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<p>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 <i>LOC644656</i> as a key regulator of GSMD in human embryonic stem cells. <i>LOC644656</i> 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, <i>LOC644656</i> mitigates DNA damage by binding DNA-PKcs and modulating the DNA damage response. In cancer, elevated <i>LOC644656</i> correlates with poor patient survival and enhanced chemoresistance. Our findings demonstrate that <i>LOC644656</i> mediates stemness suppression and resistance to genotoxic stress by coordinating DNA damage signaling and differentiation pathways. Thus, <i>LOC644656</i> represents a potential therapeutic target for overcoming chemoresistance and advancing stem cell biology.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月23日

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  • 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,
  • Tomoaki Tanaka

摘要

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.