Division of Cancer Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
Laboratory Animal Facilities and Services, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
Nat Commun. 2023 Aug 22;14(1):4521. doi: 10.1038/s41467-023-40243-8.
Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.
癌基因诱导的 DNA 复制应激（RS）和由此产生的致病 R 环形成已知会阻碍 S 期的进展。尽管如此，癌细胞仍在这种高压力的情况下通过尚未完全了解的机制不断增殖。在这里，我们报告了牛磺酸上调基因 1（TUG1）长非编码 RNA（lncRNA），它在许多类型的癌症中高度表达，是癌细胞中内在 R 环的重要调节因子。在 RS 条件下，TUG1 通过 ATR-CHK1 信号通路的激活被快速上调，与 RPA 和 DHX9 相互作用，并在某些基因座上参与 R 环的解析，特别是在 CA 重复微卫星基因座上。TUG1 的耗竭会导致 R 环的过度积累和 RS 的增强，从而显著抑制肿瘤的生长。我们的数据揭示了 TUG1 作为一种在癌细胞中解析 R 环积累的重要分子的作用，并表明靶向 TUG1 是治疗癌症的一种有效治疗方法。
