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

Ai Tamura, Kazuyuki Yamagata, Takashi Kono, Masanori Fujimoto, Takahiro Fuchigami, Motoi Nishimura, Masataka Yokoyama, Akitoshi Nakayama, Naoko Hashimoto, Ikki Sakuma, Nobuyuki Mitsukawa, Yusuke Kawashima, Osamu Ohara, Shinichiro Motohashi, Eiryo Kawakami, Takashi Miki, Atsushi Onodera and Tomoaki Tanaka ()
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Ai Tamura: Chiba University
Kazuyuki Yamagata: Chiba University
Takashi Kono: 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
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
Atsushi Onodera: Chiba University
Tomoaki Tanaka: Chiba University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59886-w

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