Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth

• DOI: 10.1038/s41467-021-21963-1
• Publication Date: 2021-03-29T10:04:22Z
• Authors: Wen-juan Li; Yao-hui He; Jing-jing Yang; Guo-sheng Hu; Yi-an Lin; Ting Ran; Bing-ling Peng; Bing-lan Xie; Ming-feng Huang; Xiang Gao; Hai-hua Huang; Helen He Zhu; Feng Ye; Wen Liu
• Keywords: Proteomics; Male; 0301 basic medicine; 570; Protein-Arginine N-Methyltransferases; Science; Heterogeneous Nuclear Ribonucleoprotein A1; RNA-binding proteins; Breast Neoplasms; Arginine; Methylation; Article; 03 medical and health sciences; Cell Line, Tumor; Humans; Amino Acid Sequence; Enzyme Inhibitors; Gene Expression Profiling; Q; Cell Cycle; Prostatic Neoplasms; 3. Good health; Gene Expression Regulation, Neoplastic; Alternative Splicing; HEK293 Cells; Female; Colorectal Neoplasms; Protein Processing, Post-Translational; Alternative splicing; Protein Binding

AbstractNumerous substrates have been identified for Type I and II arginine methyltransferases (PRMTs). However, the full substrate spectrum of the only type III PRMT, PRMT7, and its connection to type I and II PRMT substrates remains unknown. Here, we use mass spectrometry to reveal features of PRMT7-regulated methylation. We find that PRMT7 predominantly methylates a glycine and arginine motif; multiple PRMT7-regulated arginine methylation sites are close to phosphorylations sites; methylation sites and proximal sequences are vulnerable to cancer mutations; and methylation is enriched in proteins associated with spliceosome and RNA-related pathways. We show that PRMT4/5/7-mediated arginine methylation regulates hnRNPA1 binding to RNA and several alternative splicing events. In breast, colorectal and prostate cancer cells, PRMT4/5/7 are upregulated and associated with high levels of hnRNPA1 arginine methylation and aberrant alternative splicing. Pharmacological inhibition of PRMT4/5/7 suppresses cancer cell growth and their co-inhibition shows synergistic effects, suggesting them as targets for cancer therapy.