ATR/Chk1 interacting lncRNA modulates DNA damage response to induce breast cancer chemoresistance
Rong Luo,
Jiannan Wu,
Xueman Chen,
Yulan Liu,
Dequan Liu,
Erwei Song,
Man-Li Luo
Affiliations
Rong Luo
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; The First Department of Breast Cancer, The Third Affiliated Hospital, Kunming Medical University, Kunming, China
Jiannan Wu
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
Xueman Chen
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
Yulan Liu
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
Dequan Liu
The First Department of Breast Cancer, The Third Affiliated Hospital, Kunming Medical University, Kunming, China
Erwei Song
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; Corresponding author. Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Man-Li Luo
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; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Corresponding author. Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
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.
