The SUMOylated METTL8 Induces R-loop and Tumorigenesis via m3C

• Published in: iScience 2020-03, Vol.23 (3), p.100968-100968, Article 100968
• Main Authors: Zhang, Li-Hong, Zhang, Xue-Yun, Hu, Tao, Chen, Xin-Yun, Li, Jing-Jia, Raida, Manfred, Sun, Ning, Luo, Yan, Gao, Xiang
• Format: Article
• Language: English
• Subjects: Biological Sciences; Cancer; Molecular Biology; Molecular Mechanism of Gene Regulation; Molecular Structure
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.100968

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. [Display omitted] •DNA:RNA hybrid structures are regulated by RNA methyltransferase via 3-methylcytidine•SUMOylation stabilizes the RNA methyltransferase complex in the nucleus•Dysregulation of DNA:RNA hybrids may induce tumorigenesis in mammalian cells Biological Sciences; Molecular Biology; Molecular Structure; Molecular Mechanism of Gene Regulation; Cancer