IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59886-w.html
   My bibliography  Save this article

p53-inducible lncRNA LOC644656 causes genotoxic stress-induced stem cell maldifferentiation and cancer chemoresistance

Author

Listed:
  • Ai Tamura

    (Chiba University)

  • Kazuyuki Yamagata

    (Chiba University)

  • Takashi Kono

    (Chiba University
    Chiba University)

  • Masanori Fujimoto

    (Chiba University)

  • Takahiro Fuchigami

    (Chiba University)

  • Motoi Nishimura

    (Chiba University Hospital)

  • Masataka Yokoyama

    (Chiba University)

  • Akitoshi Nakayama

    (Chiba University)

  • Naoko Hashimoto

    (Chiba University
    Chiba University)

  • Ikki Sakuma

    (Chiba University)

  • Nobuyuki Mitsukawa

    (Chiba University)

  • Yusuke Kawashima

    (Kisarazu)

  • Osamu Ohara

    (Kisarazu)

  • Shinichiro Motohashi

    (Chiba University)

  • Eiryo Kawakami

    (Chiba University)

  • Takashi Miki

    (Chiba University
    Graduate School of Medicine)

  • Atsushi Onodera

    (Chiba University
    Chiba University)

  • Tomoaki Tanaka

    (Chiba University
    Chiba University)

Abstract

Genotoxic stress-induced stem cell maldifferentiation (GSMD) integrates DNA damage responses with loss of stemness and lineage-specific differentiation to prevent damaged stem cell propagation. However, molecular mechanisms governing GSMD remain unclear. Here, we identify the p53-induced long non-coding RNA LOC644656 as a key regulator of GSMD in human embryonic stem cells. LOC644656 accumulates in the nucleus upon DNA damage, disrupting pluripotency by interacting directly with POU5F1 and KDM1A/LSD1-NuRD complexes, repressing stemness genes, and activating TGF-β signaling. Additionally, LOC644656 mitigates DNA damage by binding DNA-PKcs and modulating the DNA damage response. In cancer, elevated LOC644656 correlates with poor patient survival and enhanced chemoresistance. Our findings demonstrate that LOC644656 mediates stemness suppression and resistance to genotoxic stress by coordinating DNA damage signaling and differentiation pathways. Thus, LOC644656 represents a potential therapeutic target for overcoming chemoresistance and advancing stem cell biology.

Suggested Citation

  • Ai Tamura & Kazuyuki Yamagata & Takashi Kono & Masanori Fujimoto & Takahiro Fuchigami & Motoi Nishimura & Masataka Yokoyama & Akitoshi Nakayama & Naoko Hashimoto & Ikki Sakuma & Nobuyuki Mitsukawa & Y, 2025. "p53-inducible lncRNA LOC644656 causes genotoxic stress-induced stem cell maldifferentiation and cancer chemoresistance," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59886-w
    DOI: 10.1038/s41467-025-59886-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59886-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-59886-w?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
    ---><---

    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:16:y:2025:i:1:d:10.1038_s41467-025-59886-w. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.