The ARID1A-METTL3-m6A axis ensures effective RNase H1-mediated resolution of R-loops and genome stability

  • Cell Rep. 2024 Feb 13;43(2):113779. doi: 10.1016/j.celrep.2024.113779.
Jun Zhang  1 ,  Feng Chen  1 ,  Ming Tang  2 ,  Wenchao Xu  1 ,  Yuan Tian  1 ,  Zhichao Liu  3 ,  Yuxin Shu  1 ,  Hui Yang  1 ,  Qian Zhu  1 ,  Xiaopeng Lu  1 ,  Bin Peng  4 ,  Xiangyu Liu  1 ,  Xingzhi Xu  4 ,  Monika Gullerova  3 ,  Wei-Guo Zhu  5
Affiliations
  • 1. 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.
  • 2. Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
  • 3. Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
  • 4. 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.
  • 5. 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. Electronic address: [email protected].
PMID: 38358891 DOI: 10.1016/j.celrep.2024.113779
Abstract

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.

Keywords
CP: Molecular biology.
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