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ATR/Chk1相互作用的长链非编码RNA调节DNA损伤反应以诱导乳腺癌化疗耐药。

ATR/Chk1 interacting lncRNA modulates DNA damage response to induce breast cancer chemoresistance.

作者信息

Luo Rong, Wu Jiannan, Chen Xueman, Liu Yulan, Liu Dequan, Song Erwei, Luo Man-Li

机构信息

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

出版信息

Cell Insight. 2024 Jul 14;3(5):100183. doi: 10.1016/j.cellin.2024.100183. eCollection 2024 Oct.

DOI:10.1016/j.cellin.2024.100183
PMID:39148723
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11325286/
Abstract

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 and . 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.

摘要

ATR-Chk1信号通路在细胞对DNA损伤和复制应激的反应中至关重要，而长链非编码RNA（lncRNA）在调节该信号通路中的作用在很大程度上仍不清楚。在本研究中，我们鉴定出一种与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介导的Chk1磷酸化。ACIL高表达与对DNA损伤剂的化疗耐药以及乳腺癌患者的不良预后相关。敲低ACIL可使乳腺癌细胞对DNA损伤药物敏感。ACIL通过诱导细胞周期停滞、稳定复制叉和抑制异常的复制起点激活来保护癌细胞免受DNA损伤，从而防止复制灾难并促进DNA损伤修复。这些发现揭示了一种激活ATR-Chk1信号通路的lncRNA依赖性机制，并突出了将ACIL用作化疗敏感性预测生物标志物以及靶向ACIL以逆转乳腺癌化疗耐药的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/2c6f26d3e017/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/354ff2b0b945/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/0731eac14839/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/733b859ff7b8/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/d7c9ae319e8b/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/f6f8a76867d7/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/210f0f750cbd/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/1433cf0f3da9/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/6545504e323d/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/2c6f26d3e017/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/354ff2b0b945/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/0731eac14839/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/733b859ff7b8/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/d7c9ae319e8b/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/f6f8a76867d7/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/210f0f750cbd/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/1433cf0f3da9/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/6545504e323d/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/247b/11325286/2c6f26d3e017/gr8.jpg

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