致癌基因引起的DNA复制压力（RS）和由此导致的致病性R-loop形成已知会阻碍S期进展。然而，在这种高压力条件下，癌细胞通过尚未完全理解的机制持续增殖。在这里，我们报道了在许多类型的癌症中高度表达的牛磺酸上调基因1（TUG1）长非编码RNA（lncRNA）作为癌细胞内在R-loop的重要调节因子。在RS条件下，TUG1通过激活ATR-CHK1信号通路迅速上调表达，与RPA和DHX9相互作用，并解决特定位点的R-loop，特别是在CA重复微卫星位点。TUG1的耗竭导致过多的R-loop积累和增强的RS，从而显著抑制肿瘤生长。我们的数据揭示了TUG1作为解决癌细胞中R-loop积累的重要分子的作用，并且建议以TUG1为靶点的治疗方法作为癌症治疗的有效途径。© 2023. 作者。

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.© 2023. The Author(s).