ATR-Chk1 通路在细胞对 DNA 损伤和复制应激的反应中至关重要，而长非编码 RNA (lncRNA) 在调节该通路中的作用仍然很大程度上未知。在这项研究中，我们鉴定了一个 ATR 和 Chk1 相互作用的 lncRNA（ACIL，也称为 LRRC75A-AS1 或 SNHG29），它在 DNA 损伤时促进 ATR 对 Chk1 的磷酸化。高 ACIL 水平与 DNA 损伤剂的化学耐药性和乳腺癌患者的不良预后有关。 ACIL 敲低使乳腺癌细胞在体外和体内对 DNA 损伤药物敏感。 ACIL 通过诱导细胞周期停滞、稳定复制叉和抑制计划外的起源激发来保护癌细胞免受 DNA 损伤，从而防止复制灾难并有助于 DNA 损伤修复。这些发现证明了激活 ATR-Chk1 通路的 lncRNA 依赖性机制，并强调了利用 ACIL 作为化疗敏感性预测生物标志物以及靶向 ACIL 逆转乳腺癌化疗耐药性的潜力。© 2024 作者。

The ATR-Chk1 pathway is essential in cellular responses to DNA damage and replication stress, whereas the role of long noncoding RNAs (lncRNAs) in regulating this pathway remains largely unknown. In this study, we identify an ATR and Chk1 interacting lncRNA (ACIL, also known as LRRC75A-AS1 or SNHG29), which promotes the phosphorylation of Chk1 by ATR upon DNA damages. High ACIL levels are associated with chemoresistance to DNA damaging agents and poor outcome of breast cancer patients. ACIL knockdown sensitizes breast cancer cells to DNA damaging drugs in vitro and in vivo. ACIL protects cancer cells against DNA damages by inducing cell cycle arrest, stabilizing replication forks and inhibiting unscheduled origin firing, thereby guarding against replication catastrophe and contributing to DNA damage repair. These findings demonstrate a lncRNA-dependent mechanism of activating the ATR-Chk1 pathway and highlight the potential of utilizing ACIL as a predictive biomarker for chemotherapy sensitivity, as well as targeting ACIL to reverse chemoresistance in breast cancer.© 2024 The Authors.