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The chromatin-associated lncREST ensures effective replication stress response by promoting the assembly of fork signaling factors

Author

Listed:
  • Luisa Statello

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • José Miguel Fernandez-Justel

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Jovanna González

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Marta Montes

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Alessia Ranieri

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Enrique Goñi

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Aina M. Mas

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Maite Huarte

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

Abstract

ABSTRACT Besides the well-characterized protein network involved in the replication stress response, several regulatory RNAs have been shown to play a role in this critical process. However, it has remained elusive whether they act locally at the stressed forks. Here, by investigating the RNAs localizing on chromatin upon replication stress induced by hydroxyurea, we identified a set of lncRNAs upregulated in S-phase and controlled by stress transcription factors. Among them, we demonstrate that the previously uncharacterized lncRNA lncREST (long non-coding RNA REplication STress) is transcriptionally controlled by p53 and localizes at stressed replication forks. LncREST-depleted cells experience sustained replication fork progression and accumulate un-signaled DNA damage. Under replication stress, lncREST interacts with the protein NCL and assists in engaging its interaction with RPA. The loss of lncREST is associated with a reduced NCL-RPA interaction and decreased RPA on chromatin, leading to defective replication stress signaling and accumulation of mitotic defects, resulting in apoptosis and a reduction in tumorigenic potential of cancer cells. These findings uncover the function of a lncRNA in favoring the recruitment of replication proteins to sites of DNA replication.

Suggested Citation

  • Luisa Statello & José Miguel Fernandez-Justel & Jovanna González & Marta Montes & Alessia Ranieri & Enrique Goñi & Aina M. Mas & Maite Huarte, 2024. "The chromatin-associated lncREST ensures effective replication stress response by promoting the assembly of fork signaling factors," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45183-5
    DOI: 10.1038/s41467-024-45183-5
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    References listed on IDEAS

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    1. Mathias Munschauer & Celina T. Nguyen & Klara Sirokman & Christina R. Hartigan & Larson Hogstrom & Jesse M. Engreitz & Jacob C. Ulirsch & Charles P. Fulco & Vidya Subramanian & Jenny Chen & Monica Sch, 2018. "Publisher Correction: The NORAD lncRNA assembles a topoisomerase complex critical for genome stability," Nature, Nature, vol. 563(7733), pages 32-32, November.
    2. Yolanda Sánchez & Victor Segura & Oskar Marín-Béjar & Alejandro Athie & Francesco P. Marchese & Jovanna González & Luis Bujanda & Shuling Guo & Ander Matheu & Maite Huarte, 2014. "Genome-wide analysis of the human p53 transcriptional network unveils a lncRNA tumour suppressor signature," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    3. Ruben M. Drews & Barbara Hernando & Maxime Tarabichi & Kerstin Haase & Tom Lesluyes & Philip S. Smith & Lena Morrill Gavarró & Dominique-Laurent Couturier & Lydia Liu & Michael Schneider & James D. Br, 2022. "A pan-cancer compendium of chromosomal instability," Nature, Nature, vol. 606(7916), pages 976-983, June.
    4. Mathias Munschauer & Celina T. Nguyen & Klara Sirokman & Christina R. Hartigan & Larson Hogstrom & Jesse M. Engreitz & Jacob C. Ulirsch & Charles P. Fulco & Vidya Subramanian & Jenny Chen & Monica Sch, 2018. "The NORAD lncRNA assembles a topoisomerase complex critical for genome stability," Nature, Nature, vol. 561(7721), pages 132-136, September.
    5. Damian Wollny & Benjamin Vernot & Jie Wang & Maria Hondele & Aram Safrastyan & Franziska Aron & Julia Micheel & Zhisong He & Anthony Hyman & Karsten Weis & J. Gray Camp & T.‐Y. Dora Tang & Barbara Tre, 2022. "Characterization of RNA content in individual phase-separated coacervate microdroplets," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
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