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

  • Nat Commun. 2021 Mar 29;12(1):1946. doi: 10.1038/s41467-021-21963-1.
Wen-Juan Li   #  1  2 ,  Yao-Hui He   #  1  2 ,  Jing-Jing Yang   #  1  2 ,  Guo-Sheng Hu  1  2 ,  Yi-An Lin  1  2 ,  Ting Ran  1  2 ,  Bing-Ling Peng  1  2 ,  Bing-Lan Xie  1  2 ,  Ming-Feng Huang  1  2 ,  Xiang Gao  2 ,  Hai-Hua Huang  3 ,  Helen He Zhu  4 ,  Feng Ye  5 ,  Wen Liu  6  7  8
Affiliations
  • 1. State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China.
  • 2. Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China.
  • 3. Department of Pathology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, China.
  • 4. Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
  • 5. Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Fujian, China.
  • 6. State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 7. Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 8. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • # Contributed equally.
PMID: 33782401 DOI: 10.1038/s41467-021-21963-1
Abstract

Numerous 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.

Products