The SUMOylated METTL8 Induces R-loop and Tumorigenesis via m3C
Li-Hong Zhang,
Xue-Yun Zhang,
Tao Hu,
Xin-Yun Chen,
Jing-Jia Li,
Manfred Raida,
Ning Sun,
Yan Luo,
Xiang Gao
Affiliations
Li-Hong Zhang
Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Hangzhou 310009, China
Xue-Yun Zhang
Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Hangzhou 310009, China
Tao Hu
Department of Spine Surgery, Shanghai East Hospital, Tongji University, Shanghai 200092, China
Xin-Yun Chen
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Jing-Jia Li
Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Hangzhou 310009, China
Manfred Raida
Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore
Ning Sun
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Yan Luo
Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Hangzhou 310009, China; Corresponding author
Xiang Gao
Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Hangzhou 310009, China; Corresponding author
Summary: R-loops, three-stranded DNA-DNA:RNA hybrid structures, are best known for their deleterious effects on genome stability. The regulatory factors of this fundamental genetic structure remain unclear. Here, we reveal an epigenetic factor that controls R-loop stability. METTL8, a member of the methyltransferase-like protein family that methylates 3-methylcytidine (m3C), is a key factor in the R-loop regulating methyltransferase complex. Biochemical studies show that METTL8 forms a large SUMOylated nuclear RNA-binding protein complex (∼0.8 mega daltons) that contains well-reported R-loop related factors. Genetic ablation of METTL8 results in an overall reduction of R-loops in cells. Interaction assays indicated METTL8 binds to RNAs and is responsible for R-loop stability on selected gene regions. Our results demonstrate that the SUMOylated METTL8 promotes tumorigenesis by affecting genetic organization primarily in, or in close proximity to, the nucleolus and impacts the formation of regulatory R-loops through its methyltransferase activity on m3C. : Biological Sciences; Molecular Biology; Molecular Structure; Molecular Mechanism of Gene Regulation; Cancer Subject Areas: Biological Sciences, Molecular Biology, Molecular Structure, Molecular Mechanism of Gene Regulation, Cancer
