Tamura Ai, Yamagata Kazuyuki, Kono Takashi, Fujimoto Masanori, Fuchigami Takahiro, Nishimura Motoi, Yokoyama Masataka, Nakayama Akitoshi, Hashimoto Naoko, Sakuma Ikki, Mitsukawa Nobuyuki, Kawashima Yusuke, Ohara Osamu, Motohashi Shinichiro, Kawakami Eiryo, Miki Takashi, Onodera Atsushi, Tanaka Tomoaki
Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.
Research Institute of Disaster Medicine, Chiba University, Chiba, 260-8670, Japan.
Nat Commun. 2025 May 23;16(1):4818. doi: 10.1038/s41467-025-59886-w.
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.
基因毒性应激诱导的干细胞分化异常（GSMD）将DNA损伤反应与干性丧失和谱系特异性分化整合在一起，以防止受损干细胞增殖。然而，调控GSMD的分子机制仍不清楚。在此，我们确定p53诱导的长链非编码RNA LOC644656是人类胚胎干细胞中GSMD的关键调节因子。DNA损伤时，LOC644656在细胞核中积累，通过直接与POU5F1以及KDM1A/LSD1-NuRD复合物相互作用、抑制干性基因并激活TGF-β信号传导来破坏多能性。此外，LOC644656通过结合DNA-PKcs并调节DNA损伤反应来减轻DNA损伤。在癌症中，LOC644656水平升高与患者生存率低和化疗耐药性增强相关。我们的研究结果表明，LOC644656通过协调DNA损伤信号传导和分化途径来介导干性抑制和对基因毒性应激的抗性。因此，LOC644656是克服化疗耐药性和推进干细胞生物学研究的潜在治疗靶点。
