Zhang Li-Hong, Zhang Xue-Yun, Hu Tao, Chen Xin-Yun, Li Jing-Jia, Raida Manfred, Sun Ning, Luo Yan, Gao Xiang
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.
Department of Spine Surgery, Shanghai East Hospital, Tongji University, Shanghai 200092, China.
iScience. 2020 Mar 27;23(3):100968. doi: 10.1016/j.isci.2020.100968. Epub 2020 Mar 7.
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.
R环是一种三链DNA-DNA:RNA杂交结构，因其对基因组稳定性的有害影响而广为人知。这种基本遗传结构的调控因子仍不清楚。在此，我们揭示了一种控制R环稳定性的表观遗传因子。METTL8是甲基转移酶样蛋白家族的成员，可使3-甲基胞嘧啶（m3C）甲基化，是R环调节甲基转移酶复合物中的关键因子。生化研究表明，METTL8形成一个大型的SUMO化核RNA结合蛋白复合物（约80万道尔顿），其中包含一些广为人知的与R环相关的因子。对METTL8进行基因敲除会导致细胞中R环的整体减少。相互作用分析表明，METTL8与RNA结合，并负责选定基因区域的R环稳定性。我们的研究结果表明，SUMO化的METTL8主要通过影响核仁内或其附近的基因组织促进肿瘤发生，并通过其对m3C的甲基转移酶活性影响调控性R环的形成。
