The ARID1A-METTL3-m6A axis ensures effective RNase H1-mediated resolution of R-loops and genome stability
Jun Zhang,
Feng Chen,
Ming Tang,
Wenchao Xu,
Yuan Tian,
Zhichao Liu,
Yuxin Shu,
Hui Yang,
Qian Zhu,
Xiaopeng Lu,
Bin Peng,
Xiangyu Liu,
Xingzhi Xu,
Monika Gullerova,
Wei-Guo Zhu
Affiliations
Jun Zhang
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China
Feng Chen
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China
Ming Tang
Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
Wenchao Xu
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China
Yuan Tian
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China
Zhichao Liu
Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK
Yuxin Shu
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China
Hui Yang
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China
Qian Zhu
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China
Xiaopeng Lu
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China
Bin Peng
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Cell Biology and Medical Genetics, Shenzhen University Medical School, Shenzhen 518055, China
Xiangyu Liu
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China
Xingzhi Xu
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Cell Biology and Medical Genetics, Shenzhen University Medical School, Shenzhen 518055, China
Monika Gullerova
Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK
Wei-Guo Zhu
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China; Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518055, China; School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui 241002, China; Department of Biochemistry and Molecular Biology, Peking University Health Science Centre, Beijing 100191, China; Corresponding author
Summary: R-loops are three-stranded structures that can pose threats to genome stability. RNase H1 precisely recognizes R-loops to drive their resolution within the genome, but the underlying mechanism is unclear. Here, we report that ARID1A recognizes R-loops with high affinity in an ATM-dependent manner. ARID1A recruits METTL3 and METTL14 to the R-loop, leading to the m6A methylation of R-loop RNA. This m6A modification facilitates the recruitment of RNase H1 to the R-loop, driving its resolution and promoting DNA end resection at DSBs, thereby ensuring genome stability. Depletion of ARID1A, METTL3, or METTL14 leads to R-loop accumulation and reduced cell survival upon exposure to cytotoxic agents. Therefore, ARID1A, METTL3, and METTL14 function in a coordinated, temporal order at DSB sites to recruit RNase H1 and to ensure efficient R-loop resolution. Given the association of high ARID1A levels with resistance to genotoxic therapies in patients, these findings open avenues for exploring potential therapeutic strategies for cancers with ARID1A abnormalities.
