A. Doudna & Susan M. Chang & Joanna J. Phillips & David A. Solomon & Joseph F. Costello, 2022. "Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Wei-Siang Liau & Qiongyi Zhao & Adekunle Bademosi & Rachel S. Gormal & Hao Gong & Paul R. Marshall & Ambika Periyakaruppiah & Sachithrani U. Madugalle & Esmi L. Zajaczkowski & Laura J. Leighton & Haob, 2023. "Fear extinction is regulated by the activity of long noncoding RNAs at the synapse," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Zita Gál & Stavroula Boukoura & Kezia Catharina Oxe & Sara Badawi & Blanca Nieto & Lea Milling Korsholm & Sille Blangstrup Geisler & Ekaterina Dulina & Anna Vestergaard Rasmussen & Christina Dahl & We, 2024. "Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Ilaria Rosso & Corey Jones-Weinert & Francesca Rossiello & Matteo Cabrini & Silvia Brambillasca & Leonel Munoz-Sagredo & Zeno Lavagnino & Emanuele Martini & Enzo Tedone & Massimiliano Garre’ & Julio A, 2023. "Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    6. Jérémy Sandoz & Max Cigrang & Amélie Zachayus & Philippe Catez & Lise-Marie Donnio & Clèmence Elly & Jadwiga Nieminuszczy & Pietro Berico & Cathy Braun & Sergey Alekseev & Jean-Marc Egly & Wojciech Ni, 2023. "Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Ross J. Hill & Nazareno Bona & Job Smink & Hannah K. Webb & Alastair Crisp & Juan I. Garaycoechea & Gerry P. Crossan, 2024. "p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Qin Qin & Jing Lu & Hongcheng Zhu & Liping Xu & Hongyan Cheng & Liangliang Zhan & Xi Yang & Chi Zhang & Xinchen Sun, 2014. "PARP-1 Val762Ala Polymorphism and Risk of Cancer: A Meta-Analysis Based on 39 Case-Control Studies," PLOS ONE, Public Library of Science, vol. 9(5), pages 1-12, May.
    9. Wen-Qi Ma & Xi-Qiong Han & Xin Wang & Ying Wang & Yi Zhu & Nai-Feng Liu, 2016. "Associations between XRCC1 Gene Polymorphisms and Coronary Artery Disease: A Meta-Analysis," PLOS ONE, Public Library of Science, vol. 11(11), pages 1-15, November.
    10. Zhang, L.W. & Cheng, Y.M. & Liew, K.M., 2014. "Mathematical modeling of p53 pulses in G2 phase with DNA damage," Applied Mathematics and Computation, Elsevier, vol. 232(C), pages 1000-1010.
    11. Corella S. Casas-Delucchi & Manuel Daza-Martin & Sophie L. Williams & Gideon Coster, 2022. "The mechanism of replication stalling and recovery within repetitive DNA," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    12. Pieranna Chiarella & Pasquale Capone & Renata Sisto, 2023. "Contribution of Genetic Polymorphisms in Human Health," IJERPH, MDPI, vol. 20(2), pages 1-15, January.
    13. Anne Margriet Heijink & Colin Stok & David Porubsky & Eleni Maria Manolika & Jurrian K. Kanter & Yannick P. Kok & Marieke Everts & H. Rudolf Boer & Anastasia Audrey & Femke J. Bakker & Elles Wierenga , 2022. "Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    14. Anthony Veltri & Christopher M. R. Lang & Gaia Cangiotti & Chim Kei Chan & Wen-Hui Lien, 2022. "ROR2 regulates self-renewal and maintenance of hair follicle stem cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    15. Lina Wang & Siru Li & Kai Wang & Na Wang & Qiaoling Liu & Zhen Sun & Li Wang & Lulu Wang & Quentin Liu & Chengli Song & Caigang Liu & Qingkai Yang, 2022. "DNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    16. Alessio Magis & Michaela Limmer & Venkat Mudiyam & David Monchaud & Stefan Juranek & Katrin Paeschke, 2023. "UV-induced G4 DNA structures recruit ZRF1 which prevents UV-induced senescence," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    17. Feng Shi & Weigang Hu & Jiaojiao Wu & Miaofei Han & Jiazhou Wang & Wei Zhang & Qing Zhou & Jingjie Zhou & Ying Wei & Ying Shao & Yanbo Chen & Yue Yu & Xiaohuan Cao & Yiqiang Zhan & Xiang Sean Zhou & Y, 2022. "Deep learning empowered volume delineation of whole-body organs-at-risk for accelerated radiotherapy," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    18. Hanrui Zhang & Julian Kreis & Sven-Eric Schelhorn & Heike Dahmen & Thomas Grombacher & Michael Zühlsdorf & Frank T. Zenke & Yuanfang Guan, 2023. "Mapping combinatorial drug effects to DNA damage response kinase inhibitors," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    19. Xingxing Ren & Qiuyuan Liu & Peirong Zhou & Tingyue Zhou & Decai Wang & Qiao Mei & Richard A. Flavell & Zhanju Liu & Mingsong Li & Wen Pan & Shu Zhu, 2024. "DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    20. Halh Al-Serori & Franziska Ferk & Michael Kundi & Andrea Bileck & Christopher Gerner & Miroslav Mišík & Armen Nersesyan & Monika Waldherr & Manuel Murbach & Tamara T Lah & Christel Herold-Mende & Andr, 2018. "Mobile phone specific electromagnetic fields induce transient DNA damage and nucleotide excision repair in serum-deprived human glioblastoma cells," PLOS ONE, Public Library of Science, vol. 13(4), pages 1-17, April.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40243-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.